Suprametallogels and uses thereof

Abstract

The disclosure provides nanostructures (e.g., nanospheres and nano-paddlewheels) formed through transition metal-ligand (e.g., Pd(II)-, Ni(II)-, or Fe(II)-ligand of Formula (A)) coordination and junction self-assembly. The disclosure also provides supramolecular complexes that include the nanostructures connected by divalent linkers Y. The provided supramolecular complexes are able to form gels (e.g., hydrogels). The gels are suprametallogels and exhibited excellent mechanical properties without sacrificing self-healing and showed high robustness and storage modulus. The present disclosure further provides compositions (e.g., gels) that include the nanostructures or supramolecular complexes and optionally an agent (e.g., small molecule), where the nanostructures and the nanostructure moieties of the supramolecular complexes may encapsulate and slowly release the agent. The nanostructures, supramolecular complex, and compositions may be useful in delivering an agent to a subject, tissue, or cell, as super-absorbent materials, and in treating a disease (e.g., a genetic diseases, proliferative disease (e.g., cancer or benign neoplasm), hematological disease, neurological disease, gastrointestinal disease (e.g., liver disease), spleen disease, respiratory disease (e.g., lung disease), painful condition, genitourinary disease, musculoskeletal condition, infectious disease, inflammatory disease, autoimmune disease, psychiatric disorder, or metabolic disorder). ##STR00001##

Claims

1. A macromer of Formula (B): ##STR00094## or a salt thereof, wherein: each of ##STR00095## is Ring A, wherein Ring A is of the formula: ##STR00096## each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, or a nitrogen protecting group; each instance of R.sup.A2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each instance of R.sup.B is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; m is 0, 1, 2, 3, or 4; each instance of R.sup.C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; n is 0, 1, 2, 3, or 4; Z.sup.A is a bond or a saturated or unsaturated, C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently replaced with O, S, NR.sup.ZA, N, or N, wherein each instance of R.sup.ZA is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O and halogen; Z.sup.B is a bond or a saturated or unsaturated, C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently replaced with O, S, NR.sup.ZB, N, or N, wherein each instance of R.sup.ZB is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O and halogen; and Y is a saturated or unsaturated, C.sub.30-3000 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.30-3000 hydrocarbon chain are independently replaced with O, S, NR.sup.Y, N, or N, wherein each instance of R.sup.Y is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.30-3000 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O, halogen, and unsubstituted C.sub.1-6 alkyl.

2. The macromer of claim 1, wherein the macromer is of the formula: ##STR00097## or a salt thereof.

3. The macromer of claim 1, wherein the macromer is of the formula: ##STR00098## or a salt thereof.

4. The macromer of claim 1, wherein the macromer is of the formula: ##STR00099## or a salt thereof.

5. The macromer of claim 1, wherein the macromer is of the formula: ##STR00100## or a salt thereof.

6. The macromer of claim 1, wherein the macromer is of the formula: ##STR00101## or a salt thereof.

7. A macromer of the formula: ##STR00102## each of ##STR00103## is Ring A, wherein Ring A is of the formula: ##STR00104## each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, or a nitrogen protecting group; each instance of R.sup.A2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each instance of R.sup.B is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a), SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; m is 0, 1, 2, or 3; each instance of R.sup.C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; n is 0, 1,2,3, or 4; Z.sup.A is a bond or a saturated or unsaturated, C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently replaced with O, S, NR.sup.ZA, N, or N, wherein each instance of R.sup.ZA is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O and halogen; Z.sup.B is a bond or a saturated or unsaturated, C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently replaced with O, S, NR.sup.ZB, N, or N, wherein each instance of R.sup.ZB is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.1-4 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O and halogen; and Y is a saturated or unsaturated, C.sub.30-3000 hydrocarbon chain, optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.30-3000 hydrocarbon chain are independently replaced with O, S, NR.sup.Y, N, or N, wherein each instance of R.sup.Y is independently hydrogen, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.30-3000 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O, halogen, and unsubstituted C.sub.1-6alkyl: or a salt thereof.

8. The macromer of claim 1, or a salt thereof, wherein Ring A is of the formula: ##STR00105##

9. The macromer of claim 1, or a salt thereof, wherein Ring A is of the formula: ##STR00106##

10. The macromer of claim 1, or a salt thereof, wherein Ring A is of the formula: ##STR00107##

11. The macromer of claim 1, or a salt thereof, wherein Ring A is of the formula: ##STR00108##

12. The macromer of claim 1, or a salt thereof, wherein Ring B is of the formula: ##STR00109##

13. The macromer of claim 1, or a salt thereof, wherein Ring B is of the formula: ##STR00110##

14. The macromer of claim 1, or a salt thereof, wherein Ring B is of the formula: ##STR00111##

15. The macromer of claim 1, or a salt thereof, wherein each instance of R.sup.A1 is hydrogen, and each instance of R.sup.A2 is hydrogen.

16. The macromer of claim 1, or a salt thereof, wherein each one of m and n is 0.

17. The macromer of claim 1, or a salt thereof, wherein each one of Z.sup.A and Z.sup.B is a bond.

18. The macromer of claim 1, or a salt thereof, wherein each one of Z.sup.A and Z.sup.B is CC, CCCC, or a moiety of the formula: ##STR00112##

19. The macromer of claim 1, or a salt thereof, wherein Y is a saturated or unsaturated, C.sub.80-1500 hydrocarbon chain, optionally wherein not more than one half of all instances of the chain atoms of the saturated or unsaturated, C.sub.80-1500 hydrocarbon chain are independently replaced with O, S, or NR.sup.Y, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.80-1500 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O, halogen, and unsubstituted C.sub.1-6 alkyl.

20. The macromer of claim 1, or a salt thereof, wherein Y is of the formula: ##STR00113##

21. The macromer of claim 1, or a salt thereof, wherein each chain atom, with any substituents thereon, of Y is independently CH.sub.2, CH(unsubstituted C.sub.1-6 alkyl)-, C(unsubstituted C.sub.1-6 alkyl).sub.2-, C(O), O, NH, N(unsubstituted C.sub.1-6 alkyl)-, N(nitrogen protecting group)-, or CF.sub.2.

22. The macromer of claim 7, wherein the macromer is of the formula: ##STR00114## or a salt thereof.

23. The macromer of claim 7, wherein the macromer is of the formula: ##STR00115## or a salt thereof.

24. The macromer of claim 7, or a salt thereof, wherein Ring A is of the formula: ##STR00116##

25. The macromer of claim 7, or a salt thereof, wherein Ring A is of the formula: ##STR00117##

26. The macromer of claim 7, or a salt thereof, wherein Ring A is of the formula: ##STR00118##

27. The macromer of claim 7, or a salt thereof, wherein Ring A is of the formula: ##STR00119##

28. The macromer of claim 7, or a salt thereof, wherein each instance of R.sup.A1 is hydrogen, and each instance of R.sup.A2 is hydrogen.

29. The macromer of claim 7, or a salt thereof, wherein each one of m and n is 0.

30. The macromer of claim 7, or a salt thereof, wherein each one of Z.sup.A and Z.sup.B is a bond.

31. The macromer of claim 7, or a salt thereof, wherein each one of Z.sup.A and Z.sup.B is CC, CCCC, or a moiety of the formula: ##STR00120##

32. The macromer of claim 7, or a salt thereof, wherein Y is a saturated or unsaturated, C.sub.80-1500 hydrocarbon chain, optionally wherein not more than one half of all instances of the chain atoms of the saturated or unsaturated, C.sub.80-1500 hydrocarbon chain are independently replaced with O, S, or NR.sup.Y, and optionally wherein one or more chain atoms of the saturated or unsaturated, C.sub.80-1500 hydrocarbon chain are independently substituted with one or more substituents independently selected from the group consisting of O, halogen, and unsubstituted C.sub.1-6 alkyl.

33. The macromer of claim 7, or a salt thereof, wherein Y is of the formula: ##STR00121##

34. The macromer of claim 7, or a salt thereof, wherein each chain atom, with any substituents thereon, of Y is independently CH.sub.2, CH(unsubstituted C.sub.1-6 alkyl), C (unsubstituted C.sub.1-6 alkyl).sub.2, C(O), O, NH, N(unsubstituted C.sub.1-6 alkyl), N(nitrogen protecting group), or CF.sub.2.

35. The macromer of claim 7, wherein the macromer is of the formula: ##STR00122## or a salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A shows that ligand B-2 and Pd(NO.sub.3).sub.2 formed a gel. Some instances of divalent linker

(2) ##STR00009##
were omitted for clarity. FIG. 1B, top panel, shows an exemplary proton nuclear magnetic resonance (.sup.1H NMR) spectrum (400 MHz, DMSO-d.sub.6) of ligand A-1. FIG. 1B, bottom panel, shows that ligand A-1 and Pd(NO.sub.3).sub.2 formed nanosphere I-1. FIG. 1C shows an exemplary .sup.1H NMR spectrum (400 MHz) of a gel formed by heating at 80 C. overnight a solution of ligand B-2 (0.01 M) and Pd(NO.sub.3).sub.2 in DMSO-d.sub.6 (top panel) and an exemplary .sup.1H NMR spectrum (400 MHz, DMSO-d.sub.6) of nanosphere I-1 (bottom panel).

(3) FIG. 2A shows exemplary gelation kinetics results of a reaction (gelation) mixture of FIG. 1A as indicated by rheology of the reaction mixture at different reaction times. The concentration of ligand B-2 in DMSO-d.sub.6 was 0.024 M; w was 10 rad/s; 1% strain. G: shear storage modulus. G: shear loss modulus. FIG. 2B shows an image of the equipment employed in FIG. 2A. FIG. 2C shows a proposed two-stage mechanism of the gelation of FIG. 2A. Stage i: initial disordered network formation. Stage ii: thermal equilibration to form the gel. Primary loops formed in the process are highlighted in red.

(4) FIGS. 3A and 3B show exemplary .sup.1H NMR spectra of the reaction mixtures of FIG. 1A, except the reaction temperature and time duration, which were as provided in FIGS. 3A and 3B.

(5) FIG. 4A shows the effects of concentration (in millimoles of ligand B-2 per liter of DMSO-d.sub.6) on gelation of reactions of FIG. 1A, wherein the reaction temperature was room temperature. FIG. 4B shows the effects of concentration (in millimoles of ligand B-2 per liter of DMSO-d.sub.6) on gelation of reactions of FIG. 1A. Gels at room temperature remained gels after annealing. Gelation took place at concentrations as low as 0.014 M. FIG. 4C shows the dependence of storage and loss modulus of a gel on the concentration of ligand B-2 of the gel.

(6) FIG. 5A shows exemplary rheology of gels formed from macromer B-2. FIG. 5B shows the storage and loss modulus of a gel formed by a reaction of FIG. 1A, wherein ligand B-2 was partially replaced with ligand A-1, wherein the mole amount of ligand A-1 was twice the mole amount of ligand B-2 that was replaced by ligand A-1. FIG. 5C shows the shear viscosity of the gels of FIG. 5B.

(7) FIG. 6A shows the chemical structure of doxorubicin. FIG. 6B is a photograph of a gel formed by heating in DMSO-d.sub.6 at 70 C. for 1 day a solution of ligand B-2 (100 mM) and Pd(NO.sub.3).sub.2 in the presence of doxorubicin (12 equivalents relative to the expected amount of the nanospheres (M.sub.12L.sub.24) formed from B-2 and Pd(NO.sub.3).sub.2; 100 mM). FIG. 6C is a photograph of the gel after extracting the gel of FIG. 6B four times with DMSO-d.sub.6. FIG. 6D are photographs of the four extracts of FIG. 6C. From left to right; the first to fourth extracts.

(8) FIG. 7: a scheme showing the release of tryptamine glycnamide from a gel of Example 18 by treating the gel with chymotrypsin. The details are shown in Example 19.

(9) FIG. 8 shows exemplary strain sweeps at =100 rad/s of a gel formed at room temperature. The reactants were B-2 and Pd(NO.sub.3).sub.2.2H.sub.2O, which were mixed in DMSO-d.sub.6 at room temperature to form a gel where the concentration of B-2 is 0.024 M. G: shear storage modulus. G: shear loss modulus.

(10) FIGS. 9A and 9B show exemplary .sup.1H NMR spectra (DMSO-d.sub.6) of gels III-5 (FIG. 9A) and III-6 (FIG. 9B).

(11) FIG. 10: release of doxorubicin from the gel of Example 17. The details are shown in Example 18.

(12) FIG. 11A shows the changes in shear viscosity of a reaction mixture of FIG. 15A over reaction time. FIG. 11B is a plot of storage modulus (G) and loss modulus (G) of a gel of FIG. 15A versus the strain () of the gel.

(13) FIG. 12 is an exemplary .sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) of ligand B-1.

(14) FIG. 13A illustrates the formation of a loopy nanosphere by reacting ligand B-1 with Pd(NO.sub.3).sub.2.H.sub.2O. FIG. 13B shows exemplary dynamic light scattering (DLS) results of dialyzed loopy nanospheres.

(15) FIG. 14 shows exemplary MTT proliferation assay results of nanosphere I-1 using HeLa cells.

(16) FIG. 15A shows the formation of supramolecular complexes and gels using ligand C-1 and Ni(ClO.sub.4).sub.2. FIG. 15B shows exemplary frequency sweep results of the reaction mixture at different reaction times. FIG. 15C is a cartoon illustrating a proposed structure of the formed supramolecular complexes and gels, where the black bands represent divalent linkers of the formula:

(17) ##STR00010##

(18) FIG. 16A: Schematic representations of traditional polymer metallogels (left panel) compared to suprametallogels (right panel). FIG. 16B: Chemical structures of exemplary ligands described herein along with the effect of ligand bite angle on the self-assembly of these ligands into supramolecular nanostructures. The Fujita cage and paddlewheel structures (far left panel and far right panel, respectively) were obtained from molecular dynamics simulations. FIG. 16C: Chemical structures of exemplary macromers B-3 (left panel) and B-4 (right panel) described herein.

(19) FIG. 17A: Aromatic regions of the .sup.1H NMR spectra (400 MHz, DMSO-d.sup.6, 25 C.) of, from top to bottom, L1, the initial mixture of L1 and Pd(NO.sub.3).sub.2.2H.sub.2O prepared at room temperature, and the same mixture after thermal annealing. FIG. 17B: Aromatic regions of the .sup.1H NMR spectra (400 MHz, DMSO-d.sup.6, 25 C.) of, from top to bottom, L2, the initial mixture of L2 and Pd(NO.sub.3).sub.2.2H.sub.2O prepared at room temperature, and the same mixture after thermal annealing. FIG. 17C: Low-quality crystal structure of (L2).sub.4Pd.sup.II.sub.2. Note that due to significant disorder this structure was not used to analyze bond lengths and/or angles. However, the paddlewheel connectivity of the complex was confidently assigned.

(20) FIG. 18: VT .sup.1H ssNMR spectroscopy (500 MHz, DMSO-d.sup.6, magic angle spinning at 10 kHz) of the gel derived from paddlewheel-former B-4 ([B-4]=24 mM) before (top panel) and after (bottom panel) annealing. 2: B-4.

(21) FIG. 19A: Aromatic region of the .sup.1H NMR (400 MHz, DMSO-d.sup.6) spectrum of the M.sub.12L.sub.24 spheres derived from B-3 at high dilution (4.4 mM). Inset: Cryo-TEM image of the soluble aggregates of M.sub.12L.sub.24 spheres dialyzed against Millipore water exhibits 30-nm spherical particles. FIG. 19B: Aromatic region of the .sup.1H ssNMR (500 MHz, DMSO-d.sup.6, magic angle spinning at 10 kHz) spectrum of the corresponding gel when [B-3]=24 mM. Inset: a picture of the gel.

(22) FIG. 20A: Snapshots illustrating the assembly of metal-ligand clusters for different ligand species, each initialized from random configurations at time t=0. Images from left to right correspond to the assembly of Pd.sup.2+ and L-para, L-meta, B-3, and B-4, respectively. For the suprametallogels prepared from macromers B-3 and B-4, grey lines indicate a likely configuration of the 2.2 kDa PEG chain, which is described implicitly in the simulations.

(23) FIG. 20B: Average cluster size as a function of time for systems with L-para, L-meta, and macromers B-3 and B-4. Data is plotted in black or grey to indicate L-para or L-meta based ligands, respectively. Lines or points (circles and squares) are used to differentiate free ligands from macromers, respectively. Macromer 1: B-3. Macromer 2: B-4.

(24) FIG. 20C: Distribution of cluster sizes for systems with L-para and L-meta ligands are plotted with black or grey bars, respectively. The data representing suprametallogels from macromers B-3 and B-4 are plotted with points using the same color and symbol conventions as in FIG. 20B. Inset highlights a narrower data range for the free ligands L-para and L-meta only. Macromer 1: B-3. Macromer 2: B-4.

(25) FIG. 20D: Average density of primary loops as a function of cluster size in suprametallogels from macromers B-3 and B-4 plotted using the same color and symbol convention as in FIG. 20B. The black line indicates the predicted density of loops if clusters are assembled from randomly selected ligands. Arrows provide the approximate y (cluster size) after 1 s for suprametallogels prepared from B-3 and B-4 (as obtained from FIG. 20B); they indicate the fraction of looped chains in the respective suprametallogel. Macromer 1: B-3. Macromer 2: B-4.

(26) FIGS. 21A and 21B: Frequency sweeps in oscillatory rheology at 1.0% strain amplitude before and after annealing for 4 h at 80 C. for gels derived from B-3 ([B-3]=24 mM, FIG. 21A) and B-4 ([B-4]=24 mM, FIG. 21B). Stress vs. strain plots before and after thermal annealing for gels derived from B-3 ([B-3]=24 mM, FIG. 21C) and B-4 ([B-4]=24 mM, FIG. 21D). Black arrows indicate points used for the determination of the yield stresses and strains. 1: B-3. 2: B-4.

(27) FIG. 22A to 22C show images of a gel derived from B-3 ([B-3]=24 mM) as prepared (FIG. 22A), after cutting (FIG. 22B), and after annealing for 4 h at 80 C. (FIG. 22C), respectively. The damage emphasized by the grey box was not healed. FIG. 22D to 22F show images of a gel derived from B-4 ([B-4]=24 mM) as prepared (FIG. 22D), after cutting (FIG. 22E), and after annealing for 4 h at 80 C. (FIG. 22F), respectively. The damage emphasized by the grey box was healed. In all cases, the images shown are photographs of the bottom of 1-dram vials containing the gels. No solvent was added or pressure applied to facilitate healing. FIG. 22G: representative images of suprametallogels from B-3 and B-4 after swelling for 5 days in DMSO. The swelling ratios (S.sub.1 and S.sub.2=mass of swollen gel/mass of dry gel) are provided. FIG. 22H: images of suprametallogels derived from B-3 and B-4 in the presence of pyrene. Images were taken after continuous washing of the gels with fresh DMSO for two days. Superior retention of pyrene in the paddlewheel-based gel is readily observed. 1: B-3. 2: B-4.

(28) FIG. 23A: images of gels formed from mixing C-1 and iron perchlorate (left panel) or nickel perchlorate (right panel) in acetonitrile.

(29) FIG. 23B: an image of a liquid mixture formed after 25 L of a 0.05 M K.sub.4EDTA aqueous solution was added to the gel shown in FIG. 23A left panel (left panel); and an image of a liquid mixture formed after 25 L of a 0.05 M K.sub.4EDTA aqueous solution was added to the gel shown in FIG. 23A right panel (right panel).

(30) FIGS. 24A and 24B: mechanical properties of gels formed from C-1 and Ni(ClO.sub.4).sub.2 (Ni) and Fe(ClO.sub.4).sub.2(Fe) in acetonitrile were characterized by oscillatory rheology.

(31) FIGS. 25A and 25B: effects of solvents on gelation of the gels formed from macromer C-1 and Ni(ClO.sub.4).sub.2 hydrate.

(32) FIG. 26: oscillatory rheology of the gels of Example 15.

(33) FIG. 27: cytotoxicities of (1) a gel formed from C-2 and Fe.sup.2+ (gel), (2) PEG, and (3) Fe.sup.2+ (Fe) against HeLa cells. MILLIQ water (milliQ) used as a control.

(34) FIG. 28: preparation of the gel of Example 17, where the gel contains covalently attached doxorubicin. Inset: an image of the gel.

(35) FIG. 29 shows Formula (I-A), wherein each instance of the black dot represents a transition metal ion, each instance of the gray line represents a ligand of Formula (A), and each black line represents a coordination bond.

(36) FIG. 30 shows Formula (I-B), wherein each instance of the black dot represents a transition metal ion, and each instance of the gray line represents a ligand of Formula (A).

(37) FIG. 31 shows a moiety of a nanosphere described herein.

(38) FIG. 32 shows Scheme 8, which shows exemplary synthesis of a paddlewheel (e.g., nano-paddlewheel described herein).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(39) Reversible metal-ligand coordination has emerged as a powerful tool for the formation of a broad array of materials. In the realm of soft materials (e.g., gels), reversible metal-ligand coordination is a tool for the formation of self-healing molecular networks. In the area of hard materials, reversible metal-ligand coordination enables the formation of metal-organic frameworks (MOFs) and related metallosupramolecular assemblies.

