BOTTLEBRUSH COPOLYMERS AND USES THEREOF

Abstract

Materials (e.g., particles, hydrogels) that provide extended release of one or more therapeutic agents are useful platforms for drug delivery. In part, the present invention relates to new triblock (ABC) bottlebrush copolymers which can be used in the formulation of particles and hydrogels for the extended release of therapeutic agents. In certain embodiments, the triblock bottlebrush copolymers, particles, and hydrogels described herein are thermally-responsive and gel at physiological temperature (e.g., upon administration to a subject), providing injectable and/or implantable gels which can be used for extended release drug delivery. The present invention also provides methods for extended release drug delivery, and methods of treating and/or preventing a disease or conditions in a subject, using the inventive copolymers, particles, and hydrogels. In addition, the present invention provides methods of preparing the triblock bottlebrush copolymers described herein.

Claims

1-99. (canceled)

100. A method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject a formulation comprising a triblock copolymer and one or more therapeutic agents; wherein: the triblock copolymer comprises Block A, Block B, and Block C; the triblock copolymer comprises a backbone polymer of repeating units covalently linked to polymeric sidechains; and Block A, Block B, and Block C of the copolymer comprise the polymeric sidechains covalently linked to the repeating units of the backbone polymer; provided that no two of Block A, Block B, and Block C comprise polymeric sidechains of the same polymer type.

101. The method of claim 100, wherein the condition is an ocular condition.

102-103. (canceled)

104. The method of claim 101, wherein the formulation is administered to the eye of a subject.

105. The method of claim 104, wherein the formulation is administered to the eye of a subject after ocular surgery.

106. The method of claim 100, wherein the formulation is administered intravascularly, orally, intramuscularly, or subcutaneously.

107. The method of claim 100, wherein the disease is a proliferative disease.

108. The method of claim 107, wherein the disease is cancer.

109. The method of claim 108, wherein the formulation is administered locally to the site of a tumor in the subject.

110. The method of claim 100, wherein the disease is a diabetic condition.

111-112. (canceled)

113. The method of claim 100, wherein the subject is a human.

114-125. (canceled)

126. The method of claim 100, wherein the formulation comprises a particle comprising the triblock copolymer.

127. The method of claim 100, wherein the formulation comprises a hydrogel comprising the triblock copolymer.

128. The method of claim 101, wherein at least one therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID).

129. The method of claim 101, wherein at least one therapeutic agent is a steroid.

130. The method of claim 101, wherein at least one therapeutic agent is an antibiotic.

131. The method of claim 107, wherein at least one therapeutic agent is anti-proliferative or anti-cancer agent.

132. The method of claim 110, wherein at least one therapeutic agent is insulin or a variant thereof.

133. The method of claim 100, wherein the formulation provides extended release of the one or more therapeutic agents.

134. The method of claim 100, wherein he formulation comprises a pharmaceutically acceptable carrier or excipient.

135. The method of claim 100, wherein the polymeric sidechains of Block A, Block B, and Block C are each independently selected from polyethers, polyesters, and polyacrylamides.

136. The method of claim 100, wherein the triblock copolymer is of Formula (I): ##STR00096## wherein: each of G.sup.A, G.sup.B, and G.sup.C is independently optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof; each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, and combinations thereof; each of L.sup.A, L.sup.B, and L.sup.C is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof; each of T.sup.1 and T.sup.2 is independently a terminal group selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted thiol; A, B, and C are each independently polymers selected from polyethers, polyesters, and polyacrylamides, wherein each of A are the same polymer, each of B are the same polymer, and each of C are the same polymer; provided that A, B, and C are different polymer types; and each of n, m, and p is independently an integer between 1 and 4000, inclusive.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0116] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

[0117] FIG. 1A shows an exemplary schematic illustration of a triblock bottlebrush hydrogel drug reservoir. FIG. 1B shows an outline of the general architecture of the triblock bottlebrush copolymers provided herein. FIG. 1C shows a comparison of linear three-block ABC polymers (existing systems) with bottlebrush three-block ABC polymers (this invention). Also shown are the polymers' self-assemblies into particles and hydrogels.

[0118] FIG. 2 shows gel permeation chromatography (GPC) characterization of norbornene macromonomers.

[0119] FIG. 3 shows sequential ring-opening metathesis polymerization (ROMP) of PLA macromonomers (DP=10) and PEG macromonomers (DP=40) and PNIPAM macromonomers (DP=10).

[0120] FIG. 4 shows nanoprecipitation for the formation of particles. Drugs dissolved either in DMSO or pH 10 buffer were mixed with polymer in DMSO, followed by nanoprecipitation in PBS (pH 7.4). DMSO and free drugs were removed by centrifugal filtration.

[0121] FIGS. 5A and 5B show characterization of particles from self-assembly of polymer brush/drug mixtures.

[0122] FIG. 6 shows thermal-responsive gelation behavior of the particle hydrogel.

[0123] FIG. 7 shows drug quantification (ofloxacin, dexamethasone, and ibuprofen) by liquid chromatography (LC).

[0124] FIG. 8 shows cumulative drug release profiles. Particles containing individual drug were mixed at equal volume, followed by incubation at 37 C. for gelation. Drug release in PBS at 37 C. was quantified by LC-MS.

[0125] FIG. 9 shows biocompatibility of the particle hydrogel. Samples were added to medium for human umbilical vein endothelial cells (HUVEC), the biocompatibility was evaluated by quantification of LDH in the medium after 48 h incubation.

[0126] FIG. 10 shows an exemplary ABC bottlebrush copolymer, encapsulation of hydrophobic drug molecules (e.g., anti-proliferative agents), and assembly of the nanoparticles into thermoresponsive hydrogels. Structures of exemplary hydrophobic drug molecules (e.g., anti-proliferative agents) are shown: paclitaxel (PTX), gemcitabine, SN-38, and resiquimod (R848).

[0127] FIG. 11. PTX+R848 hydrogel combo for CT-26 (0.5 M inoc.) tumor treatment. CT-26 is a colon carcinoma cell line. Resiquimod (R848) Low=1.5 mg/kg; High=3 mg/kg; 10 mg/kg of PTX in all treatment groups.

[0128] FIG. 12. PTX+R848 hydrogel combo for CT-26 (0.5 M inoc.) tumor treatment. Resiquimod (R848) Low=1.5 mg/kg; High=3 mg/kg.