(40) The present disclosure provides, in one aspect, nanostructures formed through metal-ligand coordination and junction self-assembly. The present disclosure also provides supramolecular complexes that include nanostructures described herein connected by divalent linkers Y. The provided supramolecular complexes are able to swell in various solvents (including water) without dissolution and to form gels. Advantageous over conventional gels (e.g., conventional metallogels), the gels described herein exhibited excellent mechanical properties without sacrificing self-healing. Compared to conventional gels (e.g., conventional metallogels), the gels described herein behaved as elastic solids at low oscillatory angular frequencies and showed higher robustness (e.g., showed higher storage moduli). The nanostructures, and the nanostructure moieties of a supramolecular complex or gel described herein, may encapsulate and slowly release an agent (e.g., a small molecule, a peptide or protein, or a polynucleotide). The nanostructures, supramolecular complex, and compositions (e.g., gels) may be useful in delivering effectively and efficiently an agent to a subject, tissue, or cell, as bulk materials (e.g., as super-absorbent materials and/or bioactive materials), and/or in increasing the toughness of composite materials.

(41) Nanostructures

(42) Fujita et al. have reported banana-shaped organic molecules that self-organize into Fujita spheres, which are finite, spherical coordination networks with a diameter in the order of nanometers (e.g., Tominaga et al., Angew. Chem., Int. Ed., 2004, 43, 5621-5625; Bunzen et al. Angew. Chem., Int. Ed. 2012, 51, 3161; Sun et al., Science, 2010, 328, 1144). One of such reported Fujita spheres consists of 12 equivalents of a central metal ion (e.g., Pd(II)) and 24 equivalents of a bidentate ligand and has cuboctahedral symmetry. Hupp et al. has reported metal-organic frameworks prepared from a hexacarboxylated ligand and a transition metal ion (e.g., Cu(II) or Zn(II)) (Eryazici et al., Crystal Growth & Design, 2012, 12, 1075).

(43) One aspect of the present disclosure relates to novel nanostructures, including, but not limited to, nanospheres and nano-paddlewheels. In certain embodiments, provide herein are nanospheres comprising:

(44) (i) a plurality of a transition metal ion; and

(45) (ii) a plurality of a ligand;

(46) wherein each instance of the transition metal ion and two or more instances of the ligand form through coordination bonds a coordination complex;

(47) wherein the plurality of a transition metal ion and the plurality of a ligand form through the coordination bonds one substantially spherical structure; and

(48) wherein the average outer diameter of the nanosphere is between about 1 nm and about 100 nm, inclusive.

(49) In certain embodiments, provide herein are nano-paddlewheels comprising:

(50) (i) a plurality of a transition metal ion; and

(51) (ii) a plurality of a ligand;

(52) wherein each instance of the transition metal ion and two or more instances of the ligand form through coordination bonds a coordination complex;

(53) wherein the plurality of a transition metal ion and the plurality of a ligand form through the coordination bonds one substantially paddlewheel structure; and

(54) wherein the average outer diameter of the nano-paddlewheel is between about 1 nm and about 100 nm, inclusive.

(55) In certain embodiments, each instance of the ligand is a monodentate ligand. In certain embodiments, each instance of the ligand is a polydentate (e.g., bidentate, tridentate, or tetradentate) ligand. In certain embodiments, each instance of the ligand comprises two or more pyridinyl moieties. In certain embodiments, each instance of the ligand comprises at least a first pyridinyl moiety and second pyridinyl moiety, wherein the angle (bite angle) between (1) the lone electron pair of the nitrogen atom of the first pyridinyl moiety and (2) the lone electron pair of the nitrogen atom of the second pyridinyl moiety, along the long axes of the lone electron pairs, is between 30 and 180, inclusive, when the ligand is in the minimum energy conformation. In certain embodiments, the bite angle is between 60 and 160, inclusive (e.g., about 90, about 120, about 127, or about 149). In certain embodiments, each instance of the ligand is a polydentate ligand, wherein the shortest distance between two chelation sites of the ligand is between about 5 and about 20 (e.g., between about 5 and about 10 ), inclusive, when the ligand is in the minimum energy conformation.

(56) In certain embodiments, a nanostructure described herein comprises x instances of a transition metal ion and 2 instances of a ligand of Formula (A):

(57) ##STR00011##

(58) A nanostructure described herein includes x instances of a transition metal ion. In certain embodiments, all instances of the transition metal ion in a nanostructure are the same. In certain embodiments, x is an integer (e.g., an even integer) between 2 and 48, inclusive. In certain embodiments, x is an integer (e.g., an even integer) between 2 and 30, inclusive. In certain embodiments, x is an integer (e.g., an even integer) between 2 and 24, inclusive. In certain embodiments, x is an integer (e.g., an even integer) between 2 and 18, inclusive. In certain embodiments, x is 2. In certain embodiments, x is 4. In certain embodiments, x is 6. In certain embodiments, x is 12. In certain embodiments, x is 18. In certain embodiments, x is 24. In certain embodiments, x is 30. In certain embodiments, x is 48. In certain embodiments, x is 60. In certain embodiments, x is 12; and the nanostructure is a nanosphere. In certain embodiments, x is 24; and the nanostructure is a nanosphere. In certain embodiments, x is 2; and the nanostructure is a nano-paddlewheel. In certain embodiments, each instance of the transition metal ion is Pd (e.g., Pd(II)). In certain embodiments, each instance of the transition metal ion is Rh (e.g., Rh(I)). In certain embodiments, each instance of the transition metal ion is Ir (e.g., Ir(I)). In certain embodiments, each instance of the transition metal ion is Ni (e.g., Ni(II)). In certain embodiments, each instance of the transition metal ion is Pt (e.g., Pt(II)). In certain embodiments, each instance of the transition metal ion is Fe (e.g., Fe(II) or Fe(III)). In certain embodiments, each instance of the transition metal ion is Au (e.g., Au(III)). In certain embodiments, each instance of the transition metal ion is Cd (e.g., Cd(II)), Co (e.g., Co(III)), or Cu (e.g., Cu(I) or Cu(II)). In certain embodiments, each instance of the transition metal ion is Zn(II). In certain embodiments, each instance of the transition metal ion is not Zn(II).

(59) A nanostructure described herein also includes 2x instances of a ligand of Formula (A). In certain embodiments, all instances of the ligand of Formula (A) in a nanostructure are the same. In other embodiments, at least two instances of the ligand of Formula (A) in a nanostructure are different.

(60) Formula (A) includes Ring A that includes X.sup.A, X.sup.B, X.sup.C, X.sup.D, and X.sup.E in the ring system and is unsubstituted (e.g., each instance of R.sup.A1 and R.sup.A2 is hydrogen) or substituted with one or more substituents R.sup.A1 and/or R.sup.A2 (e.g., at least one instance of R.sup.A1 or R.sup.A2 is not hydrogen). In certain embodiments, each instance of X.sup.A, X.sup.B, X.sup.C, X.sup.D, and X.sup.E is independently C or CR.sup.A2, and Ring A is a substituted or unsubstituted phenyl ring. In certain embodiments, Ring A is of the formula:

(61) ##STR00012##
In certain embodiments, Ring A is of the formula:

(62) ##STR00013##
In certain embodiments, Ring A is of the formula:

(63) ##STR00014##
In certain embodiments, Ring A is of the formula:

(64) ##STR00015##

(65) In certain embodiments, each instance of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1, C, or CR.sup.A2; at least one of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is not C or CR.sup.A2; X.sup.E is absent; and Ring A is a substituted or unsubstituted, 5-membered, monocyclic heteroaryl ring. In certain embodiments, Ring A is a substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyrrolyl ring. In certain embodiments, Ring A is of the formula:

(66) ##STR00016##
In certain embodiments, Ring A is a pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl ring, each of which is unsubstituted or substituted with R.sup.A2. In certain embodiments, each instance of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1, C, or CR.sup.A2; X.sup.E is N, C, or CR.sup.A2; at least one of X.sup.A, X.sup.B, X.sup.C, X.sup.D, and X.sup.E is not C or CR.sup.A2; and Ring A is a substituted or unsubstituted, 6-membered, monocyclic heteroaryl ring. In certain embodiments, Ring A is a substituted or unsubstituted pyridyl ring. In certain embodiments, Ring A is of the formula:

(67) ##STR00017##
In certain embodiments, Ring A is a substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl ring. In certain embodiments, Ring A is of the formula:

(68) ##STR00018##
In certain embodiments, Ring A is of the formula:

(69) ##STR00019##
In certain embodiments, Ring A is of the formula:

(70) ##STR00020##
In certain embodiments, Ring A is of the formula:

(71) ##STR00021##

(72) In certain embodiments, at least two instances of R.sup.A1 are different from each other. In certain embodiments, all instances of R.sup.A1 are the same. In certain embodiments, at least one instance of R.sup.A1 is hydrogen. In certain embodiments, each instance of R.sup.A1 is hydrogen. In certain embodiments, at least one instance of R.sup.A1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.A1 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.A1 is CH.sub.3. In certain embodiments, all instances of R.sup.A1 are CH.sub.3. In certain embodiments, at least one instance of R.sup.A1 is substituted methyl. In certain embodiments, at least one instance of R.sup.A1 is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.A1 is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.A1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is substituted aryl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A1 is substituted phenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A1 is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is C(O)R.sup.a (e.g., C(O)(substituted or unsubstituted C.sub.1-6 alkyl)), C(O)OR.sup.a (e.g., C(O)O(substituted or unsubstituted C.sub.1-6 alkyl)), or C(O)N(R.sup.a).sub.2 (e.g., C(O)NH.sub.2, C(O)NH(substituted or unsubstituted C.sub.1-6 alkyl), or C(O)N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl)). In certain embodiments, at least one instance of R.sup.A1 is a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.A1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(73) Each instance of R.sup.A1, R.sup.A2, R.sup.B, and R.sup.C may independently include one or more substituents R.sup.a. In certain embodiments, all instances of R.sup.a are the same. In certain embodiments, at least two instances of R are different from each other. In certain embodiments, at least one instance of R.sup.a is H. In certain embodiments, each instance of R.sup.a is H. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.a is CH.sub.3. In certain embodiments, at least one instance of R.sup.a is CF.sub.3, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.1-6 alkenyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.1-6 alkynyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, R.sup.a is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, R.sup.a is a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom. In certain embodiments, two instances of R.sup.a are joined to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, monocyclic, 5- to 6-membered heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of R.sup.a are joined to form a substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

(74) In certain embodiments, at least two instances of R.sup.A2 are different from each other. In certain embodiments, all instances of R.sup.A2 are the same. In certain embodiments, at least one instance of R.sup.A2 is hydrogen. In certain embodiments, each instance of R.sup.A2 is hydrogen. In certain embodiments, at least one instance of R.sup.A2 is halogen. In certain embodiments, at least one instance of R.sup.A2 is F. In certain embodiments, at least one instance of R.sup.A2 is Cl. In certain embodiments, at least one instance of R.sup.A2 is Br. In certain embodiments, at least one instance of R.sup.A2 is I (iodine). In certain embodiments, at least one instance of R.sup.A2 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.A2 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A2 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A2 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.A2 is CH.sub.3. In certain embodiments, all instances of R.sup.A2 are CH.sub.3. In certain embodiments, at least one instance of R.sup.A2 is substituted methyl. In certain embodiments, at least one instance of R.sup.A2 is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.A2 is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.A2 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A2 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A2 is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A2 is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A2 is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A2 is substituted aryl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A2 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A2 is substituted phenyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.2 is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A2 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A2 is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A2 is OR.sup.a. In certain embodiments, at least one instance of R.sup.A1 is OH. In certain embodiments, at least one instance of R.sup.A2 is O(substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.A2 is OMe. In certain embodiments, at least one instance of R.sup.A2 is OEt, OPr, or OBu. In certain embodiments, at least one instance of R.sup.A2 is OBn or OPh. In certain embodiments, at least one instance of R.sup.A2 is SR. In certain embodiments, at least one instance of R.sup.A2 is SH. In certain embodiments, at least one instance of R.sup.A2 is SMe. In certain embodiments, at least one instance of R.sup.A1 is N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.A2 is NH.sub.2. In certain embodiments, at least one instance of R.sup.A2 is NHMe. In certain embodiments, at least one instance of R.sup.2 is NMe.sub.2. In certain embodiments, at least one instance of R.sup.A2 is CN. In certain embodiments, at least one instance of R.sup.A2 is SCN. In certain embodiments, at least one instance of R.sup.A2 is C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, or C(NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.A2 is C(O)R.sup.a or C(O)OR.sup.a. In certain embodiments, at least one instance of R.sup.A2 is C(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.A2 is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.A2 is NO.sub.2. In certain embodiments, at least one instance of R.sup.A2 is NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, or NR.sup.aC(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.A2 is OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2.

(75) Formula (A) includes as Ring B a pyridyl ring that is unsubstituted (e.g., when m is 0) or substituted with one or more substituents R.sup.B (e.g., when m is 1, 2, 3, or 4). In certain embodiments, Ring B is of the formula:

(76) ##STR00022##
In certain embodiments, Ring B is of the formula:

(77) ##STR00023##
In certain embodiments, Ring B is of the formula:

(78) ##STR00024##
In certain embodiments, Ring B is of the formula:

(79) ##STR00025##
In certain embodiments, Ring B is of the formula:

(80) ##STR00026##
In certain embodiments, Ring B is of the formula:

(81) ##STR00027##
In certain embodiments, Ring B is of the formula:

(82) ##STR00028##
In certain embodiments, Ring B is of the formula:

(83) ##STR00029##

(84) In certain embodiments, at least two instances of R.sup.B are different from each other. In certain embodiments, all instances of R.sup.B are the same. In certain embodiments, at least one instance of R.sup.B is halogen. In certain embodiments, at least one instance of R.sup.B is F. In certain embodiments, at least one instance of R.sup.B is Cl. In certain embodiments, at least one instance of R.sup.B is Br. In certain embodiments, at least one instance of R.sup.B is I (iodine). In certain embodiments, at least one instance of R.sup.B is substituted alkyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.B are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.B is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.B is CH.sub.3. In certain embodiments, all instances of R.sup.B are CH.sub.3. In certain embodiments, at least one instance of R.sup.B is substituted methyl. In certain embodiments, at least one instance of R.sup.B is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.B is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.B is substituted alkenyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.B is substituted alkynyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.B is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.B is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.B is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.B is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.B is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.B is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.B is substituted aryl. In certain embodiments, at least one instance of R.sup.B is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.B is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.B is substituted phenyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.B is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.B is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.B is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.B is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is OR.sup.a. In certain embodiments, at least one instance of R.sup.B is OH. In certain embodiments, at least one instance of R.sup.B is O(substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.B is OMe. In certain embodiments, at least one instance of R.sup.B is OEt, OPr, or OBu. In certain embodiments, at least one instance of R.sup.B is OBn or OPh. In certain embodiments, at least one instance of R.sup.B is SR. In certain embodiments, at least one instance of R.sup.B is SH. In certain embodiments, at least one instance of R.sup.B is SMe. In certain embodiments, at least one instance of R.sup.B is N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.B is NH.sub.2. In certain embodiments, at least one instance of R.sup.B is NHMe. In certain embodiments, at least one instance of R.sup.B is NMe.sub.2. In certain embodiments, at least one instance of R.sup.B is CN. In certain embodiments, at least one instance of R.sup.B is SCN. In certain embodiments, at least one instance of R.sup.B is C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, or C(NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.B is C(O)R.sup.a or C(O)OR.sup.a. In certain embodiments, at least one instance of R.sup.B is C(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.B is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.B is NO.sub.2. In certain embodiments, at least one instance of R.sup.B is NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, or NR.sup.aC(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.B is OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2.

(85) In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.

(86) Formula (A) includes as Ring C a pyridyl ring that is unsubstituted (e.g., when n is 0) or substituted with one or more substituents R.sup.C (e.g., when n is 1, 2, 3, or 4). In certain embodiments, Ring C is of the formula:

(87) ##STR00030##
In certain embodiments, Ring C is of the formula:

(88) ##STR00031##
In certain embodiments, Ring C is of the formula:

(89) ##STR00032##
In certain embodiments, Ring C is of the formula:

(90) ##STR00033##
In certain embodiments, Ring C is of the formula:

(91) ##STR00034##
In certain embodiments, Ring C is of the formula:

(92) ##STR00035##
In certain embodiments, Ring C is of the formula:

(93) ##STR00036##

(94) In certain embodiments, at least two instances of R.sup.C are different from each other. In certain embodiments, all instances of R.sup.C are the same. In certain embodiments, at least one instance of R.sup.C is halogen. In certain embodiments, at least one instance of R.sup.C is F. In certain embodiments, at least one instance of R.sup.C is Cl. In certain embodiments, at least one instance of R.sup.C is Br. In certain embodiments, at least one instance of R.sup.C is I (iodine). In certain embodiments, at least one instance of R.sup.C is substituted alkyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.C are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.C is CH.sub.3. In certain embodiments, all instances of R.sup.C are CH.sub.3. In certain embodiments, at least one instance of R.sup.C is substituted methyl. In certain embodiments, at least one instance of R.sup.C is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.C is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.C is substituted alkenyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.C is substituted alkynyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.C is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.C is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.C is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.C is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.C is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.C is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.C is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.C is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.C is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.C is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.C is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.C is substituted aryl. In certain embodiments, at least one instance of R.sup.C is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.C is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.C is substituted phenyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.C is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.C is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.C is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.C is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.C is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is OR.sup.a. In certain embodiments, at least one instance of R.sup.C is OH. In certain embodiments, at least one instance of R.sup.C is O(substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.C is OMe. In certain embodiments, at least one instance of R.sup.C is OEt, OPr, or OBu. In certain embodiments, at least one instance of R.sup.C is OBn or OPh. In certain embodiments, at least one instance of R.sup.C is SR.sup.a. In certain embodiments, at least one instance of R.sup.C is SH. In certain embodiments, at least one instance of R.sup.C is SMe. In certain embodiments, at least one instance of R.sup.C is N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.C is NH.sub.2. In certain embodiments, at least one instance of R.sup.C is NHMe. In certain embodiments, at least one instance of R.sup.C is NMe.sub.2. In certain embodiments, at least one instance of R.sup.C is CN. In certain embodiments, at least one instance of R.sup.C is SCN. In certain embodiments, at least one instance of R.sup.C is C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, or C(NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.C is C(O)R or C(O)OR.sup.a. In certain embodiments, at least one instance of R.sup.C is C(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.C is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.C is NO.sub.2. In certain embodiments, at least one instance of R.sup.C is NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, or NR.sup.aC(O)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.C is OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2.

(95) In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

(96) In certain embodiments, at least one instance of R.sup.B and at least one instance of R.sup.C are different from each other. In certain embodiments, the instance of R.sup.B at the carbon atom labeled with w is the same as the instance of R.sup.C at the carbon atom labeled with w, wherein w is 2, 3, 4, 5, or 6. In certain embodiments, m and n are different from each other. In certain embodiments, m and n are the same. In certain embodiments, each of m and n is 0.

(97) Formula (A) includes a divalent linker Z.sup.A that directly covalently connects Ring A and Ring B. In certain embodiments, Z.sup.A is a bond. In certain embodiments, Z.sup.A is a substituted or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms are independently replaced with O, S, NR.sup.ZA, N, or N. In certain embodiments, when Z.sup.A is a substituted or unsubstituted C.sub.1-6 hydrocarbon chain, Z.sup.A consists of a chain, and optionally one or more hydrogen atoms and/or one or more substituents (e.g., O) on the chain, where any two substituents may optionally be joined to form a ring. In certain embodiments, Z.sup.A does not include unsaturated bonds in the chain. In certain embodiments, Z.sup.A consists of one or two unsaturated bonds in the chain. In certain embodiments, Z.sup.A is a substituted (e.g., substituted with at least one instance of halogen) C.sub.1-6 hydrocarbon chain. In certain embodiments, Z.sup.A is an unsubstituted C.sub.1-4 hydrocarbon chain. In certain embodiments, the molecular weight of Z.sup.A is not more than about 150 g/mol, not more than about 100 g/mol, not more than 80 g/mol, not more than about 50 g/mol, or not more than about 30 g/mol. In certain embodiments, Z.sup.A consists of not more than about 50 atoms, not more than about 40 atoms, not more than about 30 atoms, not more than about 20 atoms, or not more than about 10 atoms. In certain embodiments, Z.sup.A is CC or CCCC. In certain embodiments, Z.sup.A is of the formula:

(98) ##STR00037##

(99) In certain embodiments, all instances of R.sup.ZA are the same. In certain embodiments, at least two instances of R.sup.A2 are different from each other. In certain embodiments, at least one instance of R.sup.ZA is hydrogen. In certain embodiments, all instances of R.sup.ZA are hydrogen. In certain embodiments, at least one instance of R.sup.ZA is substituted or unsubstituted C.sub.1-6 alkyl (e.g., CH.sub.3, CF.sub.3, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certain embodiments, at least one instance of R.sup.ZA is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(100) In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 2 or 6 of Ring B. In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 3 or 5 of Ring B. In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 4 of Ring B.

(101) Formula (A) includes a divalent linker Z.sup.B that directly covalently connects Ring A and Ring C. In certain embodiments, Z.sup.B is a bond. In certain embodiments, Z.sup.B is a substituted or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain atoms are independently replaced with O, S, NR.sup.ZB, N, or N. In certain embodiments, when Z.sup.B is a substituted or unsubstituted C.sub.1-4 hydrocarbon chain, Z.sup.B consists of a chain, and optionally one or more hydrogen atoms and/or one or more substituents (e.g., O) on the chain, where any two substituents may optionally be joined to form a ring. In certain embodiments, Z.sup.B does not include unsaturated bonds in the chain. In certain embodiments, Z.sup.B consists of one or two unsaturated bonds in the chain. In certain embodiments, Z.sup.B is a substituted (e.g., substituted with at least one instance of halogen) C.sub.1-6 hydrocarbon chain. In certain embodiments, Z.sup.B is an unsubstituted C.sub.1-4 hydrocarbon chain. In certain embodiments, the molecular weight of Z.sup.B is not more than about 150 g/mol, not more than about 100 g/mol, not more than 80 g/mol, not more than about 50 g/mol, or not more than about 30 g/mol. In certain embodiments, Z.sup.B consists of not more than about 50 atoms, not more than about 40 atoms, not more than about 30 atoms, not more than about 20 atoms, or not more than about 10 atoms. In certain embodiments, Z.sup.B is CC or CCCC. In certain embodiments, Z.sup.B is of the formula:

(102) ##STR00038##

(103) In certain embodiments, all instances of R.sup.ZB are the same. In certain embodiments, at least two instances of R.sup.ZB are different from each other. In certain embodiments, at least one instance of R.sup.ZB is hydrogen. In certain embodiments, all instances of R.sup.ZB are hydrogen. In certain embodiments, at least one instance of R.sup.ZB is substituted or unsubstituted C.sub.1-6 alkyl (e.g., CH.sub.3, CF.sub.3, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certain embodiments, at least one instance of R.sup.ZB is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(104) In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 2 or 6 of Ring A. In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 3 or 5 of Ring A. In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 4 of Ring A.

(105) In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 2 or 6 of Ring C. In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 3 or 5 of Ring C. In certain embodiments, Z.sup.B is directly covalently attached to the carbon atom labeled with 4 of Ring C.

(106) In certain embodiments, Z.sup.A and Z.sup.B are different from each other. In certain embodiments, Z.sup.A and Z.sup.B are the same. In certain embodiments, each of Z.sup.A and Z.sup.B is a bond.

(107) In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 2 or 6 of Ring B; and Z.sup.B is directly covalently attached to the carbon atom labeled with 2 or 6 of Ring C. In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 3 or 5 of Ring B; and Z.sup.B is directly covalently attached to the carbon atom labeled with 3 or 5 of Ring C. In certain embodiments, Z.sup.A is directly covalently attached to the carbon atom labeled with 4 of Ring B; and Z.sup.B is directly covalently attached to the carbon atom labeled with 4 of Ring C.

(108) In certain embodiments, the ligand of Formula (A) is of the formula:

(109) ##STR00039##

(110) In certain embodiments, the ligand of Formula (A) is of the formula:

(111) ##STR00040##

(112) In certain embodiments, the ligand of Formula (A) is of the formula:

(113) ##STR00041##

(114) In certain embodiments, the ligand of Formula (A) is of the formula:

(115) ##STR00042##

(116) In certain embodiments, the ligand of Formula (A) is of the formula:

(117) ##STR00043##

(118) In certain embodiments, the ligand of Formula (A) is of the formula:

(119) ##STR00044##

(120) In certain embodiments, the ligand of Formula (A) is of the formula:

(121) ##STR00045##

(122) In certain embodiments, the ligand of Formula (A) is of the formula:

(123) ##STR00046##

(124) In certain embodiments, the ligand of Formula (A) is of the formula:

(125) ##STR00047##

(126) In certain embodiments, the ligand of Formula (A) is of the formula:

(127) ##STR00048##

(128) In certain embodiments, the ligand of Formula (A) is of the formula:

(129) ##STR00049##

(130) In certain embodiments, the ligand of Formula (A) is of the formula:

(131) ##STR00050##

(132) In certain embodiments, the ligand of Formula (A) is of the formula:

(133) ##STR00051##

(134) In certain embodiments, the ligand of Formula (A) is of the formula:

(135) ##STR00052##

(136) In certain embodiments, the ligand of Formula (A) is of the formula:

(137) ##STR00053##

(138) In certain embodiments, the ligand of Formula (A) is of the formula:

(139) ##STR00054##

(140) In certain embodiments, the ligand of Formula (A) is of the formula:

(141) ##STR00055##

(142) In certain embodiments, the ligand of Formula (A) is of the formula:

(143) ##STR00056##

(144) In certain embodiments, the ligand of Formula (A) is of the formula:

(145) ##STR00057##

(146) In certain embodiments, the ligand of Formula (A) is of the formula:

(147) ##STR00058##

(148) In certain embodiments, the ligand of Formula (A) is of the formula:

(149) ##STR00059##

(150) In certain embodiments, the ligand of Formula (A) is of the formula:

(151) ##STR00060##

(152) In certain embodiments, the ligand of Formula (A) is of the formula:

(153) ##STR00061##

(154) In a nanostructure described herein, each instance of the transition metal ion and two instances of the ligand of Formula (A) form through coordination bonds a coordination complex. In certain embodiments, each instance of the ligand of Formula (A) forms through coordination bonds a coordination complex with one instance of the transition metal ion. In certain embodiments, an instance of the coordination bonds is formed between an instance of the transition metal ion and the nitrogen atom labeled with 1 of an instance of the ligand of Formula (A). In certain embodiments, an instance of the coordination bonds is formed between an instance of the transition metal ion and the nitrogen atom labeled with 1 of an instance of the ligand of Formula (A). In certain embodiments, an instance of the coordination bonds is formed between an instance of the transition metal ion and the nitrogen atom labeled with 1 of an instance of the ligand of Formula (A), and another instance of the coordination bonds is formed between the instance of the transition metal ion and the nitrogen atom labeled with 1 of the instance of the ligand of Formula (A).

(155) In a nanostructure described herein, each instance of the coordination complex may be in a square planar molecular geometry. In a nanostructure described herein, each instance of the coordination complex may also be in a pseudo square planar molecular geometry.

(156) A nanostructure described herein may be a nanosphere. In certain embodiments, the nanosphere has quasi-regular polyhedral symmetry. In certain embodiments, the nanosphere has cuboctahedral symmetry. In certain embodiments, the nanosphere has icosidodecahedral symmetry. In certain embodiments, the nanosphere has regular polyhedral symmetry (e.g., cubic (regular hexahedral) or dodecahedral symmetry).

(157) A nanostructure described herein may be a nano-paddlewheel.

(158) A nanostructure described herein is hollow (e.g., including a cavity). In certain embodiments, the average (e.g., mean) outer diameter of a nanostructure described herein is not more than about 100 nm, not more than about 60 nm, not more than about 30 nm, not more than about 10 nm, not more than about 5 nm, not more than about 3 nm, or not more than about 1 nm. In certain embodiments, the average outer diameter of the a nanostructure described herein is at least about 1 nm, at least about 2 nm, at least about 5 nm, at least about 10 nm, at least about 30 nm, at least about 60 nm, or at least about 100 nm. Combinations of the above ranges (e.g., at least about 1 nm and not more than about 100 nm or at least about 1 nm and not more than about 10 nm) are also within the scope of the present disclosure. The average inner diameter of a nanostructure described herein is the average diameter of the cavity of the nanostructure. In certain embodiments, the average inner diameter of a nanostructure described herein is not more than about 100 nm, not more than about 60 nm, not more than about 30 nm, not more than about 10 nm, not more than about 5 nm, not more than about 3 nm, or not more than about 1 nm. In certain embodiments, the average inner diameter of the nanostructure described herein is at least about 1 nm, at least about 2 nm, at least about 5 nm, at least about 10 nm, at least about 30 nm, at least about 60 nm, or at least about 100 nm. Combinations of the above ranges (e.g., at least about 1 nm and not more than about 60 nm or at least about 1 nm and not more than about 5 nm) are also within the scope of the present disclosure.

(159) In certain embodiments, a nanostructure described herein is not a polymer or does not include a polymeric moiety.

(160) In certain embodiments, a nanosphere described herein is of Formula (I-A), or a salt thereof.

(161) In certain embodiments, a nanosphere described herein is of Formula (I-B), or a salt thereof.

(162) In certain embodiments, a nanosphere described herein (nanosphere I-1) is of Formula (I-A), wherein each instance of the gray line is ligand A-1. In Formula (I-A), each instance of the moiety shown in FIG. 31 is of the formula:

(163) ##STR00062##
In certain embodiments, each instance of the moiety shown in FIG. 31 is of the formula:

(164) ##STR00063##

(165) In certain embodiments, a nano-paddlewheel described herein is of the formula depicted in Scheme 8.

(166) Supramolecular Complexes

(167) Another aspect of the present disclosure relates to supramolecular complexes that include nanostructures described herein covalently connected by divalent linkers Y. In certain embodiments, a supramolecular complex described herein includes two or more (e.g., at least 10, at least 100, at least 1,000, or at least 10,000) instances of a nanostructure described herein and at least one instance of Y.

(168) Each instance of Y consists of a chain, and optionally one or more hydrogen atoms and/or one or more substituents (e.g., O, halogen, and substituted or unsubstituted C.sub.1-6 alkyl) on the chain, wherein any two substituents may optionally be joined to form a ring. In certain embodiments, at least two instances of Y are different from each other. In certain embodiments, all instances of Y are the same. In certain embodiments, at least one instance of Y does not include unsaturated bonds in the chain. In certain embodiments, at least one instance of Y consists of one or more unsaturated bonds in the chain. In certain embodiments, at least one instance of Y is a substituted or unsubstituted C.sub.30-3000 (e.g., C.sub.100-3000, C.sub.200-2500, C.sub.300-2000, C.sub.400-1500, C.sub.70-1500, C.sub.500-1000, C.sub.100-1000, C.sub.30-500, C.sub.40-400, C.sub.60-300, or C.sub.80-200) hydrocarbon chain, optionally wherein one or more chain atoms are independently replaced with O, S, NR.sup.Y, N, or N. In certain embodiments, at least one instance of Y is a substituted or unsubstituted C.sub.80-1000 hydrocarbon chain, optionally wherein one or more chain atoms are independently replaced with O, S, NR.sup.Y, N, or N. In certain embodiments, each chain atom, with any substituents thereon, of at least one instance of Y is independently CH.sub.2, CH(substituted or unsubstituted C.sub.1-6 alkyl)-, C(substituted or unsubstituted C.sub.1-6 alkyl).sub.2-, C(O), O, NH, N(substituted or unsubstituted C.sub.1-6 alkyl)-, or N(nitrogen protecting group)-. In certain embodiments, each chain atom, with any substituents thereon, of at least one instance of Y is independently CH.sub.2, CF.sub.2, C(O), O, NH, or NMe. In certain embodiments, each chain atom, with any substituents thereon, of at least one instance of Y is independently CH.sub.2, C(O), or O. In certain embodiments, at least one instance of Y comprises at least one instance of the moiety C(O)O or OC(O). In certain embodiments, each instance of Y is independently of the formula:

(169) ##STR00064##

(170) In certain embodiments, each instance of Y is independently of the formula:

(171) ##STR00065##

(172) In certain embodiments, each instance of Y is independently of the formula:

(173) ##STR00066##

(174) In certain embodiments, each instance of Y is independently of the formula:

(175) ##STR00067##

(176) In certain embodiments, each instance of Y is independently of the formula:

(177) ##STR00068##

(178) In certain embodiments, each instance of Y is independently of the formula:

(179) ##STR00069##

(180) In certain embodiments, each instance of Y is independently of the formula:

(181) ##STR00070##

(182) In certain embodiments, the molecular weight of at least one instance of Y (calculated by subtracting 2 from the molecular weight of the molecule YH.sub.2) is not more than about 100,000 g/mol, not more than about 30,000 g/mol, not more than 10,000 g/mol, not more than about 3,000 g/mol, not more than about 1,000 g/mol, not more than about 300 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of at least one instance of Y is at least about 100 g/mol, at least about 300 g/mol, at least about 1,000 g/mol, at least about 3,000 g/mol, at least about 10,000 g/mol, at least about 30,000 g/mol, or at least about 100,000 g/mol. Combinations of the above ranges (e.g., between about 300 and about 30,000 g/mol) are also within the scope of the present disclosure. In certain embodiments, at least one instance of Y consists of not more than about 30,000 atoms, not more than about 10,000 atoms, not more than about 3,000 atoms, not more than about 1,000 atoms, not more than about 300 atoms, not more than about 100 atoms, or not more than about 30 atoms. In certain embodiments, at least one instance of Y consists of at least about 30 atoms, at least about 100 atoms, at least about 300 atoms, at least about 1,000 atoms, at least about 3,000 atoms, at least about 10,000 atoms, or at least about 30,000 atoms. Combinations of the above ranges (e.g., between about 30 and about 10,000 g/mol) are also within the scope of the present disclosure.

(183) In certain embodiments, at least one instance of Y is hydrolytically unstable under physiological conditions. In certain embodiments, at least one instance of Y includes a hydrolytically unstable moiety (e.g., C(O)O or C(O)O) in the chain of Y. In certain embodiments, at least one instance of Y is hydrolytically stable under physiological conditions.

(184) In certain embodiments, all instances of R.sup.Y are the same. In certain embodiments, at least two instances of R.sup.Y are different from each other. In certain embodiments, at least one instance of R.sup.Y is hydrogen. In certain embodiments, all instances of R.sup.Y are hydrogen. In certain embodiments, at least one instance of R.sup.Y is substituted or unsubstituted C.sub.1-6 alkyl (e.g., CH.sub.3, CF.sub.3, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certain embodiments, at least one instance of R.sup.Y is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(185) An instance of Y may be directly covalently attached to an instance of the ligand of Formula (A) (e.g., by removing a hydrogen atom from the instance of the ligand of Formula (A) to form a radical (ligand radical) and directly covalently attaching one of the two radicals of the instance of Y to the ligand radical). Each instance of Y is independently directly covalently attached to an instance of the ligand of Formula (A) and directly covalently attached to another instance of the ligand of Formula (A). In certain embodiments, each instance of the ligand of Formula (A) is covalently attached to w instances of Y, wherein w is 1. In certain embodiments, each instance of the ligand of Formula (A) is covalently attached to w instances of Y, wherein w is 2. In certain embodiments, at least one instance of Y is directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of an instance of the ligand of Formula (A) and directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of another instance of the ligand of Formula (A). In certain embodiments, at least one instance of Y is directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of an instance of the ligand of Formula (A) and directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of another instance of the ligand of Formula (A). In certain embodiments, at least one instance of Y is directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of an instance of the ligand of Formula (A) and directly covalently attached to the atom labeled with 2, 3, 4, 5, or 6 (e.g., 3, 4, or 5) of another instance of the ligand of Formula (A). In a supramolecular complex described herein, at least two instances of the nanostructure are directly covalently connected by at least one instance of Y. In certain embodiments, at least about 50% (e.g., at least about 60%, at least about 70%, at least about 80%, or at least about 90%) of all instances of Y directly covalently attached to an instance of the nanostructure are directly covalently attached to other instances of the nanostructure.

(186) A nanostructure or supramolecular complex described herein may further comprise at least one instance of an anionic counterion. The anionic counterions may reduce the overall electric charge of the nanostructure or supramolecular complex, each of which includes transition metal ions that are positively charged. In certain embodiments, at least two instances of the anionic counterion are different. In certain embodiments, all instances of the anionic counterion are the same. In certain embodiments, the nanostructure or supramolecular complex is substantially electrically neutral. In certain embodiments, the nanostructure or supramolecular complex is slightly positively charged. In certain embodiments, the C-potential of the nanostructure or supramolecular complex is between about 0 and about +30 mV, inclusive (e.g., between about 0 and about 10 mV, inclusive). In certain embodiments, the nanostructure or supramolecular complex is slightly negatively charged. In certain embodiments, the -potential of the nanostructure or supramolecular complex is between about 30 and about 0 mV, inclusive (e.g., between about 10 and about 0 mV, inclusive). In certain embodiments, at least one instance of the anionic counterion is a non-coordinating anionic counterion (e.g., ClO.sub.4.sup., NO.sub.3.sup., TfO.sup., BF.sub.4.sup., PF.sub.4.sup., PF.sub.6.sup., AsF.sub.6.sup., or SbF.sub.6.sup.). In certain embodiments, at least one instance (e.g., each instance) of the anionic counterion is NO.sub.3.sup.. In certain embodiments, at least one instance of the anionic counterion is AcO.sup., F.sup., Cr.sup., Br.sup., or I.sup.. In certain embodiments, at least one instance of the anionic counterion is a coordinating anionic counterion. In certain embodiments, at least one instance (e.g., each instance) of the anionic counterion is at the outer surface of an instance of the nanostructure. In certain embodiments, at least one instance of the anionic counterion is at the inner surface of an instance of the nanostructure. In certain embodiments, at least one instance of the anionic counterion is encapsulated by an instance of the nanostructure.

(187) Macromers

(188) In another aspect, the present disclosure provides macromers of Formula (B), and salts thereof:

(189) ##STR00071##
wherein Ring A, X.sup.A, X.sup.B, X.sup.C, X.sup.D, X.sup.E, Y, Z.sup.A, Z.sup.B, R.sup.B, R.sup.C, m, and n are as described herein.

(190) In certain embodiments, the macromer of Formula (B) is of the formula:

(191) ##STR00072##
or a salt thereof, wherein each instance of X.sup.D is N or C.

(192) In certain embodiments, the macromer of Formula (B) is of the formula:

(193) ##STR00073##
or a salt thereof.

(194) In certain embodiments, the macromer of Formula (B) is of the formula:

(195) ##STR00074##
or a salt thereof.

(196) In certain embodiments, the macromer of Formula (B) is of the formula:

(197) ##STR00075##
or a salt thereof.

(198) In certain embodiments, the macromer of Formula (B) is of the formula:

(199) ##STR00076##
or a salt thereof.

(200) In certain embodiments, the macromer of Formula (B) is of Formula (B-1), (B-2), or (B-3):

(201) ##STR00077##
or a salt thereof.

(202) In another aspect, the present disclosure provides macromers of Formula (C), and salts thereof:

(203) ##STR00078##
wherein Ring A, X.sup.A, X.sup.B, X.sup.C, X.sup.D, X.sup.E, Y, Z.sup.A, Z.sup.B, R.sup.B, R.sup.C, m, and n are as described herein.

(204) In certain embodiments, the macromer of Formula (C) is of the formula:

(205) ##STR00079##
or a salt thereof.

(206) In certain embodiments, the macromer of Formula (C) is of the formula:

(207) ##STR00080##
or a salt thereof.

(208) In certain embodiments, the macromer of Formula (C) is of the formula:

(209) ##STR00081##
or a salt thereof.
Compositions

(210) In another aspect, the present disclosure provides compositions comprising a nanostructure described herein and optionally an excipient. A composition described herein may further comprise a solvent (e.g., a suitable solvent described herein, such as water or DMSO). The solvent may be encapsulated inside a nanostructure and/or be present outside of any nanostructure in the composition.

(211) In still another aspect, the present disclosure provides compositions comprising a supramolecular complex described herein and optionally an excipient.

(212) The excipient included in a composition described herein may be a pharmaceutically acceptable excipient, cosmetically acceptable excipient, dietarily acceptable excipient, or nutraceutically acceptable excipient.

(213) A composition described herein may further comprise an agent (e.g., a pharmaceutical agent or diagnostic agent). In a composition described herein, an agent may form an adduct (e.g., through covalent attachment and/or non-covalent interactions) with a nanostructure described herein (including a nanostructure moiety of a supramolecular complex described herein). In certain embodiments, a composition described herein is useful in the delivery of the agent (e.g., an effective amount of the agent) to a subject, tissue, or cell.

(214) A composition described herein may further comprise a fluid (e.g., a solvent, e.g., water, DMSO, acetonitrile, or a mixture thereof)

(215) Compositions of the disclosure may improve or increase the delivery of an agent described herein to a subject, tissue, or cell. In certain embodiments, the compositions increase the delivery of the agent to a target tissue or target cell. In certain embodiments, the target tissue is liver, spleen, or lung. In certain embodiments, the target tissue is pancreas, kidney, uterus, ovary, heart, thymus, fat, or muscle. In certain embodiments, the target cell is a liver cell, spleen cell, lung cell, pancreas cell, kidney cell, uterus cell, ovary cell, heart cell, thymus cell, or muscle cell. In certain embodiments, the compositions selectively deliver the agent to the target tissue or target cell (e.g., the compositions deliver the agent to the target tissue in a greater quantity in unit time than to a non-target tissue or deliver the agent to the target cell in a greater quantity in unit time than to a non-target cell).

(216) The delivery of an agent described herein may be characterized in various ways, such as the exposure, concentration, and bioavailability of the agent. The exposure of an agent in a subject, tissue, or cell may be defined as the area under the curve (AUC) of the concentration of the agent in the subject, tissue, or cell after administering or dosing the agent. In general, an increase in exposure may be calculated by first taking the difference in: (1) a first AUC, which is the AUC measured in a subject, tissue, or cell administered or dosed with a composition described herein; and (2) a second AUC, which is the AUC measured in a subject, tissue, or cell administered or dosed with a control composition; and then by dividing the difference by the second AUC. Exposure of an agent may be measured in an appropriate animal model. The concentration of an agent and, when appropriate, its metabolite(s), in a subject, tissue, or cell is measured as a function of time after administering or dosing the agent.

(217) Concentration of an agent, and, when appropriate, of its metabolite(s), in a subject, tissue, or cell, may be measured as a function of time in vivo using an appropriate animal model. In certain embodiments, the concentration of the agent is the concentration of the agent in a target tissue or target cell. One exemplary method of determining the concentration of an agent involves dissecting of a tissue. The concentration of the agent may be determined by HPLC or LC/MS analysis.