[0129] FIG. 13 shows that sustained release reduces systemic inflammation. The serum samples were analyzed by cytometric bead array using the CBA Mouse Inflammation Kit from BD biosciences to quantitatively measure protein levels of IL-6, IL-10, MCP-1, IFN-g, TNF, and IL-12p70 following manufacturer's instructions. Undiluted serum was mixed with capture beads (6 types of beads, each of different APC intensities, one for each cytokine, all mixed together) and phycoerythrin (PE) labeled detection reagent. The mixture was incubated for 2 hours at room temperature followed by two washes. Presence of cytokine was then measured by flow cytometric detection of PE intensity. Mean fluorescence intensity was then compared to a standard curve for each cytokine. For each cytokine ANOVA was performed on the soluble, drug combo in AB, drug combo in ABC low, and drug combo in ABC high groups. Then Dunnett's multiple comparison test was performed comparing each drug in copolymer group to the soluble drug group. Resiquimod (R848) Low=1.5 mg/kg; High=3 mg/kg. The Dunnett's comparison test significance values are noted on the graphs with stars: **P<0.005; ***P<0.0005.

[0130] FIG. 14 shows that sustained release reduces local ulceration in mice. AB bottlebrush copolymer=2 block; ABC bottlebrush copolymer=3 block.

[0131] FIG. 15. Cured mice re-challenged with CT-26 (0.1 M inoc.). In order to test whether cured mice had acquired immunity against CT-26 tumor, animals that were completely cured were re-challenged with 0.1 million of CT-26 cells on the other side of at hind flank. A group of nave mice were also inoculated as a control for CT-26 tumor growth. Resiquimod (R848) Low=1.5 mg/kg; High=3 mg/kg.

[0132] FIGS. 16A-16B. 3-drug combination treatment of A549 tumor (10 M inoc.). A549 cells are human lung adenocarcinoma cells. FIG. 16A shows sustained release of three small molecule drugs using ABC bottlebrush copolymers. In particular, in vitro release of drug payload from ABC micellular network at 37 C. in PBS. The drug-loaded gel (300 L) was incubated in 2 mL PBS solution at 37 C. The gel stays at the bottom of the vial and drug slowly diffuses out into PBS. Aliquots (100 L) were collected every 24 h for LC-MS measurement for quantification of drug release rate. The collected volume was replaced with fresh buffer. FIG. 16B shows relative tumor volume over the sustained release period. Balb/c nude mice were inoculated subcutaneously with injection of A549 cells (10 million cells in 100 L of PBS). Tumors were allowed to grow for 7 weeks before treatment. Mice bearing the tumors with similar volumes (250 mm.sup.3) were randomly selected for each cohort (n=4). Subsequently, the drug solution in DMSO or the ABC (at 4 C.) in PBS was intratumor injected to the tumors. Tumor size was measured every two or three days by a digital Vernier caliper across its longest (a) and shortest diameters (b), and its volume (V) was calculated according to the following formula: V=0.5ab.sup.2.

[0133] FIGS. 17A-17C show synthesis of bottlebrush ABC copolymers via sequential ring-opening metathesis polymerization (ROMP). FIG. 17A. Experimental procedure: In a nitrogen filled glovebox, to a 4-mL vial charged with a stir bar and Nb-PLA (Nor-PLA) macro-monomer (MM) (69.5 mg, 0.01 mmol) was added anhydrous THF (CAS 109-99-9) (230 L). To this mixture then was added Grubbs III catalyst solution in THF, all at once (50.5 L, 1 mol) to give MM: Grubbs III ratio of 10:1. The polymerization reaction mixture was stirred at room temperature for 30 min and then a 5-L aliquot was taken for size exclusion chromatography (SEC) analysis. A fresh 0.05-M solution of second MM, Nb-PEG (Nor-PEG), (184.1 mg, 0.04 mmol) in THF was prepared inside glovebox and added to reaction mixture all at once. The polymerization reaction was stirred at room temperature for another 3 h, after which 5-4, aliquot was taken and solution of third MM, Nb-PNIPAM (Nor-PNIPAM), (80.2 mg, 0.01 mmol). After stirring for another 8 h, 5-4, aliquot was taken and then ethyl vinyl ether (50 L) was added to quench the reaction. The reaction mixture was diluted with 2 mL of DMSO (CAS 67-68-5) and transferred into a 20-mL scintillation vial. The forming mixture was rapidly stirred and diluted to 20 mL by dropwise addition of milli-Q water. The forming aqueous mixture was then transferred into a spin filter with MWCO 100 kDa and concentrated to 2 mL (3000 RPM), rediluted to 10 mL and concentrated again to ensure removal of DMSO and any unreacted MM. The centrifugation was stopped at 20-min intervals to homogenize centration gradient. The product was obtained by lyophilization. FIGS. 17B-17C. Dried samples of copolymers were analyzed by SEC (FIG. 17B) and .sup.1H NMR (FIG. 17C) to estimate content of individual blocks and molecular weight of final copolymer.

[0134] FIG. 18 shows that properties of bottlebrush copolymers can be tuned via assembly using sequential ROMP. .sup.a: .sup.1H NMR estimation; .sup.b: Dynamic Light Scattering (DLS).

[0135] FIG. 19A-19B show that giant amphiphiles assemble into giant micelles. DLS measurement were performed using Wyatt Technology Mobius DLS instrument on 1 mg/mL solutions of bottle-brush copolymers in milli-Q water or PBS. Solutions of samples were filtered through a 0.45 m Nalgene filter (nylon membrane) into disposable polystyrene cuvettes, which were pre-cleaned with compressed air. Measurements were made in sets of 20 acquisitions, and the average hydrodynamic diameters were calculated using the DLS correlation function via a regularization fitting method (Dynamics 7.4.0.72 software package from Wyatt Technology).

[0136] FIG. 20 shows heat-induced physical cross-links at PNIPAM corona. Upon heating a micellular network forms and solution turns into a gel. The solution of ABC copolymer was placed onto TEM grid, subjected to air-dry either at 25 C. or 37 C., then negatively stained with uranyl acetate (4%, Electronic Microscopy Sciences), excess stain was wicked away from the grid and the sample was let to air-dry at appropriate temperature before imaging. TEM images were acquired using a FEI Tecnai Multipurpose TEM (G2 Spirit TWIN, 120 kV).

[0137] FIG. 21A. Thermoresponsive micelle aggregationvaried temperature Small Angle X-ray Scattering (SAXS). ABC Core-shell model fitting: r(core) 13 nm; r(shell) 43 nm. Transmission SAXS was conducted at the 12-ID-B beamline at the Advanced Photon Source of Argonne National Lab. The beamline detector was calibrated with silver behenate. Solution of copolymer (100 mg/mL for ABC and 80 mg/mL for A.sub.xBC) was placed into circular washer and Kapton tape was used to seal both sides of the sample. The washer was placed onto a temperature controlled holder. Sample was allowed to equilibrate for 3 min at every temperature point before acquisition.

[0138] FIG. 21B. Thermoresponsive micelle aggregation varied temperature dynamic mechanical analysis. Varied temperature rheology experiments were performed on a TA Instruments Discovery Hybrid Rheometer HR-2 rheometer outfitted with an Active Temperature Control (ATC) and environmental enclosure for temperature control. A parallel-plate geometry (radius=20 mm) was used and coupled with a bottom plate, the gap between the two plates containing copolymer solution (100 mg/mL for ABC and 80 mg/mL for AXBC) was set to 800 mm. The temperature sweep experiments were performed at 1 rad/s, 0.5% strain, and at 1 C./min

[0139] FIG. 22. SAXS data fitted with a core-shell model (Igor Pro). Core-shell model fitting: r(core) 13 nm; thickness(shell) 43 nm.

[0140] FIG. 23 shows thermoresponsive behavior of particles described herein. Replotted ABC rheology with optical density data.

[0141] FIG. 24. Local depot formation; ABC vs. AB (Cy.sub.7.5 label). Diblock and thermoresponsive triblock systems were compared. As a negative control, non-geling AB was used. The AB bottlebrush two-block copolymer forms micelles in water but because it lacks PNIPAM block, it does not undergo gelation. This exemplifies the gel forming capability of the ABC in vivo. Solutions of copolymers (100 mg/mL in PBS) were injected at hind flank of mice (n=3). Mice were imaged using Caliper IVIS Spectrum at 1 hour and 21 hour after injection.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0142] Provided herein are triblock bottlebrush copolymers; and particles, hydrogels, and formulations thereof. The particles, hydrogels, and formulations of the present invention may comprise one or more therapeutic agents, and may be administered to a subject for extended release of the one or more therapeutic agents. For example, in certain embodiments, the triblock bottlebrush copolymers, particles, and hydrogels described herein are thermally-responsive and gel at physiological temperature (e.g., upon administration to a subject), providing injectable and/or implantable gels for controlled release drug delivery. Therefore, the present invention also provides methods of using the triblock bottlebrush copolymers, particles, hydrogels, and formulations described herein (e.g., in biomedical applications such as the treatment of diseases or conditions). The present invention also provides methods of preparing triblock bottlebrush copolymers, particles, and hydrogels described herein. In yet another aspect, the present invention provides kits comprising the triblock bottlebrush copolymers, particles, hydrogels, and formulations described herein.

Triblock Bottlebrush Copolymers

[0143] One aspect of the present invention relates to triblock bottlebrush copolymers. In certain embodiments, the polymer is an ABC triblock bottlebrush copolymer comprising a Block A polymer, a Block B polymer, and a Block C polymer. A triblock bottlebrush copolymer of the present invention comprises a backbone polymer of repeating units covalently linked to polymeric sidechains; wherein Block A, Block B, and Block C of the copolymer comprise polymeric sidechains covalently linked to the repeating units of the backbone polymer; and wherein at least one of Block A, Block B, and Block C comprises polymeric sidechains that exhibit lower critical solution temperature (LCST) behavior. As described herein, each polymeric side chain of Block A is of the same polymer type, each polymeric side chain of Block B is of the same polymer type, and each polymeric side chain of Block C is of the same polymer type. Also, as described herein, Block A, Block B, and Block C comprise polymeric side chains which are of different polymer types. As a representative example, an outline of the general architecture of a triblock bottlebrush copolymer provided herein is shown in FIGS. 1B-1C.

[0144] A triblock bottlebrush copolymer comprising polymeric sidechains that exhibit LCST behavior may be thermally-responsive and capable of undergoing a phase transition at a particular temperature. Such a polymer would be useful, for example, as a thermally-responsive drug delivery vehicle. As defined herein, lower critical solution temperature (LCST) is the temperature below which a polymer is miscible in a solvent. LCST behavior refers to a characteristic of a polymer wherein the polymer exhibits a lower critical solution temperature. For example, a polymer that exhibits LCST behavior is a polymer which is miscible in a solvent at or below a certain temperature (i.e., the polymer's LCST), and which may solidify or congeal (e.g., to form a solid or a gel) in solution at or above the certain temperature. A common polymer known to exhibit LCST behavior is poly(N-isopropylacrylamide) (PNIPAM), which has a lower critical solution temperature of around 32 C. PNIPAM is a useful in biomedical applications (e.g., in drug delivery) since it has a LCST close to physiological temperature (37 C.). Other polymers that exhibit LCST behavior include, but are not limited to, poly(N,N-diethylacrylamide) (PDEAAm) (LCST from 25 to 32 C.), poly(N-vinlycaprolactam) (PVCL) (LCST between 25 and 35 C.), poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) (LCST around 50 C.), and polyethylene glycol) (PEG) (LCST of about 85 C.).

[0145] In certain embodiments, the LCST of the triblock bottlebrush copolymers provided herein is around physiological temperature (approximately 37 C.). In certain embodiments, the LCST of the triblock bottlebrush copolymers provided herein is around 33 C. In certain embodiments, the LCST of the triblock bottlebrush copolymers provided herein is between 30 and 40 C., inclusive.

[0146] The triblock bottlebrush copolymers provided herein are ABC triblock bottlebrush copolymers, meaning that the polymeric sidechains of Blocks A, B, and C are different polymers. For example, no two of Blocks A, B, and C have the same polymer sidechains. Different polymer, as used herein, refers to different polymer composition (i.e., composed of different monomer subunits). In other words, the polymeric sidechains of Blocks A, B, and C each are of a different polymer class, or of a different polymer type. For instance, when each polymeric sidechain of Block A is independently a PLA polymer and each polymeric side chain of Block B is independently a polyethylene glycol (PEG) polymer, the sidechains of A and B are considered to be different polymer types, of different polymer classes, and different polymers.