(218) In some embodiments, a composition of the disclosure increases the delivery of an agent described herein to a subject, tissue, or cell by due to the presence of a nanostructure described herein. In some embodiments, a composition of the disclosure increases the delivery of an agent described herein to a subject, tissue, or cell by due to the presence of a supramolecular complex described herein. In some embodiments, the composition increases the delivery of the agent due to the presence of an adduct formed between the nanostructure (including a nanostructure moiety of a supramolecular complex) and the agent. In some embodiments, the presence of a nanostructure or supramolecular complex described herein increase the delivery of the agent by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 100%, at least about 2-fold, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, or at least about 1000-fold. In certain embodiments, a nanostructure or supramolecular complex described herein is present in the composition in an amount sufficient to increase the delivery of the agent by an amount described herein when administered in the composition compared to the delivery of the agent when administered in the absence of the nanostructure or supramolecular complex.

(219) Compositions described herein may deliver an agent selectively to a tissue or cell. In certain embodiments, the tissue or cell to which the agent is selectively delivered is a target tissue or target cell, respectively. In certain embodiments, the compositions deliver at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 70%/o, at least about 100%, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, or at least about 1000-fold more amount of the agent in unit time to a target tissue than to a non-target tissue or to a target cell than to a non-target cell. The amount of agent may be measured by the exposure, concentration, and/or bioavailability of the agent in a tissue or cell as described herein.

(220) The compositions described herein (e.g., pharmaceutical compositions) including one or more agents (e.g., pharmaceutical agents) may be useful in treating and/or preventing a disease. In certain embodiments, the compositions are useful in gene therapy. In certain embodiments, the compositions are useful for treating and/or preventing a genetic disease. In certain embodiments, the compositions are useful for treating and/or preventing a proliferative disease. In certain embodiments, the compositions are useful for treating and/or preventing cancer. In certain embodiments, the compositions are useful for treating and/or preventing a benign neoplasm. In certain embodiments, the compositions are useful for treating and/or preventing pathological angiogenesis. In certain embodiments, the compositions are useful for treating and/or preventing an inflammatory disease. In certain embodiments, the compositions are useful for treating and/or preventing an autoimmune disease. In certain embodiments, the compositions are useful for treating and/or preventing a hematological disease. In certain embodiments, the compositions are useful for treating and/or preventing a neurological disease. In certain embodiments, the compositions are useful for treating and/or preventing a gastrointestinal disease. In certain embodiments, the compositions are useful for treating and/or preventing a liver disease. In certain embodiments, the compositions are useful for treating and/or preventing a spleen disease. In certain embodiments, the compositions are useful for treating and/or preventing a respiratory disease. In certain embodiments, the compositions are useful for treating and/or preventing a lung disease. In certain embodiments, the compositions are useful for treating and/or preventing hepatic carcinoma, hypercholesterolemia, refractory anemia, or familial amyloid neuropathy. In certain embodiments, the compositions are useful for treating and/or preventing a painful condition. In certain embodiments, the compositions are useful for treating and/or preventing a genitourinary disease. In certain embodiments, the compositions are useful for treating and/or preventing a musculoskeletal condition. In certain embodiments, the compositions are useful for treating and/or preventing an infectious disease. In certain embodiments, the compositions are useful for treating and/or preventing a psychiatric disorder. In certain embodiments, the compositions are useful for treating and/or preventing a metabolic disorder.

(221) The agents may be provided in an effective amount in a composition described herein. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease described herein. In certain embodiments, the effective amount is an amount effective for preventing a disease described herein.

(222) An effective amount of an agent may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 to about 1000 mg/kg, from about 0.01 to about 750 mg/kg, from about 0.1 to about 500 mg/kg, from about 1.0 to about 250 mg/kg, and from about 10.0 to about 150 mg/kg.

(223) In certain embodiments, a composition described herein is in the form of gels. In certain embodiments, the gels result from self-assembly of the components of the composition. The agent to be delivered by the gel may be in the form of a gas, liquid, or solid. The nanostructures and/or supramolecular complexes described herein may be combined with polymers (synthetic or natural), surfactants, cholesterol, carbohydrates, proteins, lipids, lipidoids, etc. to form gels. The gels may be further combined with an excipient to form the composition. The gels are described in more detail herein.

(224) The compositions described herein (e.g., pharmaceutical compositions) can be prepared by any method known in the art (e.g., pharmacology). In certain embodiments, such preparatory methods include the steps of bringing a nanostructure or supramolecular complex described herein into association with an agent described herein (i.e., the active ingredient), optionally with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

(225) Compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A unit dose is a discrete amount of the composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

(226) Relative amounts of the active ingredient, the excipient (e.g., the pharmaceutically or cosmetically acceptable excipient), and/or any additional ingredients in a composition described herein will vary, depending upon the identity, size, and/or condition of the subject to whom the composition is administered and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

(227) Excipients used in the manufacture of provided compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

(228) Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

(229) Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

(230) Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and mixtures thereof.

(231) Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures thereof.

(232) Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

(233) Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, and mixtures thereof.

(234) Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, and dipotassium edetateke), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, tartaric acid and salts and hydrates thereof, and mixtures thereof.

(235) Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, thimerosal, and mixtures thereof.

(236) Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, and mixtures thereof.

(237) Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, phenylethyl alcohol, and mixtures thereof.

(238) Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, phytic acid, and mixtures thereof.

(239) Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, Euxyl, and mixtures thereof.

(240) Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

(241) Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

(242) Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

(243) Additionally, the composition may further comprise an apolipoprotein. Previous studies have reported that Apolipoprotein E (ApoE) was able to enhance cell uptake and gene silencing for a certain type of materials. See, e.g., Akinc, A., et al., Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 18(7): p. 1357-64. In certain embodiments, the apolipoprotein is ApoA, ApoB, ApoC, ApoE, or ApoH, or an isoform thereof.

(244) Liquid dosage forms for oral and parenteral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the emulsions, microemulsions, solutions, suspensions, syrups and elixirs are or cosmetically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophore, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

(245) Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

(246) The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

(247) In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

(248) Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

(249) Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, excipient or carrier (e.g., pharmaceutically or cosmetically acceptable excipient or carrier) such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

(250) Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

(251) The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the formulation art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

(252) Dosage forms for topical and/or transdermal administration of a composition of this disclosure may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

(253) Suitable devices for use in delivering intradermal compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the agent in powder form through the outer layers of the skin to the dermis are suitable.

(254) Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

(255) A composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

(256) Low boiling propellants generally include liquid propellants having a boiling point of below 65 F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

(257) Compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

(258) Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

(259) Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

(260) A composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

(261) Although the descriptions of compositions provided herein are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

(262) Nanostructures and supramolecular complexes described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder, the activity of the specific active ingredient employed, the specific composition employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, route of administration, and rate of excretion of the specific active ingredient employed, the duration of the treatment, drugs used in combination or coincidental with the specific active ingredient employed, and like factors well known in the medical arts.

(263) The compositions described herein can be administered by any suitable route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. In certain embodiments, the compositions are administered by oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

(264) The exact amount of an agent required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular agent, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

(265) In certain embodiments, an effective amount of an agent for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of an agent per unit dosage form.

(266) In certain embodiments, the agents described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.

(267) It will be appreciated that dose ranges as described herein provide guidance for the administration of provided compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

(268) Compositions described herein may further include a hydrophilic polymer (e.g., polyethylene glycol (PEG)). The compositions described herein may further include a lipid (e.g., a steroid, a substituted or unsubstituted cholesterol, or a polyethylene glycol (PEG)-containing material). In certain embodiments, the lipid included in the compositions is a triglyceride, a driglyceride, a PEGylated lipid, dimyristoyl-PEG2000 (DMG-PEG2000), a phospholipid (e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), dioleoylphosphatidylethanolamine (DOPE), a substituted or unsubstituted cholesterol, a steroid an apolipoprotein, or a combination thereof. In certain embodiments, the compositions include two components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include three components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include at least four components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include a hydrophilic polymer, a phospholipid, a steroid, and a substituted or unsubstituted cholesterol. In certain embodiments, the compositions include PEG, DSPC, and substituted or unsubstituted cholesterol. In certain embodiments, the additional materials are approved by a regulatory agency, such as the U.S. FDA, for human and/or veterinary use.

(269) Compositions described herein may be useful in other applications, e.g., non-medical applications. Nutraceutical compositions described herein may be useful in the delivery of an effective amount of a nutraceutical, e.g., a dietary supplement, to a subject in need thereof. Cosmetic compositions described herein may be formulated as a cream, ointment, balm, paste, film, or liquid, etc., and may be useful in the application of make-up, hair products, and materials useful for personal hygiene, etc. Compositions described herein may be useful for other non-medical applications, e.g., such as an emulsion, emulsifier, or coating, useful, for example, as a food component, for extinguishing fires, for disinfecting surfaces, for oil cleanup, and/or as a bulk material.

(270) Agents to be Delivered

(271) Agents that are delivered by the systems (e.g., pharmaceutical compositions) described herein may be pharmaceutical (e.g., therapeutic or prophylactic), diagnostic, cosmetic, or nutraceutical agents. Any chemical compound to be administered to a subject or to be contacted with a tissue or cell may be delivered using the nanostructures, supramolecular complexes, and/or compositions described herein. The agent may be a small molecule (e.g., a small organic molecule or small inorganic molecule), protein, peptide, polynucleotide, targeting agent, isotopically labeled chemical compound, vaccine, or immunological agent. The agent may be an agent useful in bioprocessing (e.g., intracellular manufacturing of proteins, such as a cell's bioprocessing of a commercially useful chemical or fuel). For example, intracellular delivery of an agent may be useful in bioprocessing by maintaining the cell's health and/or growth, e.g., in the manufacturing of proteins. Any chemical compound to be administered to a subject or contacted with a tissue or cell may be delivered to the subject, tissue, or cell using the compositions described herein.

(272) Exemplary agents that may be included in a composition described herein include, but are not limited to, small molecules, organometallic compounds, polynucleotides, proteins, peptides, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, small molecules linked to proteins, glycoproteins, steroids, nucleotides, oligonucleotides, polynucleotides, nucleosides, antisense oligonucleotides, lipids, hormones, vitamins, cells, metals, targeting agents, isotopically labeled chemical compounds, drugs (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations), vaccines, immunological agents, agents useful in bioprocessing, and mixtures thereof. The targeting agents are described in more detail herein. In certain embodiments, the agents are nutraceutical agents. In certain embodiments, the agents are pharmaceutical agents (e.g., a therapeutic or prophylactic agent). In certain embodiments, the agent is an antibiotic agent (e.g., an anti-bacterial, anti-viral, or anti-fungal agent), anesthetic, steroidal agent, anti-proliferative agent, anti-inflammatory agent, anti-angiogenesis agent, anti-neoplastic agent, anti-cancer agent, anti-diabetic agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti-cholinergic, analgesic, immunosuppressant, anti-depressant, anti-psychotic, -adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, non-steroidal, nutritional agent, anti-allergic agent, or pain-relieving agent. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts. Therapeutic and prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, and Freund's adjuvant, etc. In certain embodiments, the agent is a small molecule. In certain embodiments, the agent is an anti-cancer agent (e.g., an anti-cancer agent disclosed in U.S. Patent Application Publication No. US 2003/065023). In certain embodiments, the agent is doxorubicin.

(273) In certain embodiments, an agent described herein is a polynucleotide. In certain embodiments, the agent is plasmid DNA (pDNA). In certain embodiments, the agent is single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA. In certain embodiments, the agent is RNA. In certain embodiments, the agent is small interfering RNA (siRNA). In certain embodiments, the agent is messenger RNA (mRNA). In certain embodiments, the agent is single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In certain embodiments, the agent is an RNA that carries out RNA interference (RNAi). The phenomenon of RNAi is discussed in greater detail, for example, in the following references: Elbashir et al., 2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806; Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000, 404:293; Zamore et al., 2000, Cell, 101:25; Chakraborty, 2007, Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther., 13:553. In certain embodiments, upon delivery of an RNA into a subject, tissue, or cell, the RNA is able to interfere with the expression of a specific gene in the subject, tissue, or cell. In certain embodiments, the agent is a pDNA, siRNA, mRNA, or a combination thereof.

(274) In certain embodiments, the polynucleotide may be provided as an antisense agent or RNAi. See, e.g., Fire et al., Nature 391:806-811, 1998. Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double-stranded polynucleotides, or derivatives thereof, which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and/or genomic DNA, or mutants thereof, so as to inhibit the expression of the encoded protein, e.g., by inhibiting transcription and/or translation. See, e.g., Crooke, Molecular mechanisms of action of antisense drugs, Biochim. Biophys. Acta 1489(1):31-44, 1999; Crooke, Evaluating the mechanism of action of anti-proliferative antisense drugs, Antisense Nucleic Acid Drug Dev. 10(2):123-126, discussion 127, 2000; Methods in Enzymology volumes 313-314, 1999. The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix (i.e., triple helix formation). See, e.g., Chan et al., J. Mol. Med. 75(4):267-282, 1997.

(275) The RNA and/or RNAi described herein can be designed and/or predicted using one or more of a large number of available algorithms. To give but a few examples, the following resources can be utilized to design and/or predict polynucleotides: algorithms found at Alnylum Online; Dharmacon Online; OligoEngine Online; Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online; Chang Bioscience Online; Invitrogen Online; LentiWeb Online GenScript Online; Protocol Online; Reynolds et al., 2004, Nat. Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res., 34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005, Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics, 7: 271.

(276) The polynucleotide included in a composition described herein may be of any size or sequence, and they may be single- or double-stranded. In certain embodiments, the polynucleotide includes at least about 30, at least about 100, at least about 300, at least about 1,000, at least about 3,000, or at least about 10,000 base pairs. In certain embodiments, the polynucleotide includes not more than about 10,000, not more than about 3,000, not more than about 1,000, not more than about 300, not more than about 100, or not more than about 30 base pairs. Combinations of the above ranges (e.g., at least about 100 and not more than about 1,000) are also within the scope of the disclosure. The polynucleotide may be provided by any suitable means known in the art. In certain embodiments, the polynucleotide is engineered using recombinant techniques. See, e.g., Ausubel et al., Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press: 1989). The polynucleotide may also be obtained from natural sources and purified from contaminating components found normally in nature. The polynucleotide may also be chemically synthesized in a laboratory. In certain embodiments, the polynucleotide is synthesized using standard solid phase chemistry. The polynucleotide may be isolated and/or purified. In certain embodiments, the polynucleotide is substantially free of impurities. In certain embodiments, the polynucleotide is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% free of impurities.

(277) The polynucleotide may be modified by physical, chemical, and/or biological means. The modifications include methylation, phosphorylation, and/or end-capping, etc. In certain embodiments, the modifications lead to increased stability of the polynucleotide.

(278) Wherever a polynucleotide is employed in the present disclosure, a derivative of the polynucleotide may also be used. These derivatives include products resulted from modifications of the polynucleotide in the base moieties, sugar moieties, and/or phosphate moieties of the polynucleotide. Modified base moieties include, but are not limited to, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties include, but are not limited to, 2-fluororibose, ribose, 2-deoxyribose, 3-azido-2,3-dideoxyribose, 2,3-dideoxyribose, arabinose (the 2-epimer of ribose), acyclic sugars, and hexoses. The nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA. Modified linkages include, but are not limited to, phosphorothioate and 5-N-phosphoramidite linkages. Combinations of the various modifications may be used in a single polynucleotide. These modified polynucleotides may be provided by any suitable means known in the art; however, as will be appreciated by those of skill in the art, the modified polynucleotides may be prepared using synthetic chemistry in vitro.

(279) The polynucleotide described herein may be in any form, such as a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, or an artificial chromosome.

(280) The polynucleotide described herein may be of any sequence. In certain embodiments, the polynucleotide encodes a protein or peptide. The encoded protein may be an enzyme, structural protein, receptor, soluble receptor, ion channel, active (e.g., pharmaceutically active) protein, cytokine, interleukin, antibody, antibody fragment, antigen, coagulation factor, albumin, growth factor, hormone, or insulin, etc. The polynucleotide may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA boxes, ribosomal binding sites, and stop sites for transcription. In certain embodiments, the polynucleotide is not intended to encode a protein. For example, the polynucleotide may be used to fix an error in the genome of the cell being transfected.

(281) In certain embodiments, the polynucleotide described herein comprises a sequence encoding an antigenic peptide or protein. A composition containing the polynucleotide can be delivered to a subject to induce an immunologic response sufficient to decrease the chance of a subsequent infection and/or lessen the symptoms associated with such an infection. The polynucleotide of these vaccines may be combined with interleukins, interferon, cytokines, and/or adjuvants described herein.

(282) The antigenic protein or peptides encoded by the polynucleotide may be derived from bacterial organisms, such as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and Camphylobacter jejuni; from viruses, such as smallpox virus, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, measles virus, HIV virus, varicella-zoster virus, herpes simplex 1 virus, herpes simplex 2 virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus, rubella virus, coxsackieviruses, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus; and from fungal, protozoan, or parasitic organisms, such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni.

(283) An agent described herein may be covalently or non-covalently attached to (e.g., complexed to and/or encapsulated in) a nanostructure or supramolecular complex (e.g., attached to a nanostructure of the supramolecular complex) described herein, or included in a composition described herein. In certain embodiments, at least one instance of the nanostructure encapsulates the agent. In certain embodiments, at least one molecule of the agent is not encapsulated in any instance of the nanostructure. In certain embodiments, upon delivery of the agent into a cell, the agent is able to interfere with the expression of a specific gene in the cell.

(284) In certain embodiments, an agent described herein may be a mixture of two or more agents that may be useful as, e.g., combination therapies. A composition including the mixture can be used to achieve a synergistic effect. In certain embodiments, the composition including the mixture can be used to improve the activity and/or bioavailability, reduce and/or modify the metabolism, inhibit the excretion, and/or modify the distribution of at least one of the two or more agents in a subject, tissue, or cell to which the mixture is administered or dosed. It will also be appreciated that the composition including the mixture may achieve a desired effect for the same disorder, and/or it may achieve different effects. The two or more agents in the mixture may be useful for treating and/or preventing a same disease or different diseases described herein.

(285) The compositions (e.g., pharmaceutical compositions) described herein can be administered concurrently with, prior to, or subsequent to the one or more agents (e.g., pharmaceutical agents). Each one of the agents may be administered at a dose and/or on a time schedule determined for that agent. The agents may also be administered together with each other and/or with the composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

(286) Targeting Agents

(287) Since it is often desirable to target a particular cell, collection of cells, or tissue, a composition described herein may further include targeting moieties or targeting agents. In certain embodiments, a nanostructure described herein (including a nanostructure moiety of a supramolecular complex described herein) is modified to include targeting moieties or targeting agents. For example, a targeting moiety or targeting agent may be included throughout a nanostructure or supramolecular complex (e.g., throughout a nanostructure of the supramolecular complex) described herein or may be only at the surface (e.g., outer or inner surface) of the nanostructure or supramolecular complex (e.g., at the surface of a nanostructure of the supramolecular complex). A targeting agent may be a protein, peptide, carbohydrate, glycoprotein, lipid, small molecule, or polynucleotide, and a targeting moiety may be a fragment of the targeting agent. The targeting moiety or targeting agent may be used to target specific cells or tissues or may be used to promote endocytosis or phagocytosis of the nanostructure and/or supramolecular complex. The targeting moieties or targeting agents include the ones known in the art. See, e.g., Cotten et al., Methods Enzym. 217:618, 1993. Examples of the targeting moieties and targeting agents include, but are not limited to, antibodies, proteins, peptides, carbohydrates, small molecules, metals, receptor ligands, sialic acid, aptamers, and fragments thereof. If a targeting moiety or targeting agent is included throughout a nanostructure or supramolecular complex, the targeting agent may be included in the mixture that is used to form the nanostructure or supramolecular complex. If the targeting agent is only on the surface of a nanostructure or supramolecular complex, the targeting agent may be associated with (e.g., by covalent or non-covalent (e.g., electrostatic, hydrophobic, hydrogen bonding, van der Waals, - stacking) interactions) the nanostructure or supramolecular complex using standard chemical techniques.

(288) Adducts of a Nanostructure and an Agent

(289) The present disclosure contemplates that the nanostructures described herein (including the nanostructure moieties of the supramolecular complexes described herein) are useful in the delivery of an agent described herein (e.g., a small molecule, peptide, protein, or a polynucleotide) to a subject, tissue, or cell. Without wishing to be bound by any particular theory, the nanostructures have several desirable properties that make a composition that includes the nanostructures and an agent suitable for delivering the agent to a subject, tissue, or cell. Encapsulation of an agent within a nanostructure described herein may have desirable properties for delivering an agent to a subject, tissue, or cell, including protection from degradation of the agent by ubiquitous nucleases, passive and active targeting, and/or evasion of endosomal Toll-like receptors. Other desirable properties include: 1) the ability of the nanostructures to form an adduct with and protect the agent that may otherwise be labile (e.g., labile at least due to chemical and/or enzymatical (e.g., by nucleases) degradation); 2) the ability of the nanostructures to buffer the pH in an endosome of the cell; 3) the ability of the nanostructures to act as a proton sponge and cause endosomolysis; and 4) the ability of the nanostructures to substantially neutralize the negative or positive charges of the agent. Challenges to the efficient delivery of an agent exist, including particle dissociation via serum proteins, cellular uptake, endosomal escape, and appropriate intracellular disassembly. To address some of these challenges, single parameter studies that evaluate the effect of chemical structure on a single biological property or on delivery performance have been reported. Furthermore, high-throughput synthetic methods have been exploited for the accelerated discovery of potent lipid nanoparticles (LNPs) and evaluation of structure activity relationships (SARs). In spite of these efforts, the relationships between physicochemical properties of nanoparticles and biological barriers, and that between biological barriers and gene silencing activity remain unclear. This lack of clarity has also resulted in poor in vitro-in vivo translation.

(290) In certain embodiments, a nanostructure described herein encapsulates an agent described herein. In certain embodiments, the ratio of the amount of a nanostructure described herein to the amount of an agent encapsulated in the nanostructure is at least about 1:1, at least about 2:1, at least about 5:1, at least about 10:1, at least about 20:1, at least about 50:1, at least about 100:1, at least about 200:1, or at least about 500:1 mol/mol. In certain embodiments, the ratio of the nanostructure or supramolecular complex to the agent is not more than about 500:1, not more than about 200:1, not more than about 100:1, not more than about 50:1, not more than about 20:1, not more than about 10:1, not more than about 5:1, not more than about 2:1, or not more than about 1:1 mol/mol. Combinations of the above ranges (e.g., at least about 1:1 and not more than about 100:1) are also within the scope of the disclosure.

(291) A nanostructure and agent described herein may form an adduct. An adduct may be formed by covalently attaching an agent to a nanostructure or by non-covalent interactions (e.g., electrostatic interactions, hydrophobic interactions, hydrogen bonding, van der Waals interactions, and/or - stacking) between an agent and a nanostructure. An agent may be contacted with a nanostructure, or the components thereof (e.g., ligands of Formula (A) and transition metal ions, and optionally anionic counterions), under conditions suitable to form an adduct.

(292) Micelles, Liposomes, and Lipoplexes

(293) A composition including a nanostructure and agent described herein may be in the form of a micelle or liposome. In certain embodiments, the nanostructures are in the form of a micelle or liposome. An agent described herein may be inside a micelle or liposome, and a nanostructure described herein may be inside the micelle or liposome. In certain embodiments, in a micelle or liposome, an agent is encapsulated in a nanostructure. Micelles and liposomes are typically useful in delivering an agent, such as a hydrophobic agent, to a subject, tissue, or cell. When the micelle or liposome is complexed with (e.g., encapsulates or covers) a polynucleotide, the resulting complex may be referred to as a lipoplex. Many techniques for preparing micelles and liposomes are known in the art, and any such method may be used to make micelles and liposomes.

(294) In certain embodiments, liposomes are formed through spontaneous assembly. In some embodiments, liposomes are formed when thin lipid films or lipid cakes are hydrated and stacks of lipid crystalline bilayers become fluid and swell. The hydrated lipid sheets detach during agitation and self-close to form large, multilamellar vesicles (LMV). This may prevent interaction of water with the hydrocarbon core of the bilayers at the edges. Once these liposomes have formed, reducing the size of the liposomes can be modified through input of sonic energy (sonication) or mechanical energy (extrusion). See, e.g., Walde, P. Preparation of Vesicles (Liposomes) In Encylopedia of Nanoscience and Nanotechnology; Nalwa, H. S. Ed. American Scientific Publishers: Los Angeles, 2004; Vol. 9, pp. 43-79; Szoka et al., Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes) Ann. Rev. Biophys. Bioeng. 9:467-508, 1980; each of which is incorporated herein by reference. The preparation of lipsomes may involve preparing a nanostructure described herein for hydration, hydrating the nanostructures with agitation, and sizing the vesicles to achieve a homogenous distribution of liposomes. A nanostructure described herein may be first dissolved in a solvent in a container to result in a homogeneous mixture. The solvent is then removed to form a film. This film is thoroughly dried to remove residual amount of the solvent, e.g., by placing the container in vacuo for a period of time. Hydration of the film may be accomplished by adding an aqueous medium and agitating the resulting mixture. Disruption of LMV suspensions using sonic energy typically produces small unilamellar vesicles (SUV) with diameters in the range of 15-50 nm. Lipid extrusion is a technique in which a lipid suspension is forced through a polycarbonate filter with a defined pore size to yield particles having a diameter near the pore size of the filter used. Extrusion through filters with 100 nm pores typically yields large, unilamellar vesicles (LUV) with a mean diameter of 120-140 nm. In certain embodiments, the amount ofa nanostructure described herein in the liposome is between about 30 mol % and about 80 mol %, between about 40 mol % and about 70 mol %, or between about 60 mol % and about 70 mol %, inclusive. In certain embodiments, the nanostructures further complexes an agent, such as a small molecule.

(295) Liposomes and micelles may also be prepared according to methods in the following scientific papers: Narang et al., Cationic Lipids with Increased DNA Binding Affinity for Nonviral Gene Transfer in Dividing and Nondividing Cells, Bioconjugate Chem. 16:156-68, 2005; Hofland et al., Formation of stable cationic lipid/DNA complexes for gene transfer, Proc. Natl. Acad. Sci. USA 93:7305-7309, July 1996; Byk et al., Synthesis, Activity, and StructureActivity Relationship Studies of Novel Cationic Lipids for DNA Transfer, J. Med. Chem. 41(2):224-235, 1998; Wu et al., Cationic Lipid Polymerization as a Novel Approach for Constructing New DNA Delivery Agents, Bioconjugate Chem. 12:251-57, 2001; Lukyanov et al., Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs, Advanced Drug Delivery Reviews 56:1273-1289, 2004; Tranchant et al., Physicochemical optimisation of plasmid delivery by cationic lipids, J. Gene Med. 6:S24-S35, 2004; van Balen et al., Liposome/Water Lipophilicity: Methods, Information Content, and Pharmaceutical Applications, Medicinal Research Rev. 24(3):299-324, 2004.

(296) Gels

(297) Gels are much different from classical mechanics of materials, in that the timescale associated with the imposed stress or strain can affect the mechanical response by several orders of magnitude. These viscoelastic characteristics of gels are significant to many applications, and better understanding of the spatial and temporal mechanisms which effect desirable mechanical properties will lead to better materials designs. In gels, the timescales over which mechanical interactions occur are highly important; materials can have apparent fluid-like properties at long timescales yet apparent solid-like properties at short timescales. Typically, gels possess little long-range spatial ordering. Instead, the molecules in the gels arrange themselves in a wide array of spatial conformations. This spatial heterogeneity effects a corresponding temporal heterogeneity: upon application of a stress, the material begins to relax by deforming. Each of the local conformations relax at a distinct timescale. The mechanical properties (e.g., viscoelastic properties) of gels are important for the gels to be used in various applications. For example, it has been shown that substrate elasticity can determine mesenchymal stem cell differentiation (Engler et al. Cell, 2006, 126, 677-689). There is a need for gels with designer viscoelasticity, the ability to create gels with a specifically engineered viscoelastic spectrum. Conventional methods for designing the mechanical properties of gels include changing the molecular weight or molecular weight distribution of the polymer matrix, increasing the degree of crosslinking between polymer chains, changing the stiffness of the polymer backbone, and changing the bulkiness of the side groups. However, these conventional techniques alter the properties of the polymer matrix such that they add other features which may be undesirable.

(298) Coordination chemistry typically features bonds between metals and ligands that are intermediate in bond-energy between covalent bonds and non-covalent interactions (e.g., van der Waals interactions and H-bonding). Such bonds can be reversible or dynamic under appropriate conditions; they have been extensively used for the formation of a class of gel networksmetallogelsthat features stimuli-responsive properties..sup.1-32 Due to their low branch functionality and dynamic bonds, most metallogels are soft elastic materials (storage moduli of G20 kPa at 2-10 wt. % polymer network) that often display viscous flow behavior at low shear strain frequencies..sup.6,7,21,26,29 These weak mechanical properties severely limit the possible applications of metallogels; the desirable dynamic properties inevitably come at the expense of structural integrity.

(299) Recently, transition metal-organic ligand complexes have been suggested to reinforce the mechanical properties and self-healing nature of marine mussel adhesion fibers (byssi) (Harrington et al. Science, 2010, 328, 216-220; Harrington et al. The Journal of Experimental Biology, 2007, 210, 4307-4318; Holten-Andersen et al. Nature Materials, 2007, 6, 669-672; Lee et al. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103, 12999-13003). Efforts have been made to mimic the extraordinary mechanical properties of the byssi using simplified synthetic analogs (Holten-Andersen et al. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108, 2651-2655; Holten-Andersen et al., Journal of Materials Chemistry B, 2014, 2, 2467-2472; Lee et al. Annual Review of Materials Research, 2011, 41, 99-132; Barrett et al. Advanced functional materials, 2013, 23, 1111-1119; Fullenkamp et al. Macromolecules, 2013, 46, 1167-1174). Craig et al. has reported the formation and dynamic mechanical properties of metallo-supramolecular networks formed by mixtures of bis-Pd(II) and Pt(II) cross-linkers with poly(4-vinylpyridine) in DMSO. These networks have relaxation timescales that vary across several orders of magnitude. Also reported are that the kinetics of metal-ligand dissociation could be used to tune the apparent mechanical properties of a metallogel within a relevant timescale..sup.24-26 Furthermore, it has been shown that the thermodynamics of coordination can serve as a partially complementary parameter to tune the mechanical properties of gels..sup.26 Though manipulation of the kinetic and thermodynamic properties of individual metal-ligand bonds offers one way to modulate bulk properties, this strategy is ultimately limited in terms of the magnitude of changes that can be induced. Furthermore, it requires the design and synthesis of an assortment of ligand architectures and/or the use of different metals to induce changes in network behavior, which may not be compatible with a given application.

(300) Tetrazine derivatives are another ligand that is useful in transition metal-ligand complexes. Interest in tetrazine reactivity has recently resurged largely due to its use in bioconjugate and polymer chemistry (Wollack, J. W.; Monson, B. J.; Dozier, J. K.; Dalluge, J. J.; Poss, K.; Hilderbrand, S. A.; Distefano, M. D. Chemical Biology & Drug Design 2014, 84, 140; Darko, A.; Wallace, S.; Dmitrenko, O.; Machovina, M. M.; Mehl, R. A.; Chin, J. W.; Fox, J. M. Chemical Science 2014, 5, 3770; Wu, H.; Cisneros, B. T.; Cole, C. M.; Devaraj, N. K. Journal of the American Chemical Society 2014, 136, 17942; Hansell, C. F.; Espeel, P.; Stamenovi, M. M.; Barker, I. A.; Dove, A. P.; Du Prez, F. E.; O'Reilly, R. K. Journal of the American Chemical Society 2011, 133, 13828; Blackman, M. L.; Royzen, M.; Fox, J. M. Journal of the American Chemical Society 2008, 130, 13518; Cok, A. M.; Zhou, H.; Johnson, J. A. Macromolecular Symposia 2013, 329, 108; Zhou, H.; Woo, J.; Cok, A. M.; Wang, M.; Olsen, B. D.; Johnson, J. A. Proceedings of the National Academy of Sciences 2012). Certain tetrazine species are known for their binding to various metal ions; specifically, 3,6-bis(2-pyridyl)-1,2,4,5-tetrazines (bptz), has been studied for additional purposes by several groups as ligands in self-assembled structures. The Dunbar group reported the synthesis of molecular triangles, squares, and pentagons using bptz and various metal ions including Fe.sup.2+, Ni.sup.2+, and Ag.sup.+, respectively. Additional accounts of using bptz include gold surface modification and its use as a ligand for rhenium to use its MLCT for study in photoinduced charge separation (Skomski, D.; Tempas, C. D.; Smith, K. A.; Tait, S. L. Journal of the American Chemical Society 2014, 136, 9862; Li, G.; Parimal, K.; Vyas, S.; Hadad, C. M.; Flood, A. H.; Glusac, K. D. J. Am. Chem. Soc. 2009, 131, 11656).

(301) It has previously reported that covalent A.sub.2+B.sub.3 type end-linked polymer networks was synthesized using a tris-bptz trifunctional crosslinker and norbomene-terminated poly(ethylene glycol) (PEG) telechelic polymers (Hansell, C. F.; Espeel, P.; Stamenovi, M. M.; Barker, I. A.; Dove, A. P.; Du Prez, F. E.; O'Reilly, R. K. Journal of the American Chemical Society 2011, 133, 13828; Cok, A. M.; Zhou, H.; Johnson, J. A. Macromolecular Symposia 2013, 329, 108; Zhou, H.; Woo, J.; Cok, A. M.; Wang, M.; Olsen, B. D.; Johnson, J. A. Proceedings of the National Academy of Sciences 2012; Zhou, H.; Johnson, J. A. Angew. Chem., Int. Ed. 2013, 52, 2235). Strained alkenes and tetrazines undergo facile inverse-electron demand Diels-Alder reactions with the extrusion of nitrogen, which make them useful for efficiently synthesizing catalyst-free, two component polymer networks. Subsequent work by Anseth and coworkers used this chemistry to construct cytocompatible gels that could be photochemically patterned (Alge, D. L.; Azagarsamy, M. A.; Donohue, D. F.; Anseth, K. S. Biomacromolecules 2013, 14, 949). However, there are no known references of bptz-metal coordination as a mode of crosslinking for the formation of end-linked polymer networks and the applications thereof.

(302) A key component of polymer network structures that cannot be readily addressed by traditional metallogels is the network branch functionality, f, which is the average number of chains that emanate from junctions within a network. According to the phantom network model of rubber elasticity, the modulus of a gel increases with f..sup.33 In traditional metallogels, the junctions are single metal centers (FIG. 1A, left); f is dictated by the number of ligands that can bind to that metal, which is typically limited to values between two and four. Thus, metallogels are typically very soft materials, and it is very difficult to tune f without complete redesign of the network components.

(303) It was envisioned that dramatic enhancements in f could be realized if network junctions were created through metal-ligand self-assembly into higher-order cage-like structures (FIG. 16A, right panel). Such suprametallogels would retain the dynamic properties of metallogels while potentially featuring broadly tunable branch architectures and enhanced mechanical properties. Indeed, Mother Nature uses hierarchical, multivalent assembly of weakly interacting species to produce biological gels with robust mechanical properties and dynamic behavior. Similar concepts have been adopted to increase the mechanical stability of synthetic networks;.sup.34 however, to our knowledge, the use of programmed metallosupramolecular assembly for gelation has not been explored. As demonstrated here, such an approach is attractive because it enables tuning of gel properties over a wide range using the same metal and polymer, and very simple ligand modifications.

(304) Numerous examples of ligand-metal combinations are known to provide discrete self-assembled cage-like structures..sup.35-48 Reports of Fujita and coworkers on the formation of M.sub.12L.sub.24 spherical cages from the assembly of twenty-four phenyl-3,5-bis-(para-pyridine) ligands (e.g., L-para and L1, FIG. 16B) and 12 Pd.sup.2+ atoms were inspiring. In several studies, these authors have shown that these assemblies can be synthesized in quantitative yield, that they are robust towards a diverse range of ligand substitutions (R in FIG. 16B),.sup.49,50 and that they can serve as small molecule hosts and nano-reactors..sup.36 Thus, incorporation of these supramolecular cages as junctions within a polymer network could afford suprametallogels with additional advantagesaside from mechanical onesover conventional metallogels such as the ability to encapsulate and release species within the junction cages, or conduct reactions in confined spaces within the gel.

(305) Two questions were to be answered. First, if bis-pyridyl moieties similar to those used by Fujita et al..sup.36 are appended onto the ends of linear polymer chains (e.g., macromers B-3 and B-4, FIG. 16C), will those polymer chains form suprametallogels in the presence of Pd.sup.2+ through the self-assembly of the polymer chain ends? This question is non-trivial, because gelation has the potential to dramatically perturb the dynamics of cage self-assembly. Second, if an isomeric bis-pyridyl ligand, one that does not generate spherical cages but an alternative assembly, can be used to tune the network branch functionality in a rational manner? For example, in contrast to the defined 120 bite angle of the para-pyridine isomers, the corresponding meta isomers (L-meta and L2, FIG. 16B) have infinitely many possible bite angles between 0 and 240 depending on the relative orientation of the two pyridines. Ditopic ligands with similar geometry are known to self-assemble into M.sub.2L.sub.4 paddlewheels (FIG. 16B) with several types of metal ions, including Pd.sup.2+..sup.51-65 The 1-hydroxymethyl derivative of L-meta (L2, FIG. 16B) was synthesized, and it was confirmed that it quantitatively forms M.sub.2L4 paddlewheels in the presence of Pd.sup.2+ ions. Thus, assuming no network defects and perfect self-assembly, polymers terminated with ligand L1 (macromer B-3, FIG. 16C) may provide suprametallogels with f=24 cage-like junctions, while analogous polymers terminated with ligand L2 (macromer B-4, FIG. 16C) may provide suprametallogels with f=4 paddlewheel junctions. In other words, a small difference in macromer ligand structure may provide materials with different bulk properties. Notably, this approach stands in stark contrast to gels that are formed via pre-assembly of metal-ligand-derived nanostructures that feature orthogonal groups for subsequent crosslinking..sup.66-68 Presented here are the first examples of gelation induced through metal-ligand bond formation and concomitant metallosupramolecular assembly (e.g., induced exclusively through metal-ligand bond formation and concomitant metallosupramolecular assembly).

(306) The present disclosure also provides a new use of bptz as a ligand appended to PEG that binds to metals as a method for gelation. In addition, it has been shown that the bptz motif can act as a bifunctional moiety: first, as a ligand for coordinating metal ions and second, as a reactive site for functionalization.

(307) Therefore, in another aspect, the present disclosure provides compositions that are gels or in the form of a gel (e.g., hydrogel), the compositions including a supramolecular complex and optionally an agent described herein. The gels described herein are suprametallogels. A supramolecular complex described herein and/or an adduct of a supramolecular complex and an agent (supramolecule-agent adduct) may be able to form a gel upon contacting a fluid. In certain embodiments, the fluid is a suitable solvent described herein (e.g., water). In certain embodiments, the supramolecular complex and/or supramolecule-agent adduct form a gel at least through the complexation of ligands of Formula (A) and transition metal ions and optionally also through other non-covalent interrelations (e.g., electrostatic interactions, hydrophobic interactions, hydrogen bonding, van der Waals interactions, and/or - stacking). A supramolecular complex and/or supramolecule-agent adduct described herein may form a gel upon contacting a fluid when the concentration of the supramolecular complex and/or supramolecule-agent adduct in the fluid is a suitable concentration described herein (e.g., between about 10 and about 500 millimoles of a reactant or reagent (e.g., a ligand of Formula (A); a macromer of Formula (B) or (C); or a transition metal salt) per liter of the fluid, inclusive). The structure of a gel described herein includes the primary structure (e.g., the structure of the nanostructure moieties of the gel) and secondary structure (e.g., the way how different instances of the nanostructure moieties are connected by divalent linkers Y and the degree of entanglement of the supramolecular complexes in the gel). In a supramolecular complex, an instance of divalent linker Y may be intrastructural or interstructural. An intrastructural instance of Y forms a loopy structure, whereas an interstructural instance of Y forms a chain structure. When all instances of divalent linker Y included in a gel described herein are intrastructural (e.g., when the concentration of the nanostructure moieties of a supramolecular complex in the fluid is below a critical concentration (in other words, under an overly high dilution), a loopy nanostructure forms. In certain embodiments, the critical concentration is about 5 mM, about 10 mM, about 15 mM, or about 25 mM. In certain embodiments, a gel described herein does not include loopy nanostructures. A supramolecular complex may include more than two instances of the nanostructure moiety covalently connected by more than one interstructural instance of Y. An instance of the supramolecular complex may entangle within itself, and two or more instances of the supramolecular complex may also entangle. The entangled supramolecular complex(es) form a molecular network that includes cavities, which may be filled with a fluid when the supramolecular complex(es) are contacted with the fluid, and the supramolecular complex(es) may retain the fluid and be swelled, rather than be dissolved, by the fluid to form a gel. A high degree of entanglement of the supramolecular complexes may be beneficial for the formation of a gel when the supramolecular complexes are contacted with a fluid. A high ratio of the number of interstructural divalent linkers Y to the number of intrastructural divalent linkers Y may also be beneficial for the formation of a gel at least because such a high ratio may increase the entanglement of the supramolecular complexes in the gel. In certain embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of all instances of divalent linker Y included in a gel described herein are interstructural.

(308) Conventional gels (e.g., gels formed by swelling a covalently cross-linked polymer with a fluid) are typically not able to flow under a suitable stress (a suitable shear stress) and to self-heal when damaged. The gels described herein are advantageous over the conventional gels at least in that the gels described herein are able to flow under a suitable stress and to self-heal when damaged. While a conventional gel is usually thermally irreversible, the gels described herein are thermoreversible. A change in physical and/or chemical conditions (e.g., stress, temperature, and/or concentration) from a first condition to a second condition may result in a change in the degree of gelation of a gel described herein from a first degree of gelation to a second degree of gelation. A change in physical and/or chemical conditions (e.g., stress, temperature, and/or concentration) from the second condition to the first condition may result in a change in the degree of gelation of a gel described herein from the second degree of gelation to the first degree of gelation. The molecular network of a gel described herein may reversibly deform at least through weakening or strengthening, or breaking or reforming, the coordination bonds between the ligands of Formula (A) and the transition metal ions by changing physical and/or chemical conditions. In contrast, the covalent bonds in a conventional gel typically cannot be reversibly weakened or strengthened, or broken or reformed, by changing physical and/or chemical conditions. The aggregation of the molecules in a gel described herein is more dynamic, compared to the aggregation of the molecules in a conventional gel, and the more dynamic aggregation in a gel described herein is at least due to the non-covalent interactions between the molecules therein. Conventional gels typically cannot be easily characterized using spectroscopic techniques. In contrast, the gels described herein allow facile characterizations using readily available spectroscopic techniques (e.g., UV-vis absorption spectroscopy and Raman spectroscopy) under various conditions. Combination of chemical spectroscopy with mechanical tests will then beget spatial structure-temporal structure-mechanical property relationships; this allows for shape design criteria for engineering the mechanical properties of gels (vis--vis modulating the modes of the relaxation spectrum).