[0147] It is also to be understood that each polymeric sidechain of Block A are the same polymer, each polymeric sidechain of Block B are the same polymer, and each polymeric sidechain of Block C are the same polymer (i.e., composed of the same monomer subunits, i.e., of the same polymer type/class). However, any two polymeric sidechains of Block A, of Block B, or of Block C may be of the same or different length, or of the same or different molecular weight. Same polymer, as used here, refers to the same polymer composition (i.e., composed of the same monomers), and does not necessarily mean polymers of the same length, molecular weight, or structure. Polymers that are the same polymer can have different polymer lengths, molecular weight, terminal groups, etc. For instance, all of A are considered the same polymer if all of A are polylactic acid (PLA) side chains, even if each A is a PLA side chain has a different length and molecular weight.

[0148] The triblock bottlebrush copolymers provided herein comprise a backbone polymer of repeating units (backbone units). The repeating backbone units of any two of Blocks A, B, and C may be same or different. Further, any two of Blocks A, B, and C may comprise the same or a different number of repeating backbone units. In certain embodiments, each of Blocks A, B, and C independently comprise 1 to 4000 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 4000 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 2000 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 1000 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 500 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 200 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 2 to 100 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 5 to 100 repeating backbone units, inclusive. In certain embodiments, each of Blocks A, B, and C independently comprise 5 to 50 repeating backbone units, inclusive. In certain embodiments, each repeating backbone unit of the triblock bottlebrush copolymer is covalently linked to a polymeric sidechain. In certain embodiments, some but not all repeating backbone units are covalently linked to polymeric sidechains.

[0149] The polymeric sidechains of Block A, Block B, and Block C of the triblock bottlebrush copolymer may comprise any polymer. Examples of classes of polymers include, but are not limited to, polyvinyl polymers (e.g., polyvinyl chloride), polyethylenes (e.g., polyethylene, polytetrafluoroethylene), polypropylenes, polyacetylenes, polyethers (e.g., polyethylene glycol, polyoxymethylene, polypropylene glycol, polytetramethylene glycol, poly(ethyl ethylene) phosphate, poly(oxazoline)), polyamines, polyesters (e.g., polyglycolic acid, polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyhydroxyalkanoate, polyhydroxybutryate, polyethylene adipate, polybutylene succinate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polysilanes, polysiloxanes (e.g., polydimethylsiloxane), polyacrylates (e.g., polymethacrylate, poly(n-butyl acrylate), poly(tert-butyl acrylate)), polystyrenes, polylactides (e.g., polylactic acid), polyamino acids, polypeptides, polyamides, polyacrylamides (e.g., polymethylacrylamide), and polysaccharides. The polymeric sidechains may be homopolymers or copolymers. The polymeric sidechains may be linear or branched. In certain embodiments, the polymeric sidechains are linear.

[0150] In certain embodiments, one or more of Block A, Block B, and Block C of the triblock bottlebrush copolymer comprise polyester sidechains. In certain embodiments, Block A of the triblock bottlebrush copolymer comprises polyester sidechains. In certain embodiments, Block B of the triblock bottlebrush copolymer comprises polyester sidechains. In certain embodiments, Block C of the triblock bottlebrush copolymer comprises polyester sidechains. Examples of polyesters include, but are not limited to, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), polyhydroxybutryate (PHB), polyethylene adipate (PEA), polybutylene succinate (PBS), or poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). In certain embodiments, the triblock bottlebrush copolymer comprises polylactic acid (PLA) sidechains. In certain embodiments, the triblock bottlebrush copolymer comprises polyglycolic acid (PGA) or poly(lactic-co-glycolic acid) (PLGA) sidechains. In certain embodiments, Block A of the triblock bottlebrush copolymer comprises a polylactic acid (PLA), polyglycolic acid (PGA), or poly(lactic-co-glycolic acid) (PLGA) sidechain. In certain embodiments, Block A of the triblock bottlebrush copolymer comprises PLA sidechains. In certain embodiments, Block B of the triblock bottlebrush copolymer comprises PLA sidechains. In certain embodiments, Block C of the triblock bottlebrush copolymer comprises PLA sidechains.

[0151] In certain embodiments, one or more of Block A, Block B, and Block C of the triblock bottlebrush copolymer comprise polyether sidechains. In certain embodiments, Block B of the triblock bottlebrush copolymer comprises polyether sidechains. In certain embodiments, Block A of the triblock bottlebrush copolymer comprises polyether sidechains. In certain embodiments, Block C of the triblock bottlebrush copolymer comprises polyether sidechains. Examples of polyethers include, but are not limited to, polyethylene glycol (PEG), polyoxymethylene (POM), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), poly(ethyl ethylene) phosphate (PEEP), and poly(oxazoline). In certain embodiments, the triblock bottlebrush copolymer comprises polyethylene glycol (PEG) sidechains. In certain embodiments, Block B of the triblock bottlebrush copolymer comprises PEG sidechains.

[0152] As generally described herein, at least one of Block A, Block B, and Block C of the triblock bottlebrush copolymer comprises polymeric sidechains that exhibit LCST behavior. In certain embodiments, Block C comprises polymeric sidechains composed of a polymer that exhibits LCST behavior. In certain embodiments, Block A comprises polymeric sidechains composed of a polymer that exhibits LCST behavior. In certain embodiments, Block B comprises polymeric sidechains composed of a polymer that exhibits LCST behavior. In certain embodiments, the triblock bottlebrush copolymer comprises polyacrylamide sidechains. In certain embodiments, the triblock bottlebrush copolymer comprises poly(N-alkylacrylamide) sidechains. In certain embodiments, the triblock bottlebrush copolymer comprises poly(N-isopropylacrylamide) (PNIPAM) sidechains. In certain embodiments, Block C comprises poly(N-alkylacrylamide) sidechains. In certain embodiments, Block C comprises PNIPAM sidechains. In certain embodiments, Block A comprises PNIPAM sidechains. In certain embodiments, Block B comprises PNIPAM sidechains.

[0153] In certain embodiments, Block A comprises polyester sidechains, Block B comprises polyether sidechains, and Block C comprises polyacrylamide sidechains. For example, in a particular embodiment, Block A comprises PLA sidechains, Block B comprises PEG sidechains, and Block C comprises PNIPAM sidechains. In certain embodiments, Block A comprises polyacrylamide sidechains, Block B comprises polyester sidechains, and Block C comprises polyether sidechain. For instance, in another particular embodiment, Block A comprises PNIPAM sidechain, Block B comprises PLA sidechains, and Block C comprises PEG sidechains.