(309) The gels described herein are also advantageous over conventional nanostructures (e.g., nanoparticles without divalent linkers that are covalently attached to different instances of the nanoparticles). Individual instances of a conventional nanostructure are not covalently linked to each other, and therefore, the conventional nanostructures typically lack robustness and storage modulus. Conversely, in a gel described herein, at least two instances of the nanostructure are covalently linked by at least one instance of divalent linker Y. The covalent bonding between the individual nanostructures in a gel described herein is stronger than the non-covalent interactions, if any, between the individual nanostructures in conventional nanostructures. Therefore, compared to conventional nanostructures, the gels described herein show higher robustness and/or higher storage modulus.

(310) The supramolecular complexes and compositions (e.g., gels) may also be able to absorb a large amount of a fluid (e.g., absorb at least 100 times by weight of the fluid, compared to the weight of the supramolecular complex or the dry weight of the composition (weight of the composition minus the weight of the fluid included in the composition) and, therefore, may be useful as super-absorbent materials.

(311) Kits

(312) Also described herein are kits (e.g., packs). The kits provided may comprise (1) a transition metal salt, ligand of Formula (A); a macromer of Formula (B); a macromer of Formula (C); a nanostructure; a supramolecular complex; and/or a composition (e.g., gel) described herein; and (2) a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, a kit described herein further includes a second container comprising an excipient for dilution or suspension of a nanostructure, supramolecular complex, or composition described herein. In some embodiments, the nanostructure, supramolecular complex, or composition provided in the first container and the nanostructure, supramolecular complex, or composition provided in the second container are combined to form one unit dosage form.

(313) In certain embodiments, the kits described herein are useful for delivering an agent to a subject, tissue, or cell. In certain embodiments, the kits are useful for delivering an agent to a target tissue described herein. In certain embodiments, the kits are useful for treating a disease described herein. In certain embodiments, the kits are useful for preventing a disease described herein.

(314) In certain embodiments, the described kits further include instructions for administering a nanostructure, supramolecular complex, or composition described herein. The kits may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits, including the instructions, provide for delivering an agent described herein to a subject, tissue, or cell. In certain embodiments, the kits, including the instructions, provide for treating a disease described herein. In certain embodiments, the kits, including the instructions, provide for preventing a disease described herein. The kit described herein may include one or more agents described herein as a separate composition.

(315) Methods of Preparing the Nanostructures, Supramolecular Complexes, and Gels; and the Nanostructures, Supramolecular Complexes, and Gels Prepared by the Methods

(316) The nanostructures, supramolecular complexes, and compositions (e.g., gels) described herein may be prepared by complexation reactions. In another aspect, the present disclosure provides methods of preparing a nanostructure (Method A), the methods including reacting a ligand of Formula (A), or a salt thereof, with a transition metal salt to provide the nanostructure.

(317) In certain embodiments, the transition metal salt is salt of a transition metal ion described herein. In certain embodiments, the transition metal salt is a solvate (e.g., hydrate). In certain embodiments, the transition metal salt is not a solvate (e.g., is anhydrous). In certain embodiments, the transition metal salt is a Pd (e.g., Pd(II)) salt. In certain embodiments, the transition metal salt is a Ni (e.g., Ni(II)) salt. In certain embodiments, the transition metal salt is a Fe (e.g., Fe(II) or Fe(III)) salt. In certain embodiments, the transition metal salt is a Rh (e.g., Rh(l)) salt, Ir (e.g., Ir(I)) salt, Pt (e.g., Pt(II)) salt, or Au (e.g., Au(III)) salt. In certain embodiments, the transition metal salt is a Cd (e.g., Cd(II)) salt, Co (e.g., Co(III)) salt, or Cu (e.g., Cu(I) or Cu(II)) salt. In certain embodiments, the transition metal salt includes an anionic counterion described herein (e.g., ClO.sub.4.sup., NO.sub.3.sup., TfO.sup., BF.sub.4.sup., PF.sub.4.sup., PF.sub.6.sup., AsF.sub.6.sup., SbF.sub.6.sup., AcO.sup., F.sup., Cl.sup., Br.sup., or I.sup.). In certain embodiments, the transition metal salt is Pd(NO.sub.3).sub.2, or a solvate or hydrate thereof (e.g., Pd(NO.sub.3).sub.2.H.sub.2O or Pd(NO.sub.3).sub.2.2H.sub.2O). In certain embodiments, the transition metal salt is Ni(ClO.sub.4).sub.2, or a solvate or hydrate thereof. In certain embodiments, the transition metal salt is Fe(ClO.sub.4).sub.2, or a solvate or hydrate thereof.

(318) In another aspect, the present disclosure provides methods of preparing a supramolecular complex (Method B), the methods including complexing a macromer of Formula (B) or (C), or a salt thereof, with a transition metal salt to provide the supramolecular complex.

(319) In another aspect, the present disclosure provides methods of preparing a gel (Method C), the methods including complexing a macromer of Formula (B) or (C), or a salt thereof, with a transition metal salt in the presence of a fluid to provide the gel. In certain embodiments, the step of complexing of Method C further comprises the presence of an agent (e.g., a small molecule, such as an anticancer agent (e.g., doxorubicin)). In certain embodiments, the step of complexing of Method C further comprises crosslinking the macromer, before or after the step of complexing, in the presence of a crosslinking agent (crosslinker). In certain embodiments, the crosslinker is a norbornene crosslinker (e.g., tri-norbornene crosslinker).

(320) The step(s) of the methods of preparing the nanostructures, supramolecular complexes, and/or compositions (e.g., gels) described herein may be performed under any suitable conditions. A suitable condition is a combination of physical and chemical parameters under which an intended product (e.g., a nanostructure, supramolecular complex, or composition (e.g., gel) described herein) or intermediate may be formed using the methods.

(321) A suitable condition may include the absence of a solvent (i.e., neat). A suitable condition may include a suitable solvent. In certain embodiments, the suitable solvent is an organic solvent. In certain embodiments, the suitable solvent is an inorganic solvent (e.g., water). In certain embodiments, the suitable solvent is an aprotic organic solvent (e.g., acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, methyl t-butyl ether (MTBE), dimethoxyethane (DME), diglyme, acetone, butanone, dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane). In certain embodiments, the suitable solvent is DMSO. In certain embodiments, the suitable solvent is acetonitrile. In certain embodiments, the suitable solvent is a protic organic solvent (e.g., an alcohol, such as methanol, ethanol, propanol, or butanol). In certain embodiments, the suitable solvent is a mixture of two or more solvents (e.g., a mixture of water and DMSO). In certain embodiments, the suitable solvent is commercially available.

(322) A suitable condition may also include a suitable concentration of a ligand of Formula (A) or macromer of Formula (B) or (C) in a fluid or suitable solvent. In certain embodiments, the concentration of a ligand of Formula (A) or macromer of Formula (B) or (C), or a salt thereof, in a fluid or suitable solvent is at least about 1, at least about 3, at least about 10, at least about 15, at least about 25, at least about 50, at least about 100, at least about 250, at least about 500, or at least about 1,000 millimoles per liter of the fluid or suitable solvent. In certain embodiments, the concentration of the a ligand of Formula (A) or macromer of Formula (B) or (C), or a salt thereof, in a fluid or suitable solvent is not more than about 1,000, not more than about 500, not more than about 250, not more than about 100, not more than about 50, not more than about 25, not more than about 15, not more than about 10, not more than about 3, or not more than about 1 millimoles per liter of the fluid or suitable solvent. Combination of the above ranges (e.g., between about 5 and about 500 millimoles per liter of the fluid or suitable solvent, inclusive) is also within the scope of the present disclosure. In certain embodiments, the concentration of a ligand of Formula (A) or macromer of Formula (B) or (C), or a salt thereof, in a fluid or suitable solvent is between 5 and 500, between 5 and 100, between 10 and 500, between 15 and 500, inclusive, or at least about 10 or about 15 millimoles per liter of the fluid or suitable solvent, inclusive.

(323) A suitable condition may also include a suitable molar ratio of (1) the ligand of Formula (A) or macromer of Formula (B) or (C) to (2) the transition metal salt. In certain embodiments, the molar ratio of the ligand of Formula (A) to the transition metal salt is about 2:1. In certain embodiments, the molar ratio of the macromer of Formula (B) or (C) to the transition metal salt is about 1:1.

(324) A suitable condition may also include a suitable temperature under which a step of a method of preparing a nanostructure, supramolecular complex, or composition (e.g., gel) described herein is performed. In certain embodiments, the suitable temperature is at least about 20 C., at least about 40 C., at least about 60 C., at least about 70 C., at least about 80 C., at least about 100 C., at least about 120 C., or at least about 140 C. In certain embodiments, the suitable temperature is not more than about 140 C., not more than about 120 C., not more than about 100 C., not more than about 80 C., not more than about 70 C., not more than about 60 C., not more than about 40 C., or not more than about 20 C. Combinations of the above-referenced ranges (e.g., between about 20 C. and about 120 C., inclusive) are also within the scope of the disclosure. In certain embodiments, the suitable temperature is between about 20 C. and about 30 C., inclusive. In certain embodiments, the suitable temperature is about 23 C. In certain embodiments, the suitable temperature is between about 60 C. and about 80 C., inclusive. In certain embodiments, the suitable temperature is about 70 C. In certain embodiments, the suitable temperature is about 80 C. In certain embodiments, the suitable temperature is about 120 C. A suitable temperature may be a variable temperature (e.g., from 20 C. to about 70 C.) during a step of a method described herein.

(325) A suitable condition may also include a suitable pressure under which a step of a method described herein is performed. In certain embodiments, the suitable pressure is about 1 atmosphere.

(326) A suitable condition may also include a suitable atmosphere under which a step of a method described herein is performed. In certain embodiments, the suitable atmosphere is air. In certain embodiments, the suitable atmosphere is an inert atmosphere. In certain embodiments, the suitable atmosphere is a nitrogen or argon atmosphere.

(327) A suitable condition may also include a suitable time duration that a step of a method described herein lasts. In certain embodiments, the suitable time duration is in the order of minutes (e.g., about 30 minutes), hours (e.g., about 1 hour, about 2 hours, about 4 hours, about 6 hours, or about 12 hours), or days (e.g., about 1 day, 2 days, or 3 days). In certain embodiments, the suitable time duration is between about 12 hours to about 2 days, inclusive (e.g., about 1 day).

(328) The nanostructures, supramolecular complexes, and compositions (e.g., gels) prepared by the methods described herein may be isolated and/or purified using methods known in the art, such as chromatography (e.g., normal phase chromatography (e.g., silica gel flash chromatography), reverse phase chromatography (e.g., high performance liquid chromatography (HPLC)), precipitation, decanting, filtration, centrifuge, trituration, crystallization, recrystallization, liquid-liquid phase separation, evaporation, and drying.

(329) Another aspect of the present disclosure relates to nanostructures, supramolecular complexes, and compositions (e.g., gels) prepared by a method described herein. In certain embodiments, described herein are supramolecular complexes prepared by Method B, wherein the macromer is of Formula (B-1), (B-2), (B-3), or (B-4); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof, and optionally the molar ratio of the macromer to the transition metal salt is about 1:1. In certain embodiments, described herein are supramolecular complexes prepared by Method B, wherein the macromer is of Formula (C-1) or (C-2); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1.

(330) In certain embodiments, described herein are gels prepared by Method C. In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-1), (B-2), (B-3), or (B-4); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is water, DMSO, acetonitrile, or a mixture thereof (e.g., an about 1:1 (v:v) mixture of water and acetonitrile); and optionally the concentration of the macromer is between about 5 and about 500 millimoles per liter of the fluid (e.g., between about 5 and about 100 millimoles per liter of the fluid), inclusive; and optionally the step of complexing is performed at a temperature of between about 20 C. and about 100 C. (e.g., between about 20 C. and about 80 C.), inclusive.

(331) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-1); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2, [(MeCN).sub.4Pd.sup.2+](BF.sub.4.sup.).sub.2, or a Pd(II) salt that is not Pd(OAc).sub.2), a Ni(II) salt, or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is DMSO, water, acetonitrile, or a mixture thereof and optionally the concentration of the macromer is at least 5 millimoles per liter of the fluid (e.g., between 5 and 100 millimoles per liter of the fluid, inclusive; or between 15 and 100 millimoles per liter of the fluid, inclusive); and optionally the step of complexing is performed at a temperature of between 60 C. and 80 C., inclusive (e.g., about 70 C.).

(332) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-2); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2, [(MeCN).sub.4Pd.sup.2+](BF.sub.4.sup.).sub.2, or a Pd(II) salt that is not Pd(OAc).sub.2), a Ni(II) salt, or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is DMSO, water, acetonitrile, or a mixture thereof; and optionally the concentration of the macromer is at least 5 millimoles per liter of the fluid (e.g., between 5 and 100 millimoles per liter of the fluid, inclusive; or between 15 and 100 millimoles per liter of the fluid, inclusive); and optionally the step of complexing is performed at a temperature of between 60 C. and 80 C., inclusive (e.g., about 70 C.).

(333) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-3); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), or a solvate or hydrate thereof, and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is water, and optionally the concentration of the macromer is at least 14 millimoles per liter of the fluid (e.g., between 14 and 100 millimoles per liter of the fluid, inclusive); and optionally the step of complexing is performed at a temperature of between 20 C. and 30 C., inclusive (e.g., about 23 C.).

(334) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-4); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is water, and optionally the concentration of the macromer is at least 9.5 millimoles per liter of the fluid (e.g., between 9.5 and 100 millimoles per liter of the fluid, inclusive); and optionally the step of complexing is performed at a temperature of between 20 C. and 30 C., inclusive (e.g., about 23 C.).

(335) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (B-4); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is water, and optionally the concentration of the macromer is at least 9.5 millimoles per liter of the fluid (e.g., between 9.5 and 100 millimoles per liter of the fluid, inclusive); and optionally the step of complexing is performed at a temperature of between 60 C. and 80 C., inclusive (e.g., about 70 C.).

(336) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (C-1) or (C-2); and optionally the transition metal salt is a Pd(II) salt (e.g., Pd(NO.sub.3).sub.2), Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is water, DMSO, acetonitrile, or a mixture thereof (e.g., an about 1:1 (v:v) mixture of water and acetonitrile); and optionally the concentration of the macromer is between about 5 and about 500 millimoles per liter of the fluid (e.g., between about 10 and about 100 millimoles per liter of the fluid), inclusive; and optionally the step of complexing is performed at a temperature of between about 40 C. and about 100 C. (e.g., between about 60 C. and about 80 C.), inclusive.

(337) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (C-1); and optionally the transition metal salt is a Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is acetonitrile; and optionally the concentration of the macromer is at least 10 millimoles per liter of the fluid (e.g., between about 10 and about 100 millimoles per liter of the fluid), inclusive; and optionally the step of complexing is performed at a temperature of between about 20 C. and about 30 C., inclusive (e.g., about room temperature).

(338) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (C-1) or (C-2); and optionally the transition metal salt is a Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is acetonitrile.

(339) In certain embodiments, the gel is a gel prepared by method C, wherein the macromer is of Formula (C-1) or (C-2); and optionally the transition metal salt is a Ni(II) salt (e.g., Ni(ClO.sub.4).sub.2), Fe(II) salt (e.g., Fe(ClO.sub.4).sub.2), or a solvate or hydrate thereof; and optionally the molar ratio of the macromer to the transition metal salt is about 1:1; and optionally the fluid is an about 1:1 (v:v) mixture of water and acetonitrile.

(340) In certain embodiments, described herein are gels prepared by Method C, wherein the step of complexing of Method C further comprises the presence of an agent (e.g., a small molecule, such as an anticancer agent (e.g., doxorubicin)). The nanostructures, supramolecular complexes, and gels described herein may also be modified to covalently attach to a -linker- agent moiety, and the resulting modified nanostructures, supramolecular complexes, and gels are also within the scope of the present disclosure. In certain embodiments, the linker is a diradical of a peptide (e.g., a peptide of not more than 5, not more than 10, not more than 30, or not more than 100 amino acid residues). In certain embodiments, the linker is biodegradable. In certain embodiments, the linker is cleavable by an enzyme under physiological conditions. In certain embodiments, the linker is -Ile-Phe-Gly-. In certain embodiments, the agent is a monoradical of a pharmaceutical agent (e.g., therapeutic agent or diagnostic agent). In certain embodiments, the pharmaceutical agent is an pharmaceutical agent approved by the FDA for use in a human or animal.

(341) Methods of Treatment and Uses

(342) One of the major problems in the development of formulations of pharmaceutical agents (e.g., anti-cancer agents) is the delivery of the pharmaceutical agents with adequately high bioavailability for therapeutic intentions. Using conventional delivery techniques, many pharmaceutical agents cannot be delivered effectively to the target tissues or target cells. Gels, such as hydrogels, have emerged as an important class of materials for biomedical applications due to their unique properties that bridge the gap between solid and liquid states. The gels described herein are advantageous over conventional gels that typically include a covalently cross-linked polymer network at least because the molecular network of a gel described herein is formed at least by non-covalent interactions, such as complexation of a ligand and a transition metal ion, and thus is thermoreversible, able to flow (e.g., under a high shear stress), and able to self-heal when damaged. An agent may be encapsulated in a gel described herein (e.g., encapsulated in a nanostructure moiety of a supramolecular complex of the gel) and is delivered to a tissue or cell (e.g., a target tissue or target cell). The gel may dissociate in the tissue or cell to release the agent to the tissue or cell. In certain embodiments, a nanostructure moiety of a supramolecular complex of the gel dissociates (e.g., by breaking the coordination bonds between (1) the ligands of Formula (A) or macromers of Formula (B) or (C) and (2) the transition metal ions, and optionally by breaking divalent linkers Y by, e.g., hydrolysis) to release the agent that was encapsulated in the nanostructure moiety before the dissociation. The gels described herein are also advantageous over conventional nanoparticles at least because the gels described herein are more robust and has higher storage modulus than the conventional nanoparticles.

(343) In another aspect, the present disclosure provides methods of delivering an agent described herein (e.g., small molecule) to a subject, tissue, or cell. In certain embodiments, described herein are methods of delivering the agent to a target tissue or target cell described herein. In certain embodiments, described herein are methods of selectively delivering the agent to a target tissue, compared to a non-target tissue. In certain embodiments, described herein are methods of selectively delivering the agent to a target cell, compared to a non-target cell. In certain embodiments, the agent is delivered into the subject, tissue, or cell by the methods described herein. In certain embodiments, the agent is selectively delivered into the target tissue or target cell by the methods described herein, compared to a non-target tissue or non-target cell, respectively.

(344) Another aspect of the present disclosure relates to methods of increasing the delivery of an agent to a subject, tissue, or cell. In certain embodiments, the delivery of the agent to the subject, tissue, or cell is increased by a method described herein. In certain embodiments, the delivery of the agent to the subject, tissue, or cell by a method described herein is increased compared to the delivery of the agent to the subject, tissue, or cell by a control method that does not involve a composition described herein.

(345) In another aspect, the present disclosure provides methods of treating a disease described herein in a subject in need thereof.

(346) In another aspect, the present disclosure provides methods of preventing a disease described herein in a subject in need thereof.

(347) In certain embodiments, a disease described herein is a genetic disease. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is a benign neoplasm. In certain embodiments, the disease is pathological angiogenesis. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an autoimmune disease. In certain embodiments, the disease is a hematological disease. In certain embodiments, the disease is a neurological disease. In certain embodiments, the disease is a gastrointestinal disease. In certain embodiments, the disease is a liver disease. In certain embodiments, the disease is a spleen disease. In certain embodiments, the disease is a respiratory disease. In certain embodiments, the disease is a lung disease. In certain embodiments, the disease is a painful condition. In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition is associated with an inflammatory disorder and/or an autoimmune disorder. In certain embodiments, the disease is a genitourinary disease. In certain embodiments, the disease is a musculoskeletal condition. In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is a psychiatric disorder. In certain embodiments, the disease is a metabolic disorder. In certain embodiments, the disease is hepatic carcinoma. In certain embodiments, the disease is hypercholesterolemia. In certain embodiments, the disease is refractory anemia. In certain embodiments, the disease is familial amyloid neuropathy.

(348) Another aspect of the present disclosure relates to methods of genetically engineering a subject. In certain embodiments, the subject is genetically engineered to increase the growth of the subject. In certain embodiments, the subject is genetically engineered to increase the subject's resistance to pathogenic organisms and/or microorganisms (e.g., viruses, bacteria, fungi, protozoa, and parasites).

(349) In certain embodiments, a method described herein includes administering to the subject a composition described herein. In certain embodiments, a method described herein includes administering to the subject an effective amount of a composition described herein.

(350) In certain embodiments, a method described herein includes contacting the tissue with a composition described herein. In certain embodiments, a method described herein includes contacting the tissue with an effective amount of a composition described herein.

(351) In certain embodiments, a method described herein includes contacting the cell with a composition described herein. In certain embodiments, a method described herein includes contacting the cell with an effective amount of a composition described herein.

(352) In certain embodiments, a subject described herein is a human. In certain embodiments, the subject is an animal. In certain embodiments, the subject is a non-human animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a fish. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal. In certain embodiments, the subject is a human with a disease described herein. In certain embodiments, the subject is a human suspected of having a disease described. In certain embodiments, the subject is a human at risk of developing a disease described herein.

(353) In certain embodiments, a cell described herein is in vivo. In certain embodiments, a cell described herein is in vitro.

(354) Another aspect of the present disclosure relates to uses of a nanostructure described herein in a method described herein (e.g., uses for delivering an agent to a subject, tissue, or cell; uses for treating a disease in a subject in need thereof; and uses for preventing a disease in a subject).

(355) Another aspect of the present disclosure relates to uses of a supramolecular complex described herein in a method described herein (e.g., uses for delivering an agent to a subject, tissue, or cell; uses for treating a disease in a subject in need thereof; and uses for preventing a disease in a subject).

(356) Another aspect of the present disclosure relates to uses of a composition (e.g., gel) described herein in a method described herein (e.g., uses for delivering an agent to a subject, tissue, or cell; uses for treating a disease in a subject in need thereof; and uses for preventing a disease in a subject).

EXAMPLES

(357) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the nanostructures, supramolecular complexes, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

(358) Preparation of the Nanostructures, Supramolecular Complexes, and Compositions (e.g., Gels)

(359) The nanostructures, supramolecular complexes, and compositions (e.g., gels) described herein can be prepared from readily available starting materials using the following general methods and procedures (e.g., the methods shown in any one of Schemes 1 to 4). It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization.

(360) ##STR00082##

(361) In Scheme 1, each instance of U is independently an organoboron moiety (e.g., B(OH).sub.2, a borate moiety

(362) ##STR00083##
and each instance of V.sup.A and V.sup.B is independently halogen (e.g., Cl, Br, or I) or OTf.

(363) ##STR00084##

(364) ##STR00085##

(365) ##STR00086##

Example 1. Preparation and Characterization of Ligand B-1

(366) In an exemplary set of experiments, diacids

(367) ##STR00087##
such as

(368) ##STR00088##
were synthesized according to the method shown in Scheme 5 (see, e.g., U.S. Pat. No. 8,067,505), wherein the number-average molecular weight (M.sub.n) of the PEG moiety

(369) ##STR00089##
was about 2 kDa, 4.6 kDa, 6 kDa, 10 kDa, 25 kDa, and 35 kDa. The yields were at least about 80%.

(370) ##STR00090##

(371) In an exemplary set of experiments, diacid

(372) ##STR00091##
was synthesized according to the method shown in Scheme 6 in a 92.4% yield, and the product was pure by .sup.1H NMR and mass spectroscopy (MALDI-TOF).

(373) ##STR00092##

(374) In an exemplary set of experiments, telechelic bromo-poly(n-butyl acrylate) (telechelic bromo-pNBA) with a M.sub.n of 4.2 kDa (degree of polymerization (DP) was about 30; and polydispersity (PDI) was about 1.13 as determined by GPC) or 13.9 kDa (DP was about 106); and PDI was about 1.08 as determined by GPC).

(375) In an exemplary set of experiments, ligand B-1 was prepared according to the method shown in Scheme 7. An exemplary .sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) is shown in FIG. 12.

(376) ##STR00093##

Example 2. Preparation and Characterization of Nanosphere I-1

(377) In an exemplary set of experiments, nanosphere I-1 was prepared according to the method in Scheme 3, steps (b-1) and (b-2), wherein the ligand of Formula (A) was ligand A-1, and the Pd(II) salt was Pd(NO.sub.3).sub.2. To a 2-mL vial with A-1 (13.13 mg, 0.05006 mmol) dissolved in 366.7 L of DMSO-d.sub.6 was added via micropipette a solution of Pd(NO.sub.3).sub.2.2H.sub.2O (6.67 mg, 0.02503 mmol) in 133.3 L of DMSO-d.sub.6. The head-space of the vial was briefly purged with argon, the vial was closed with a screw-cap, and the resultant mixture was immediately vortexed, giving rise to a light-yellow liquid with small gelatinous pieces dispersed in it. The mixture was heated at 70 C. for 8 h, during the course of which, it became a light yellow homogeneous solution. A liquid was formed, which contained predominantly one supramolecular species. An exemplary .sup.1H NMR spectrum (DMSO-d.sub.6) of the resulting nanosphere I-1 evidenced the formation of nanospheres. Exemplary MTT proliferation assay results of nanosphere I-1 using HeLa cells are shown in FIG. 14, which indicate that nanosphere I-1 was toxic to HeLa cells with an IC.sub.50 of 7.9 M.

Example 3. Preparation and Characterization of Supramolecular Complexes and Gels

(378) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method of FIG. 1A. The formation of the supramolecular complexes and gels were evidenced by .sup.1H NMR (FIG. 1C). Gelation was virtually instantaneous at the sites where the reactants came into contact. After the reaction mixture was heated at 70 C. for 8 hours or 80 C. for 4 hours, it became homogeneous. When ligand B-2 and Pd(NO.sub.3).sub.2 were combined at a concentration of 0.01 M with a 15% excess of ligand B-2, the reaction mixture became a homogeneous liquid after heating at 100 C. overnight; the .sup.1H NMR spectrum of the resulting mixture suggested formation of nanospheres. The rate of gelation can be tuned by adjusting the reactivity of the transition metal (e.g., Pd(II)) salt. In some cases, the more labile the counterion of the transition metal salt, the more rapid the gelation is. Pd(NO.sub.3).sub.2 and [(MeCN).sub.4Pd.sup.2+](BF.sub.4.sup.).sub.2 resulted in rapid gelation, while no gelation was observed seen when Pd(OAc).sub.2 was used. In some cases, the counterion of the transition metal salt is a non-coordinating counterion. In some cases, the counterion of the transition metal salt provides a sufficient kinetic barrier to reduce the rate of gelation. For instance, is was observed that 3-chloropyridine can be used as such an auxiliary ligands that can be used with a Pd(II) salt. See, e.g., Scheme 3. From the frequency sweeps spanning 0.1 and 100 rad/s, shortly after mixing of all the reaction components, a storage modulus G of about 16-21 kPa and a about 15-fold lower G (0.74-1.4 kPa) were observed (FIGS. 21A and 5B), confirming that the observed gelation had, indeed, taken place. During the subsequent heating stage at 70 C., G dropped, reaching a plateau after 5 hours at 8.8-11 kPa; G, on the other hand, increased to 3.7-5.5 kPa. Thus, the reaction mixture remained a gel, but it lost a significant amount of elasticity and became more liquid-like. These observations are consistent with the hypothesis that upon mixing ligand B-2 and Pd(NO.sub.3).sub.2, a largely random network is formed, and during the heating stage, this network transformed to linked nanospheres through reversible coordination of the Pd(II) ions with the nitrogen atoms labeled with 1 and 1 of the pyridinyl moieties. Because of the small size of the PEG2000 divalent linkers and the relatively large size of the nanospheres, as well as the fact that there were 24 PEG2000 divalent linkers extending from each nanosphere, it may be very difficult to have each chain link two different nanospheres. Thus, loopy nanospheres may have formed, which led to a reduced G and elevated G.

(379) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method of FIG. 2C, where the concentration of ligand B-2 in DMSO-d.sub.6 was 0.025 M. The reaction (gelation) was monitored by measuring the rheology (e.g., shear storage modulus and shear loss modulus) of the reaction mixture using equipment shown in FIG. 2B. The results were shown in FIG. 2A, where the shear rate was 10 rad/s, and the reaction temperature was 70 during the duration of the experiment. The results of the reaction mixture at 70 C. were fitted to exponential curves.

(380) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method of FIG. 1A, wherein the reaction temperature and time duration were according to FIGS. 3A and 3B. The formation of the supramolecular complexes and gels were evidenced by .sup.1H NMR (FIGS. 3A and 3B).

(381) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method of FIG. 1A, wherein the concentration of ligand B-2 were as provided in FIGS. 4A and 4B, and the reaction temperature was room temperature (FIG. 4A) and 70 C. (FIG. 4B). Also shown in FIGS. 4A and 4B are images of the reaction mixtures, which indicate that reaction mixtures containing 15 mM or 25 mM of ligand B-2 in DMSO-d.sub.6 were able to form gels, whereas reaction mixtures containing 10 mM or 5 mM of ligand B-2 in DMSO-d.sub.6 were not able to form gels. FIG. 4C shows the rheology of gels formed from different concentrations of ligand B-2.

(382) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method of FIG. 1A, wherein ligand B-2 was partially replaced with ligand A-1, wherein the mole amount of ligand A-1 was twice the mole amount of ligand B-2 that was replaced by ligand A-1. Exemplary modulus and shear viscosity results are shown in FIGS. 5B and 5C. Even replacement of 80% of ligand B-2 with 2 equivalents of ligand A-1, a gel was still formed.

(383) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method in Scheme 4, wherein the Pd(II) salt was Pd(NO.sub.3).sub.2, and the concentration of ligand B-1 in DMSO was 5 mM (gel III-5), 10 mM (gel III-6), or 100 mM (gels III-1 to III-4). Exemplary .sup.1H NMR spectra are shown in FIG. 9A (gel III-5) to 9B (gel III-6). Differential scanning calorimetry (DSC) experiments were performed on the gels prepared from 100 mM solutions. The reaction mixtures were quenched at 0 min (gel III-1), 2.5 h (gel III-2), 5.5 h (gel III-3), and 8.5 h (gel III-4), respectively, by addition of diethyl ether to the reaction mixtures to extract DMSO and provide a poor solvent. The DSC graphs showed a melting transition for gel III-1 at about 40 C., corresponding to PEG melting. No melting transition was observed for gels III-2 to III-4. The gels (gel III-5) obtained from a 5 mM solution was dialyzed against water (2700 mL). The gels all turned from purple to orange upon addition of an aqueous solution of Ni(ClO.sub.4).sub.2. Similar results were obtained when B-2 was used instead of B-1.

(384) In another exemplary set of experiments, supramolecular complexes and gels were prepared according to the method in FIG. 15A. The concentration of ligand C-1 in acetonitrile was 10 mM. Initial rheology measurements indicated that gelation was completed within seconds. Oscillatory rheology measurements in a frequency sweep from 0.1-628 rad/s over 100 minutes showed that G had already crossed G before the first measurement (FIG. 15B). After mixing all the reactants and reagents, a storage modulus was measured to be close to 110.sup.6 Pa, and a loss modulus was measured to be 110.sup.5 Pa, which are high moduli for networks whose junctions are presumably dynamic. The increase in G and G after 43.9 minutes may be attributed to evaporation of the solvent. The supramolecular complexes and gels may be formed through junction self-assembly as shown in FIG. 15C. The gelation as indicated by the shear viscosity of the reaction mixture over reaction time is shown in FIG. 11A. FIG. 11A indicates that the gel formed at different rates for different solvents (immediately for MeCN and after about 2 hrs for water). The frequency sweep as indicated by a plot of shear storage modulus (G) and shear loss modulus (G) of the gel versus the strain () is shown in FIG. 11B. FIGS. 11A and 11B indicate that the different solvents affected the kinetics of the gel formation (e.g., the kinetics of forming the secondary structure of the gel) but did not show a clear effect on the frequency behavior of the gel.

(385) In another exemplary set of experiments, supramolecular complexes or gels were not formed using the method in Scheme 4, wherein the Pd(II) salt was replaced with a Zn(II) salt (e.g., Zn(ClO.sub.4).sub.2), and the molar ratio of ligand B-1 or B-2 to the Zn(II) salt was 2:1 or 3:1.

Example 4. Preparation and Characterization of Loopy Nanospheres

(386) In another exemplary set of experiments, loopy nanospheres were prepared according to the method in FIG. 13A, wherein the concentration of ligand B-1 in DMSO-d.sub.6 was below 10 mM. The formation of loopy nanospheres was evidenced by .sup.1H NMR and DLS results (FIG. 13B). The average diameter Dh of the PEG moieties of ligands B-1 was about 2.5 nm, and the average diameter of the nanosphere without the PEG moieties was about 2.8 nm.

Example 5. Preparation and Characterization of Supramolecular Complexes and Gels, Each of which Contained Doxorubicin

(387) Bright red supramolecular complexes and gels were formed by heating in DMSO-d.sub.6 at 70 C. for 1 day a solution of ligand B-2 (100 mM) and Pd(NO.sub.3).sub.2.H.sub.2O in the presence of doxorubicin (100 mM). An image of the resulting gel is shown in FIG. 6B. The gel of FIG. 6B four times with DMSO-d.sub.6 (4300 mL) an image of the gel after the extractions is shown in FIG. 6C, and images of the four extracts are shown in FIG. 6D. Unencapsulated doxorubicin was removed by extraction with fresh DMSO-d.sub.6, leaving a light-red gel with encapsulated doxorubicin. While the color of the first DMSO-d.sub.6 extract was bright red, the subsequent extracts had virtually identical faint-orange color, indicating that an approximately constant low level of doxorubicin was released each time after the first wash. This observation is consistent with expected encapsulation and subsequent slow release of the doxorubicin from the nanospheres in the formed supramolecular complexes and gels.

Example 6. Solution Assembly of Ligands L1 and L2

(388) Prior to the formation of suprametallogels, it was first sought to confirm that L1 and L2 form the expected Pd.sub.12L.sub.24 and Pd.sub.2L.sub.4 assemblies, respectively. Exposure of L1 to Pd(NO.sub.3).sub.2. 2H.sub.2O in DMSO-d.sup.6 (0.100 M) initially provided a gelatinous mixture characterized by highly broadened downfield-shifted peaks in the .sup.1H NMR spectrum (FIG. 17A). This mixture transformed into a clear light-yellow solution upon heating for 8 h at 70 C. The .sup.1H NMR spectrum of this solution contained one set of broad ligand-based resonances consistent with a highly symmetric nanoscopic assembly (FIG. 17A); the resonances in the aromatic region were shifted downfield compared to those of L1, and the corresponding chemical shifts were virtually identical to those reported previously by Fujita and coworkers for methanofullerene-functionalized spheres constructed from the same ligand..sup.50

(389) Likewise, upon mixing L2 with Pd(NO.sub.3).sub.2.2H.sub.2O in DMSO-d.sup.6 (0.100 M), a mixture of different L2-Pd.sup.2+ species was obtained as gathered from the presence of many sets of ligand-based resonances in the aromatic region of the .sup.1H NMR spectrum (FIG. 17B). Remarkably, upon annealing for 2 h at 70 C., this mixture coalesced into a single highly symmetric small assembly, as inferred from the single set of slightly broadened ligand-based resonances in the .sup.1H NMR spectrum (FIG. 17B). Annealing for 8 h at 100 C. afforded an identical spectrum, implying that the assembly is stable under these conditions. Fourier transform ion cyclotron resonance (FT-ICR) electron spray ionization mass spectrometry (ESI-MS) exhibited a dominant species with mass/charge (m/z) corresponding to the triply cationic paddlewheel mono-nitrate. X-ray crystallography confirmed the M.sub.2L.sub.4 paddlewheel connectivity of this assembly (FIG. 17C)..sup.69 Considered collectively, these data confirm that both L1 and L2 initially form complex mixtures of assemblies upon exposure to Pd(NO.sub.3).sub.2.2H.sub.2O in DMSO-d.sup.6 at room temperature, and that these mixtures quantitatively convert to well-defined assemblies under thermodynamic control.

Example 7. Preparation of Suprametallogels Using (1) B-3 or B-4 and (2) Pd(NO3)2.2H2O; and Annealing Experiments of the Suprametallogels

(390) L1 and L2 were coupled onto the ends of carboxylic acid terminated 2.2 kDa polyethylene glycol (PEG) to generate macromers B-3 and B-4, respectively (FIG. 16C). Exposure of B-3 to Pd(NO.sub.3).sub.2.2H.sub.2O at in DMSO-d.sub.6 23 C. resulted in immediate gelation when [Pd.sup.2+]=[B-3]14 mM (0.043 g/mL). Macromer B-4 formed gels at all concentrations tested above 9.5 mM (0.026 g/mL).

(391) In an exemplary preparation, to a 1-dram scintillation vial was added 20.25 mg (7.5 mol) of macromer (B-3 or B-4) and then 210.0 L DMSO-d.sup.6. In a 2-mL scintillation vial, a stock solution of Pd(NO.sub.3).sub.2.2H.sub.2O in DMSO-d.sup.6 was prepared at a concentration of 11.1 mg Pd(NO.sub.3).sub.2.2H.sub.2O per 1.00 mL DMSO-d.sup.6 (after vortexing for 1 min, a clear orange solution forms). 90 L of this solution was transferred via micropipette to the solution of the macromer, and gelation was observed immediately, although the gel coloration is inhomogeneous. The headspace of the vial is briefly purged with argon, the vial is sealed, and heated at 80 C. for 4 h to give rise to a homogeneous light-yellow gel (translucent if derived from B-4, opaque if derived from B-3). Molarity of macromer in the gel (in this case 24 mM) was determined by dividing the number of moles of the macromer used by the total volume of the gel, accounting for the non-negligible contribution of the polymer to the total volume.

(392) The observation that the paddlewheel-former B-4 gels at a significantly lower concentration compared to B-3 suggests that that even upon initial mixing, gels derived from B-3 and B-4 have fundamentally different network structures despite their identical composition.

(393) Based on the solution assembly studies described above, it was expected that gels formed upon immediate mixing of B-3 or B-4 and Pd.sup.2+ at room temperature are crosslinked through a complex mixture of branched coordination polymers rather than the well-defined target assemblies. Thus, these gels were annealed under conditions similar to those used to induce self-assembly of the free ligands. The annealing process was monitored by variable temperature .sup.1H solid state NMR (VT .sup.1H ssNMR) spectroscopy (FIGS. 18 and 19). In the case of paddlewheel-former B-4, the spectra revealed a transformation similar to that observed for free ligand L2: prior to annealing there were multiple sets of ligand-derived resonances in the .sup.1H ssNMR spectrum, which coalesced and sharpened into single resonances that mapped closely onto the solution .sup.1H NMR spectrum of the L2-based paddlewheels. These data suggest that the network junctions are converted into symmetric, paddlewheel structures within 1 h at 70 C.

(394) In the case of gels prepared from macromer B-3, structural changes upon thermal annealing by ssNMR could not be resolved due to significant peak broadening (FIG. 19B). However, the peaks of these resonances have the same chemical shifts as those observed in solution .sup.1H NMR spectra of spheres formed from free L1 after annealing (FIG. 17A) and also soluble, nanoscale coordination polymers formed from mixing B-3 with Pd.sup.2+ at very high dilution followed by annealing (FIG. 19A, inset cryo-TEM image shows nanoscale coordination polymers of B-3 and Pd.sup.2+ formed at high dilution). Nevertheless, while the self-assembly of M.sub.12L.sub.24 cage-like junctions may occur in these gels,.sup.70 this cannot be confirmed conclusively from ssNMR. Branched assemblies, which may consist of sphere fragments or larger (>24 ligand) clusters, could lead to similar ssNMR spectra. Regardless, these data clearly demonstrate that the choice of meta-versus para-pyridine ligands gives rise to networks with significantly different structure.

Example 8. Simulations of Assembly and Gelation Processes

(395) To gain deeper insight into the impact of ligand identity on network assembly, it was turned to computer simulation (FIGS. 20A and 16B). Our approach extended the molecular dynamics simulations of Yoneya and Fujita.sup.71,72 in which the details of metal-ligand binding were captured empirically through Coulombic interactions, and mediated by an implicit solvent. This model.sup.71 have been adapted to include the meta-substituted version of the bis-pyridine ligand and the ability to simulate the case where individual pairs of ligands are attached to each other via a long flexible polymer chain. Our scheme for generating trajectories, which was chosen to mimic the sudden introduction of Pd.sup.2+ into a well-mixed solution of ligands, involved propagating a randomly distributed mixture of metal ions and ligand molecules under experimental conditions (e.g., temperature and concentration). As illustrated in FIG. 20A, simulations consisted of 98 metal ions and 192 bis-pyridine ligand molecules (or 96 ligand-terminated macromers) in a periodically replicated cubic simulation box with a volume of 6540 nm.sup.3. Five different trajectory ensembles were generated corresponding to the assembly of cage-forming ligands (L-para), paddlewheel-forming ligands (L-meta), L1-terminated 2.2 kDa PEG (macromer B-3), and L2-terminated 2.2 kDa PEG (macromer B-4). A more detailed description of our simulations, which are nearly identical to those presented in Reference 71,.sup.71 are presented in the supporting information. In our analysis, cluster size was refer to in terms of the number of ligands in a given metal-ligand cluster, denoted with the quantity y as in M.sub.xL.sub.y. Our particular focus is on the relationship between ligand identity (i.e., meta- or para-substituted bis-pyridine) and metal-ligand cluster formation, how that relationship is affected by the linking of monomers by flexible polymer chains, and finally in characterizing the inter-cluster connectivity (as it relates to gelation) that accompanies the spontaneous assembly of tethered ligand dimers. Below, the solution assembly of Pd.sup.2+ and ligand monomers are described, and the network-forming consequence of linking monomers with flexible polymer chains is discussed.