[0154] The polymeric sidechains of Blocks A, B, and C may be of any molecular weight. In certain embodiments, the polymeric sidechains of Blocks A, B, and C each independently have a molecular weight ranging from approximately 50 to approximately 10000 Da, approximately 100 to approximately 10000 Da, approximately 500 to approximately 10000 Da, approximately 1000 to approximately 10000 Da, or approximately 2000 to approximately 10000 Da; each range being inclusive. In certain embodiments, the polymeric sidechains of Blocks A, B, and C each independently have molecular weight greater than 10000 Da.

[0155] In certain embodiments, a triblock bottlebrush copolymer of the present invention is of Formula (I):

##STR00006##

wherein:

[0156] each of G.sup.A, G.sup.B, and G.sup.C is independently optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, and combination thereof;

[0157] each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, and combinations thereof;

[0158] each of L.sup.A, L.sup.B, and L.sup.C is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;

[0159] each of T.sup.1 and T.sup.2 is independently a terminal group selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted thiol;

[0160] each of A, B, and C is independently a polymer, wherein all of A are the same polymer, all of B are the same polymer, and all of C are the same polymer;

[0161] provided that A, B, and C are different polymers; and

[0162] each of n, m, and p is independently an integer between 1 and 4000, inclusive.

[0163] In certain embodiments, each of A, B, and C is independently a polymer, wherein all of A are the same polymer, all of B are the same polymer, and all of C are the same polymer; provided that A, B, and C are different polymers; and provided that at least one of A, B, or C is a polymer that exhibits LCST behavior. In certain embodiments, A, B, and C are independently selected from the group consisting of polyesters, polyethers, and polyacrylamides; provided that A, B, and C are different polymers. The polyester group may be any polyester described herein. Likewise, the polyether group may be any polyether described herein. Additionally, the polyacrylamide group may be any polyacrylamide described herein.

[0164] As described herein, the triblock bottlebrush copolymers provided herein are ABC triblock bottlebrush copolymers, meaning that groups A, B, and C are different polymers. Different polymer, as used herein, refers to different polymer composition (i.e., composed of different monomer subunits). In other words, A, B, and C each are of a different polymer class, or of a different polymer type. For instance, when each of A is independently a PLA polymer and each of B is independently a polyethylene glycol (PEG) polymer, A and B are considered to be different polymer types, of different polymer classes, and therefore different polymers. However, as also described herein, each of A are the same polymer, each of B are the same polymer, and each of C are the same polymer (i.e., composed of the same monomer subunits, i.e., of the same polymer type/class). Same polymer, as used here, refers to the same polymer composition (i.e., composed of the same monomers). Any two of A, any two of B, or any two of C may be of the same or different length, or of the same or different molecular weight. Polymers that are the same polymer can have different polymer lengths, molecular weight, terminal groups, etc. For instance, all of A are considered the same polymer if all of A are polylactic acid (PLA) side chains, even if each A is a PLA side chain has a different length and molecular weight.

[0165] As generally defined herein, group A is a polymer. As described herein, each A is the same polymer (i.e., of the same polymeric composition, i.e., composed of the same monomers). In certain embodiments, group A is a polymer that exhibits LCST behavior. In certain embodiments, group A is a polymer group selected from the group consisting of polyesters, polyethers, and polyacrylamides. In certain embodiments, group A is a polyester. In certain embodiments, group A is a polyether. In certain embodiments, group A is a polyacrylamide. In certain embodiments, group A is a polyester selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), polyhydroxybutryate (PHB), polyethylene adipate (PEA), polybutylene succinate (PBS), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). In certain embodiments, group A is polylactic acid (PLA). In certain embodiments, group A is polyglycolic acid (PGA) or poly(lactic-co-glycolic acid) (PLGA). In certain embodiments, group A is a polyether. In certain embodiments, group A is polyether selected from the group consisting of polyethylene glycol (PEG), polyoxymethylene (POM), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), poly(ethyl ethylene) phosphate (PEEP), and poly(oxazoline). In certain embodiments, group A is polyethylene glycol (PEG). In certain embodiments, group A is a polyacrylamide. In certain embodiments, group A is a poly(N-alkylacrylamide). In certain embodiments, group A is poly(N-isopropylacrylamide).

[0166] As generally defined herein, group B is a polymer. As described herein, each B is the same polymer (i.e., of the same polymeric composition, i.e., composed of the same monomers). In certain embodiments, group B is a polymer that exhibits LCST behavior. In certain embodiments, group B is a polymer group selected from the group consisting of polyesters, polyethers, and polyacrylamides. In certain embodiments, group B is a polyester. In certain embodiments, group B is a polyether. In certain embodiments, group B is a polyacrylamide. In certain embodiments, group B is polyether selected from the group consisting of polyethylene glycol (PEG), polyoxymethylene (POM), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), poly(ethyl ethylene) phosphate (PEEP), and poly(oxazoline). In certain embodiments, group B is polyethylene glycol (PEG). In certain embodiments, group B is a polyester. In certain embodiments, group B is a polyester selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), polyhydroxybutryate (PHB), polyethylene adipate (PEA), polybutylene succinate (PBS), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). In certain embodiments, group B is polylactic acid (PLA). In certain embodiments, group B is polyglycolic acid (PGA) or poly(lactic-co-glycolic acid) (PLGA). In certain embodiments, group B is a polyacrylamide. In certain embodiments, group B is a poly(N-alkylacrylamide). In certain embodiments, group B is poly(N-isopropylacrylamide).

[0167] As generally defined herein, group C is a polymer. As described herein, each B is the same polymer (i.e., of the same polymeric composition, i.e., composed of the same monomers). In certain embodiments, group C is a polymer that exhibits LCST behavior. In certain embodiments, group C is a polymer group selected from the group consisting of polyesters, polyethers, and polyacrylamides. In certain embodiments, group C is a polyacrylamide. In certain embodiments, group C is a poly(N-alkylacrylamide). In certain embodiments, group C is poly(N-isopropylacrylamide). In certain embodiments, group C is a polyether. In certain embodiments, group C is polyether selected from the group consisting of polyethylene glycol (PEG), polyoxymethylene (POM), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), poly(ethyl ethylene) phosphate (PEEP), and poly(oxazoline). In certain embodiments, group C is polyethylene glycol (PEG). In certain embodiments, group C is a polyester. In certain embodiments, group C is a polyester selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), polyhydroxybutryate (PHB), polyethylene adipate (PEA), polybutylene succinate (PBS), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). In certain embodiments, group C is polylactic acid (PLA). In certain embodiments, group C is polyglycolic acid (PGA) or poly(lactic-co-glycolic acid) (PLGA).