Example 9. Solution Assembly of Free Ligands L-Para and L-Meta

(396) Trajectories initialized with randomly distributed ligand and metal ion positions exhibit the rapid formation of relatively unstable metal-ligand clusters followed by the slow annealing of the cluster morphology as the system evolves towards a more thermodynamically favorable configuration. This behavior is illustrated in FIG. 20B, which contain plots of the time-dependent (over 1 s) average cluster size,

(397) $\stackrel{\_}{y}\left(t\right)=\frac{1}{N\left(t\right)}\underset{i=1}{\overset{N\left(t\right)}{.Math.}}{y}_i\left(t\right),$
where the summation is taken over all of the N(t) clusters that exist at time t, and y.sub.i(t) is the number of ligands present in the i.sup.th cluster at time t. More specifically, the black and grey lines correspond to the average cluster size in solutions containing L-para and L-meta ligands, respectively. While both systems exhibit a clear separation of timescales between initial cluster formation (t100 ns) and the subsequent annealing of network morphology (t200 ns), the average cluster size for the sphere-forming L-para ligand (4020) is significantly larger than that of the paddlewheel-forming L-meta ligands (6.30.5). The origin of this difference can be understood by considering the cluster size distributions (FIG. 20C). FIG. 20C shows histograms of the probability, P.sub.y, that at time t1 s, a given ligand belongs to a cluster with size y. The results for the cage-forming L-para ligand (shown in black), indicate that there is not a particularly strong preference for the formation of the schematic target M.sub.12L.sub.24 cluster (such as the one shown in FIG. 16B), which is consistent with the findings of Yoneya and Fujita..sup.71 In fact, the distribution of cluster sizes for L-para clusters after 1 s is broad and, for the concentration that has been considered, predicts the prevalence of very large clusters such as those shown in FIG. 20A, far left. In stark contrast, for the paddlewheel-forming L-meta ligand P.sub.y is narrowly distributed and peaked at y=4 (see FIG. 20C), which corresponds to the schematic target M.sub.2L.sub.4 paddlewheel shown in FIG. 16B. Such clusters are also readily observed in FIG. 20A, second from the left. Taken together, these simulated results support the key notion underlying our suprametallogel design: the geometry of L-para facilitates the formation of large clusters while L-meta exhibits a strong preference for small M.sub.2L.sub.4 clusters. It should be noted, however, that it has been observed the occasional presence of system-spanning L-pra clusters, which is an indication that our results may contain artifacts due to system size effects, for example in the preferential stabilization of clusters that are large enough to interact with themselves through the periodic boundaries of our simulation. Indeed when simulations were perform at lower concentration (larger simulation cell), a significantly reduced probability for the formation of large (y>60) clusters was observed. These effects, combined with our inability to simulate the long timescales associated with the real assembly process, contribute to a lower than expected yield of M.sub.12L.sub.24 clusters based on experimental observation. In fact, our simulations more likely reflect the experimental systems prior to annealing (FIGS. 17A to 17C).

Example 10. Simulating the Assembly of Suprametallogels

(398) To investigate suprametallogel formation, simulations were performed in which pairs of ligand monomers were tethered together via a model flexible polymer chain (see FIG. 20A, right). The polymer chain was described implicitly in the form of a ligand-ligand pair potential that exerted a bias on the relative position of bound ligands. This bias potential, equal to the potential of mean force governing the end-to-end distance of a three-dimensional self-avoiding random walk, was chosen to mimic details of the PEG chains used in our experiments (e.g., macromers B-3 and B-4). Similar to the free ligand simulations described above, trajectories were initiated from configurations with randomly distributed metal ions and macromers whose end-ligands were initially separated by the mean end-to-end distance of the model polymer chains. FIG. 20A shows snapshots of suprametallogels derived from macromers B-3 and B-4.

(399) The average cluster size y and the cluster size distributions P.sub.y for macromers B-3 and B-4 are shown along side the free ligand results in FIGS. 20B and 20C. It was found that the qualitative difference between y for the para- and meta-pyridine based ligands, specifically on the tendency for para- to form a broad distribution of larger clusters and meta- to form a narrow distribution of small clusters, is preserved upon the addition of a flexible polymer tether. For both species, however, the presence of a polymer linker tends to favor the formation of smaller clusters (relative to the free ligands) and thereby lower y (FIG. 20B); after 1 s networks comprised of macromers B-3 and B-4 display y values (y.sub.1 and y.sub.2, respectively) of 216 and 5.30.7. It is clear from FIG. 20B, however, that the L-para based systems are not in a state of dynamic equilibrium after 1 s. Thus, it cannot be distinguished whether the decrease in average cluster size upon addition of a polymer linker is the result of a thermodynamic shift in cluster size distribution or rather due to retardation of network relaxation. Based upon the results from L-meta based clusters, it was hypothesized that the effect is kinetic in nature, but ultimately the resolution requires longer simulations. Nonetheless, these results confirm that the assembly preferences between para-versus meta-substituted pyridine ligands effectively translate into suprametallogels, and corroborate the NMR results discussed above.

Example 11. Analysis of Network Connectivity and Elastically Inactive Defects

(400) To explain the unique mechanical properties of suprametallogels, simulations were expanded to include analysis of key network defects that impact bulk mechanical properties. Specifically, the interconnectivity of metal-ligand clusters was computed, and quantifying the elastically inactive primary cyclic, or loop defects, was focused on, that are formed when both ligand ends of a single macromer belong to the same assembled metal-ligand cluster. For a given cluster with y ligands, the quantity .sub.L has been computed, which is the density of ligands in that cluster that are members of loop defects. FIG. 20D shows plots of the average value of .sub.L as a function of cluster size for macromers B-3 and B-4. Our simulations have a finite number of macromers, and thus there is a trivial correlation between loop density and cluster size that can be understood by considering clusters composed of randomly selected ligands. In this case, loop density is expected to scale linearly with cluster size between the trivial end points, .sub.L=0 for y=1 and .sub.L=1 for y=192 (black curve, FIG. 20D). In suprametallogels comprised of B-3 and B-4 it was found that loop formation increases rapidly with cluster size. Furthermore, there is a slightly greater prevalence of loops for B-3 compared to B-4. Keeping in mind that networks comprised of B-3 contain a broad range of cluster sizes, including very large ones, and that networks comprised of B-4 feature small, fairly uniform clusters, the data presented in FIG. 20D provides a critical insight: networks comprised of B-3 have a much greater prevalence of elastically inactive loop defects compared to networks comprised of B-4 (see arrows, FIG. 20D).

Example 12. Mechanical Properties of Suprametallogels

(401) The data described above supports our initial hypothesis that metallosupramolecular assembly induced gelation of polymers bearing isomeric bis-pyridine ligands can provide suprametallogels with dramatically different structure based on tuning the average cluster size, e.g., branch functionality. It was next sought to assess the impact of these structural differences on bulk suprametallogel mechanical properties. Oscillatory rheology was used to monitor the storage and loss moduli (G and G, respectively) for 6.3 wt. % gels derived from B-3 and B-4 as a function of oscillation angular frequency (w) and strain both before and after thermal annealing.

(402) As shown in FIGS. 21A to 21D, these gels behaved as elastic solidstheir G values were always larger than their G valuesover the entire range of tested frequencies both before and after annealing. Thus, these suprametallogels do not display a viscous flow regime at low frequencies at 25 C. Despite this similarity, other mechanical properties of the gels were strikingly different. For example, prior to thermal annealing, the high-frequency G of gels based on sphere-former B-3 (123 kPa, FIG. 21A) was a factor of four greater than that of gels based on paddlewheel-former B-4 (3.00.5 kPa, FIG. 21B). This observation implies a significantly greater average elastically active junction functionality, e.g., cluster size, in gels based on B-3 prior to annealing, which agrees well with our NMR and molecular dynamics simulations..sup.73

(403) Upon thermal annealing, a decrease was observed in the high frequency G value for both sets of gels; the final G values were 5.20.3 kPa and 1.90.2 kPa for suprametallogels derived from B-3 and B-4, respectively (FIGS. 21A and 21B, grey curves). Notably, this decrease is greater for networks derived from B-3. Our simulations show that systems based on para-ligands initially have a broad distribution of cluster sizes with many clusters that can be much larger than the target 24 ligands, whereas those based on meta-ligands are more narrowly distributed near the target 4 ligands. Thus, assuming that thermal annealing drives these systems towards the target cluster size (as shown in FIGS. 17 and 18), suprametallogels based on para ligands should experience a greater decrease in cluster size and a corresponding greater decrease in G. Our simulations also show that as cluster size decreases, the number of elastically inactive loops should decrease; this effect should provide a compensatory increase in the bulk modulus. Based on our data, the cluster size effect on G outweighs possible changes in the loop fraction. The relationship between loop defect formation and cluster structure in suprametallogels will provide an interesting avenue for future experimental and theoretical research.

(404) Strain sweeps in oscillatory shear at 10 rad/s performed into the nonlinear regime illustrate that the bite angle of the ligand and the state of assembly (before or after annealing) both have a significant impact on the yield behavior of the gels (FIGS. 21C and 21D). The yield stress of gels derived from B-4 (2,570400 Pa, FIG. 21D) was comparable to that for suprametallogels derived from B-3 prior to annealing (2,080840 Pa, FIG. 21C). However, while the former showed only a 28% (to 1840140 Pa) decrease in yield stress after annealing, the latter exhibited an 87% decrease (to 260110 Pa). Furthermore, while the yield strain of suprametallogels derived from B-3 exhibited a decrease from 18% to 6.3% after annealing (FIG. 21C), the yield strain of gels derived from B-4 increased after annealing from 83% to 110% (FIG. 21D). Notably, suprametallogels derived from B-4 could withstand more than 17 times as much strain as those derived from B-3. These data agree with our picture of suprametallogel structure. Though macromer B-3 provides somewhat stiffer materials due to an increase in f(5.20.3 kPa for B-3 versus 1.90.2 kPa for B-4), the presence of large clusters in these networks and the fact that the 2.2 kDa PEG chains have roughly the same radius as the target M.sub.12L.sub.24 cages lead to brittle materials; the PEG chains in networks of B-3 are either elastically inactive (in loops), or highly extended to bridge the large clusters. These extended PEG chains cannot bear significant stress. In contrast, the PEG chains in networks comprised of B-4 are less extended and more capable of bearing stress. In future studies, increasing the PEG chain length should facilitate enhancements in yield stress in networks build form para-pyridine ligands.

(405) Lastly, it was sought to assess whether networks comprised of B-3 or B-4 could self-heal upon thermal annealing (FIGS. 22A to 22F). Samples of suprametallogels derived from B-3 (FIG. 22A) and B-4 (FIG. 22D) were cut with a razor blade to introduce macroscopic fractures (FIGS. 22B and 22E, fractures labeled with arrows). These samples were then subjected to heating for 4 h at 80 C., and healing was assessed based on macroscopic observation, e.g., did the two separated gel pieces become one uniform piece after annealing? Note that no additional solvent was added, and no pressure was applied to bring the two pieces into contact. Based on the collective data presented above, it was expected that networks comprised of B-3 would be more difficult to heal, since healing in these materials would require complete reassembly of large clusters; loop defect shuffling within disconnected clusters could be more rapid than inter-cluster healing. The smaller junctions in networks prepared from B-4 would facilitate the bridging of gaps formed during the fracture. Indeed, it was found that suprametallogels prepared from B-3 were unable to heal under these conditions (FIG. 22C), while those from B-4 completely recovered their initial state.

(406) A major advantage of the suprametallogels described herein is the ability to program nano-scale architectures within a polymeric network, which could give rise to emergent, unexpected properties. When the swelling behavior of suprametallogels comprising B-3 or B-4 was examined, it was surprised to find that the suprametallogels comprising B-4 were capable of absorbing a remarkable 1579 times their own weight in solvent (DMSO), whereas the suprametallogels comprising B-3 absorbed only 232 times their own weight (FIG. 22G). The latter value (232) is typical for a covalent network whereas the former value (1579) is on par with the best superabsorbent polymers known (Chen, J., Park, H. & Park, K. Synthesis of superporous hydrogels: Hydrogels with fast swelling and superabsorbent properties. Journal of biomedical materials research 44, 53-62, (1999). These observations suggest that suprametallogels derived from B-4 and other paddlewheel forming ligands could have promising applications as super-absorbent materials.

Example 13. Preparation of Macromer C-2

(407) A telechelic bis-pyridyl-tetrazine macromer (C-2) was synthesized by appending the bptz moiety on the ends of poly(ethylene glycol) (MW: 2000 Da) with a carbon spacer, through modified procedures of published work (Cok, A. M.; Zhou, H.; Johnson, J. A. Macromolecular Symposia 2013, 329, 108; Zhou, H.; Woo, J.; Cok, A. M.; Wang, M.; Olsen, B. D.; Johnson, J. A. Proceedings of the National Academy of Sciences 2012).

Example 14. Preparation of Gels Using (1) Macromer C-1 and (2) Ni(ClO4)2 Hydrate or Fe(CO4)2 Hydrate; and Characterizations of the Gels

(408) Mixing macromer C-1 with Ni(ClO.sub.4).sub.2 hydrate or Fe(ClO.sub.4).sub.2 hydrate in a 1:1 metal to ligand ratio in acetonitrile (100 mg/mL of C-1 at room temperature) resulted in qualitatively fast formation of gels with an accompanying color change. This observation leads to the conclusion that the bptz end-groups and metal ions must be aggregating in some higher order; otherwise, the macromer would merely undergo linear extension and not form a gel. A solution of C-1 does not gel on its own, which means that these gels are not merely physical gels from - stacking or other interactions.

(409) To demonstrate that the metal-ligand bonds are responsible for the gelation, gels (FIG. 23A) were first formed with C-1 and iron perchlorate or nickel perchlorate in acetonitrile; none of the components form gels independently. Then, 25 L of a 0.05 M K.sub.4EDTA aqueous solution was added to the gels, and upon vortexing, the gels immediately dissolved and formed a liquid mixture (FIG. 23B).

(410) The mechanical properties of gels formed from C-1 and Ni(ClO.sub.4).sub.2 and Fe(ClO.sub.4).sub.2 in acetonitrile were characterized by oscillatory rheology. Exemplary results are shown in FIGS. 24A and 24B. Frequency sweeps for both gels showed storage moduli of approximately 22 kPa for nearly the entire frequency range. Strain sweeps of the two gels displayed a difference in crossover point between G and G; the gel made using Fe.sup.2+ becomes more fluid-like at about 18% strain, while the gel made using Ni.sup.2+ retains its network structure until approximately 42% strain.

(411) Also studied were the effect of solvents on gelation of the Ni.sup.2+ coordinated gels. Exemplary results are shown in FIGS. 25A and 25B. As in the original condition, a 1:1 ratio of metal and ligand in acetonitrile results in fast gelation; the G/G crossover point lies beyond the leftmost point on the frequency axis. Performing the reaction in water results in slower gelation, although the value for G approaches that of the gelation in acetonitrile at the highest frequencies tested. Interestingly, gelation in 1:1 acetonitrile/water results in a higher frequency crossover point for G and G than for either water or acetonitrile alone. This is unexpected, as it was predicted that the crossover point for the solvent mixture to lie between the two solvents separately.

Example 15. Preparation of Gels with Mixed Crosslinking Modalities and Characterizations of the Gels

(412) The capability of the bptz moiety to react with strained alkenes as well as metals led us to examine the mechanical properties of gels with mixed crosslinking modalities. By using a tris-norbornene crosslinker, 25% or 50% of the tetrazines were crosslinked to form soluble hyperbranched networks. Then, the remaining tetrazines were reacted with an amount of Ni(ClO.sub.4).sub.2 such that the metals and ligands were in a 1:1 ratio. The metal-ligand crosslinking and tetrazine-norbornene crosslinking could not be done simultaneously; the metal-ligand coordination is much faster than the tetrazine-norbornene reaction and the latter cannot occur at a high enough efficiency after gelation. Furthermore, solution-state .sup.1H-NMR experiments showed that after coordination of metal to the unfunctionalized bptz ligand, a model norbomene compound did not react with bptz with any detectable conversion.

(413) Oscillatory rheology of these gels showed a slight increase in the storage and loss moduli due to the addition of the covalent crosslinker (FIG. 26). Interestingly, the gel with 50% covalent crosslinks has similar mechanical properties to the gel made with 25% covalent crosslinks (FIG. 26).

Example 16. Cytotoxicity Against HeLa Cells

(414) Because C-2 forms gels with Fe.sup.2+ salts, which are biocompatible, these gels may have applications as therapeutic devices. First, the cytotoxicity of these gels was tested on HeLa cells to determine the effect of the components of the gels on cell viability. Due to the difficulty in assessing the toxicity of gel materials, the components of the gels were tested separately. The iron and macromer show little cytotoxicity compared to MILLIQ water, which was used as a control (FIG. 27).

Example 17. Preparation of Gels that Contain Covalently Attached Doxorubicin

(415) Due to the biocompatibility of Fe.sup.2+ salts, it was sought to create a metallogel that could serve as a drug-releasing therapeutic. For this purpose, a photocleavable doxorubicin-conjugated, norbornene-terminated PEG macromer was used and reacted with 10% of the available tetrazines of C-2 to produce a statistical mixture of bifunctionalized (1%), monofunctionalized (18%), and unfunctionalized (81%) macromer (FIG. 28). However, since most of C-2 remained unfunctionalized after the reaction, it was predicted that the doxorubicin-loaded macromers would simply become dangling ends on a gel that was structurally supported by unfunctionazlied C-2. The macromer mixture was dried out and redissolved in water and then reacted with an amount of Fe(ClO4).sub.2 such that the metal to remaining tetrazine was 1:1. Gelation, as determined by the vial inversion test, occurred within seconds (FIG. 28, inset).

Example 18. Release of Doxorubicin from the Gel of Example 17

(416) To test the release of doxorubicin, the gel was covered with 100 L of water, then irradiated with a UV lamp, and its extract was removed and replaced with water at various time intervals. The release was tracked by LCMS by observing absorbance at 490 nm and mass over time. Exemplary results are shown in FIG. 10. At 0 minutes, the gel shows no release of doxorubicin, and after 10 minutes, begins to show release of doxorubicin at an elution time of approximately 4 minutes; its identity was confirmed by the corresponding m/z from the negative ion mode trace of the ESI-MS. After 105 minutes, the gel continued to show release of doxorubicin. The peak with the greatest absorbance at an elution time of approximately 5 minutes is the macromer mixture, which is slowly released by the gel. Though the material remained a gel for the duration of the experiment, when the gel was layered with water and left to stand, the entire mixture eventually dissolved within a week.

(417) The release of doxorubicin was slow for two reasons. Because the coordination of iron to the bipyridyl tetrazines produces colored complexes, the penetration of light into the gel beyond the surface is minimal. In addition, once the doxorubicin is released from the gel, it must diffuse through the gel into the water to be observed by LCMS. Nevertheless, slow doxorubicin release was observed for 105 minutes after exposure to UV light and extraction by water.

Example 18. Preparation of Gels that Contain Covalently Attached Biodegradable Peptide-Tryptamine

(418) A demonstration of another method of functionalizing the gel described herein is the appendage of a biodegradable peptide and its subsequent cleavage by an enzyme. Molecule X, which contains the peptide sequence Ile-Phe-Gly and is terminated by tryptamine, was used to functionalize 10 mol % of the tetrazines on macromer C-2. This mixture was combined in a 1:1 metal-ligand ratio with FeSO.sub.4.7H.sub.2O, which resulted in qualitatively quick gelation. Iron sulfate also formed gels in water with a similar storage modulus as that of iron perchlorate in acetonitrile.

Example 19. Release of Tryptamine Glycnamide from the Gel of Example 18

(419) The potentially biocompatible gel of Example 18 was placed in 100 L of a buffered solution (100 mM Tris, 10 mM CaCl.sub.2, pH 7.8) and treated with chymotrypsin, at a concentration of 1.9 M in enzyme. After 45 minutes, the release of tryptamine glycnamide was observed by LC-MS (observed [M+1].sup.+: 218.0, expected [M+1].sup.+: 218.1), confirming the cleavage of the peptide between phenylalanine and glycine (FIG. 7). Though tryptamine glycinamide has no known biological function, in principle, any amine can be coupled to the N-terminus of the peptide chain and be released by a chymotrypsin digest of the gel.

CONCLUSIONS

(420) Herein, a novel strategy has been introduced for gelation that makes use of metallosupramolecular assembly of ligands appended to the ends of polymer chains. Using this approach, the average junction size and architecture is encoded in the bite angles of the ligands and the coordination geometry of the metal ions. Solid-state NMR, rheometry, and molecular dynamics simulations reveal that these differences are a direct consequence of the preference for these meta- and para-substituted ligands to self-assemble into Pd.sub.2L.sub.4 paddlewheel or Pd.sub.12L.sub.24 cage-like assemblies, respectively. Compared to conventional metallogels, the suprametallogels behave as elastic solids at oscillatory angular frequencies as low as 0.1 rad/s, and they exhibit high storage moduli (1.90.2 and 5.20.7 kPa) at 10-fold lower concentration of pyridine ligands for the same concentration of palladium(II) and 1.6 times lower mass fraction of the polymer network. Suprametallogels bridge the gap between conventional soft metallogels and hard crystalline supramolecular architectures. It has been confirmed that assembly, indeed, takes place within the gels during the course of thermal annealing at moderate temperatures (70-80 C.), and that the size of the self-assembled cages at the junctions dictates the mechanical properties of the materials. Lastly, the ability of suprametallogels to undergo self-healing of extensive macroscopic fractures has been demonstrated, thanks to the reversible nature of coordination bonding. Hence, it is anticipated that the implementation of the present strategy is to become a vital tool for the synthesis of novel robust, yet dynamic materials with novel properties.

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EQUIVALENTS AND SCOPE

(422) In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

(423) Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

(424) This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

(425) Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.