[0168] In certain embodiments, each of A, each of B, or each of C is a polyester group of the following formula:

##STR00007##

wherein:

[0169] R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl;

[0170] R.sup.O is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and

[0171] s is an integer between 5 and 2000, inclusive.

[0172] As generally defined herein, R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl. In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted alkenyl. In certain embodiments, R.sup.1 is optionally substituted alkynyl. In certain embodiments, R.sup.1 is optionally substituted aryl. In certain embodiments, R.sup.1 is optionally substituted heteroaryl. In certain embodiments, R.sup.1 is optionally substituted carbocyclyl. In certain embodiments, R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted acyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. In certain embodiments, R.sup.1 is methyl.

[0173] In certain embodiments, each of A, each of B, or each of C is a polyester group of the following formula:

##STR00008##

wherein:

[0174] R.sup.O is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and

[0175] s is an integer between 5 and 2000, inclusive.

[0176] As generally defined herein, R.sup.O hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.O is hydrogen. In certain embodiments, R.sup.O is optionally substituted alkyl. In certain embodiments, R.sup.O is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.O is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.O is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. In certain embodiments, R.sup.O is optionally substituted alkenyl. In certain embodiments, R.sup.O is optionally substituted alkynyl. In certain embodiments, R.sup.O is optionally substituted aryl. In certain embodiments, R.sup.O is optionally substituted heteroaryl. In certain embodiments, R.sup.O is optionally substituted carbocyclyl. In certain embodiments, R.sup.O is optionally substituted heterocyclyl. In certain embodiments, R.sup.O is optionally substituted acyl. In certain embodiments, R.sup.O is an oxygen protecting group.

[0177] As generally defined herein, s is an integer between 5 and 2000, inclusive. In certain embodiments, s is an integer between 5 and 1000, inclusive. In certain embodiments, s is an integer between 5 and 1000, inclusive. In certain embodiments, s is an integer between 5 and 500, inclusive. In certain embodiments, s is an integer between 5 and 200, inclusive. In certain embodiments, s is an integer between 5 and 100, inclusive. In certain embodiments, s is an integer between 50 and 2000, inclusive. In certain embodiments, s is an integer between 100 and 2000, inclusive. In certain embodiments, s is an integer between 200 and 2000, inclusive. In certain embodiments, s is an integer between 500 and 2000, inclusive. In certain embodiments, s is an integer between 1000 and 2000, inclusive.

[0178] In certain embodiments, each of A, each of B, or each of C is a polyether group of the following formula:

##STR00009##

wherein:

[0179] R.sup.O is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and

[0180] q is an integer between 5 and 2000, inclusive.

[0181] As generally defined herein, q is an integer between 5 and 2000, inclusive. In certain embodiments, q is an integer between 5 and 1000, inclusive. In certain embodiments, q is an integer between 5 and 1000, inclusive. In certain embodiments, q is an integer between 5 and 500, inclusive. In certain embodiments, q is an integer between 5 and 200, inclusive. In certain embodiments, q is an integer between 5 and 100, inclusive. In certain embodiments, q is an integer between 50 and 2000, inclusive. In certain embodiments, q is an integer between 100 and 2000, inclusive. In certain embodiments, q is an integer between 200 and 2000, inclusive. In certain embodiments, q is an integer between 500 and 2000, inclusive. In certain embodiments, q is an integer between 1000 and 2000, inclusive.

[0182] In certain embodiments, each of A, each of B, or each of C is a polyacrylamide group of the following formula:

##STR00010##

wherein:

[0183] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two R.sup.N on the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

[0184] R.sup.C is hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, or optionally substituted thiol; and

[0185] r is an integer between 5 and 2000, inclusive.

[0186] As generally defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two R.sup.N on the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.N is hydrogen. In certain embodiments, R.sup.N is optionally substituted alkyl. In certain embodiments, R.sup.N is optionally substituted alkenyl. In certain embodiments, R.sup.N is optionally substituted alkynyl. In certain embodiments, R.sup.N is optionally substituted carbocyclyl. In certain embodiments, R.sup.N is optionally substituted heterocyclyl. In certain embodiments, R.sup.N is optionally substituted aryl. In certain embodiments, R.sup.N is optionally substituted heteroaryl. In certain embodiments, R.sup.N is or a nitrogen protecting group. In certain embodiments, R.sup.N on the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.N is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. In certain embodiments, R.sup.N is iso-propyl.

[0187] In certain embodiments, each of A, each of B, or each of C is a polyacrylamide group of the following formula:

##STR00011##

Wherein R.sup.C, R.sup.N, and r are as defined herein.

[0188] In certain embodiments, each of A, each of B, or each of C is a polyacrylamide group of the following formula:

##STR00012##

wherein:

[0189] R.sup.C is hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, or optionally substituted thiol; and

[0190] r is an integer between 5 and 2000, inclusive.

[0191] As generally defined herein, R.sup.C is hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, or optionally substituted thiol. In certain embodiments, R.sup.C is hydrogen. In certain embodiments, R.sup.C is halogen. In certain embodiments, R.sup.C is CN. In certain embodiments, R.sup.C is optionally substituted alkyl. In certain embodiments, R.sup.C is optionally substituted alkenyl. In certain embodiments, R.sup.C is optionally substituted alkynyl. In certain embodiments, R.sup.C is optionally substituted aryl. In certain embodiments, R.sup.C is optionally substituted heteroaryl. In certain embodiments, R.sup.C is optionally substituted carbocyclyl. In certain embodiments, R.sup.C is optionally substituted heterocyclyl. In certain embodiments, R.sup.C is optionally substituted acyl. In certain embodiments, R.sup.C is optionally substituted amino. In certain embodiments, R.sup.C is optionally substituted hydroxyl. In certain embodiments, R.sup.C is optionally substituted thiol. In certain embodiments, R.sup.C is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.C is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.C is of the formula:

##STR00013##

[0192] As generally defined herein, r is an integer between 5 and 2000, inclusive. In certain embodiments, r is an integer between 5 and 1000, inclusive. In certain embodiments, r is an integer between 5 and 1000, inclusive. In certain embodiments, r is an integer between 5 and 500, inclusive. In certain embodiments, r is an integer between 5 and 200, inclusive. In certain embodiments, r is an integer between 5 and 100, inclusive. In certain embodiments, r is an integer between 50 and 2000, inclusive. In certain embodiments, r is an integer between 100 and 2000, inclusive. In certain embodiments, r is an integer between 200 and 2000, inclusive. In certain embodiments, r is an integer between 500 and 2000, inclusive. In certain embodiments, r is an integer between 1000 and 2000, inclusive.

[0193] As generally defined herein, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, and combinations thereof. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is optionally substituted alkylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is optionally substituted heteroalkylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is optionally substituted alkynylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is optionally substituted alkenylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is substituted alkenylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is unsubstituted alkenylene. In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is of the formula:

##STR00014##

In certain embodiments, each of L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is of the formula:

##STR00015##

In certain embodiments, each L.sup.1, L.sup.2, L.sup.3, and L.sup.4 is of the formula:

##STR00016##

[0194] In certain embodiments, L.sup.1 is optionally substituted alkylene. In certain embodiments, L.sup.1 is optionally substituted heteroalkylene. In certain embodiments, L.sup.1 is optionally substituted alkynylene. In certain embodiments, L.sup.1 is optionally substituted alkenylene. In certain embodiments, L.sup.1 substituted alkenylene. In certain embodiments, L.sup.1 is unsubstituted alkenylene. In certain embodiments, L.sup.1 is of the formula:

##STR00017##

In certain embodiments, L.sup.1 is of the formula:

##STR00018##

In certain embodiments, L.sup.1 is of the formula:

##STR00019##

[0195] In certain embodiments, L.sup.2 is optionally substituted alkylene. In certain embodiments, L.sup.2 is optionally substituted heteroalkylene. In certain embodiments, L.sup.2 is optionally substituted alkynylene. In certain embodiments, L.sup.2 is optionally substituted alkenylene. In certain embodiments, L.sup.2 substituted alkenylene. In certain embodiments, L.sup.2 is unsubstituted alkenylene. In certain embodiments, L.sup.2 is of the formula:

##STR00020##

In certain embodiments, L.sup.2 is of the formula:

##STR00021##

In certain embodiments, L.sup.2 is of the formula:

##STR00022##

[0196] In certain embodiments, L.sup.3 is optionally substituted alkylene. In certain embodiments, L.sup.3 is optionally substituted heteroalkylene. In certain embodiments, L.sup.3 is optionally substituted alkynylene. In certain embodiments, L.sup.3 is optionally substituted alkenylene. In certain embodiments, L.sup.3 substituted alkenylene. In certain embodiments, L.sup.3 is unsubstituted alkenylene. In certain embodiments, L.sup.3 is of the formula:

##STR00023##

In certain embodiments, L.sup.3 is of the formula:

##STR00024##

In certain embodiments, L.sup.3 is of the formula:

##STR00025##

[0197] In certain embodiments, L.sup.4 is optionally substituted alkylene. In certain embodiments, L.sup.4 is optionally substituted heteroalkylene. In certain embodiments, L.sup.4 is optionally substituted alkynylene. In certain embodiments, L.sup.4 is optionally substituted alkenylene. In certain embodiments, L.sup.4 substituted alkenylene. In certain embodiments, L.sup.4 is unsubstituted alkenylene. In certain embodiments, L.sup.4 is of the formula:

##STR00026##

In certain embodiments, L.sup.4 is of the formula:

##STR00027##

In certain embodiments, L.sup.4 is of the formula:

##STR00028##

[0198] In certain embodiments, the triblock bottlebrush copolymer of Formula (I) is of Formula (I-a):

##STR00029##

wherein T.sup.1, T.sup.2, G.sup.A, G.sup.B, G.sup.C, L.sup.A, L.sup.B, L.sup.C, A, B, C, n, m, and p are as described herein.

[0199] As generally defined herein, each of G.sup.A, G.sup.B, and G.sup.C is independently optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C are independently optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a combination thereof. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C is optionally substituted carbocyclylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C is optionally substituted heterocyclylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C comprises optionally substituted 5-membered carbocyclylene or 5-membered heterocyclylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C comprises optionally substituted cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothiophenylene, or pyrrolidinylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C is independently optionally substituted bicyclic heterocyclylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C are substituted bicyclic heterocyclylene. In certain embodiments, each of G.sup.A, G.sup.B, and G.sup.C are of the following formula:

##STR00030##

In other embodiments, each of G.sup.A, G.sup.B, and G.sup.C may independently be of any of the following formulae:

##STR00031##

[0200] As generally defined herein, G.sup.A is optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a combination thereof. In certain embodiments, G.sup.A is optionally substituted carbocyclylene. In certain embodiments, G.sup.A is optionally substituted heterocyclylene. In certain embodiments, G.sup.A comprises optionally substituted 5-membered carbocyclylene or 5-membered heterocyclylene. In certain embodiments, G.sup.A comprises optionally substituted cyclopentylene, cyclohexyl ene, tetrahydrofuranylene, tetrahydrothiophenyl ene, or pyrrolidinylene. In certain embodiments, G.sup.A is optionally substituted bicyclic heterocyclylene. In certain embodiments, G.sup.A is substituted bicyclic heterocyclylene. In certain embodiments, G.sup.A is of the following formula:

##STR00032##

wherein X.sup.A and A.sup.R are as defined herein. In certain embodiments, G.sup.A is of the following formula:

##STR00033##

In certain embodiments, G.sup.A is of the following formula:

##STR00034##

In certain embodiments, G.sup.A is of the following formula:

##STR00035##

[0201] As generally defined herein, G.sup.B is optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a combination thereof. In certain embodiments, G.sup.B is optionally substituted carbocyclylene. In certain embodiments, G.sup.B is optionally substituted heterocyclylene. In certain embodiments, G.sup.B is optionally substituted bicyclic heterocyclylene. In certain embodiments, G.sup.B comprises optionally substituted 5-membered carbocyclylene or 5-membered heterocyclylene. In certain embodiments, G.sup.B comprises optionally substituted cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothiophenylene, or pyrrolidinylene. In certain embodiments, G.sup.B is substituted bicyclic heterocyclylene. In certain embodiments, G.sup.B is of the following formula:

##STR00036##

wherein X.sup.B and B.sup.R are as defined herein. In certain embodiments, G.sup.B is of the following formula:

##STR00037##

In certain embodiments, G.sup.B is of the following formula:

##STR00038##

In certain embodiments, G.sup.B is of the following formula:

##STR00039##

[0202] As generally defined herein, G.sup.C is optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a combination thereof. In certain embodiments, G.sup.C is optionally substituted carbocyclylene. In certain embodiments, G.sup.C is optionally substituted heterocyclylene. In certain embodiments, G.sup.C is optionally substituted bicyclic heterocyclylene. In certain embodiments, G.sup.C comprises optionally substituted 5-membered carbocyclylene or 5-membered heterocyclylene. In certain embodiments, G.sup.C comprises optionally substituted cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothiophenylene, or pyrrolidinylene. In certain embodiments, G.sup.C is substituted bicyclic heterocyclylene. In certain embodiments, G.sup.C is of the following formula:

##STR00040##

wherein X.sup.C and C.sup.R are as defined herein. In certain embodiments, G.sup.C is of the following formula:

##STR00041##

In certain embodiments, G.sup.C is of the following formula:

##STR00042##

In certain embodiments, G.sup.C is of the following formula:

##STR00043##

[0203] In certain embodiments, the triblock bottlebrush copolymer of Formula (I) is of Formula (I-b):

##STR00044##

wherein:

[0204] each of X.sup.A, X.sup.B, and X.sup.C is independently selected from the group consisting of CH.sub.2, CH.sub.2CH.sub.2, O, and S; and

[0205] each of A.sup.R, B.sup.R, and C.sup.R is independently optionally substituted carbocylyl or optionally substituted heterocyclyl.

[0206] As generally defined herein, each of X.sup.A, X.sup.B, and X.sup.C is independently selected from the group consisting of CH.sub.2, CH.sub.2CH.sub.2, O, and S. In certain embodiments, each of X.sup.A, X.sup.B, and X.sup.C is CH.sub.2. In certain embodiments, each of X.sup.A, X.sup.B, and X.sup.C is CH.sub.2CH.sub.2. In certain embodiments, each of X.sup.A, X.sup.B, and X.sup.C is O. In certain embodiments, each of X.sup.A, X.sup.B, and X.sup.C is S. In certain embodiments, X.sup.A is CH.sub.2. In certain embodiments, X.sup.A is CH.sub.2CH.sub.2. In certain embodiments, X.sup.AO. In certain embodiments, X.sup.A is S. In certain embodiments, X.sup.B is CH.sub.2. In certain embodiments, X.sup.B is CH.sub.2CH.sub.2. In certain embodiments, X.sup.B O. In certain embodiments, X.sup.B is S. In certain embodiments, X.sup.C is CH.sub.2. In certain embodiments, X.sup.C is CH.sub.2CH.sub.2. In certain embodiments, X.sup.CO. In certain embodiments, X.sup.C is S.

[0207] In certain embodiments, the triblock bottlebrush copolymer of Formula (I) is of Formula (I-c):

##STR00045##

wherein T.sup.1, T.sup.2, A.sup.R, B.sup.R, C.sup.R, L.sup.A, L.sup.B, L.sup.C, A, B, C, n, m, and p are ad defined herein.

[0208] As generally defined herein, each of A.sup.R, B.sup.R, and C.sup.R is independently optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, each of A.sup.R, B.sup.R, and C.sup.R is optionally substituted carbocyclyl. In certain embodiments, each of A.sup.R, B.sup.R, and C.sup.R is optionally substituted heterocyclyl. In certain embodiments, each of A.sup.R, B.sup.R, and C.sup.R is optionally substituted five-membered heterocyclyl. In certain embodiments, each of A.sup.R, B.sup.R, and C.sup.R is a succinimide ring. In certain embodiments, A.sup.R is optionally substituted carbocyclyl. In certain embodiments, A.sup.R is optionally substituted heterocyclyl. In certain embodiments, A.sup.R is optionally substituted five-membered heterocyclyl. In certain embodiments, A.sup.R is a succinimide ring. In certain embodiments, A.sup.R is optionally substituted carbocyclyl. In certain embodiments, B.sup.R is optionally substituted heterocyclyl. In certain embodiments, B.sup.R is optionally substituted five-membered heterocyclyl. In certain embodiments, B.sup.R is a succinimide ring. In certain embodiments, C.sup.R is optionally substituted carbocyclyl. In certain embodiments, C.sup.R is optionally substituted heterocyclyl. In certain embodiments, C.sup.R is optionally substituted five-membered heterocyclyl. In certain embodiments, C.sup.R is a succinimide ring.

[0209] In certain embodiments, the triblock bottlebrush copolymer of Formula (I) is a triblock bottlebrush copolymer of Formula (I-d):

##STR00046##

wherein T.sup.1, T.sup.2, L.sup.A, L.sup.B, L.sup.C, A, B, C, n, m, and p are as defined herein.

[0210] As generally defined herein, each of T.sup.1 and T.sup.2 is independently a terminal group selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted thiol. In certain embodiments, T.sup.1 is hydrogen. In certain embodiments, T.sup.1 is halogen. In certain embodiments, T.sup.1 is optionally substituted alkyl. In certain embodiments, T.sup.1 is optionally substituted alkenyl. In certain embodiments, T.sup.1 is optionally substituted alkynyl. In certain embodiments, T.sup.1 is optionally substituted carbocyclyl. In certain embodiments, T.sup.1 is optionally substituted heterocyclyl. In certain embodiments, T.sup.1 is optionally substituted aryl. In certain embodiments, T.sup.1 is optionally substituted phenyl. In certain embodiments, T.sup.1 is unsubstituted phenyl (-Ph). In certain embodiments, T.sup.1 is optionally substituted heteroaryl. In certain embodiments, T.sup.1 is optionally substituted acyl. In certain embodiments, T.sup.1 is optionally substituted hydroxyl. In certain embodiments, T.sup.1 is optionally substituted amino. In certain embodiments, T.sup.1 is optionally substituted thiol. In certain embodiments, T.sup.2 is hydrogen. In certain embodiments, T.sup.2 is halogen. In certain embodiments, T.sup.2 is optionally substituted alkyl. In certain embodiments, T.sup.2 is optionally substituted alkenyl. In certain embodiments, T.sup.2 is optionally substituted alkynyl. In certain embodiments, T.sup.2 is optionally substituted carbocyclyl. In certain embodiments, T.sup.2 is optionally substituted heterocyclyl. In certain embodiments, T.sup.2 is optionally substituted aryl. In certain embodiments, T.sup.2 is optionally substituted phenyl. In certain embodiments, T.sup.2 is unsubstituted phenyl (-Ph). In certain embodiments, T.sup.2 is optionally substituted heteroaryl. In certain embodiments, T.sup.2 is optionally substituted acyl. In certain embodiments, T.sup.2 is optionally substituted hydroxyl. In certain embodiments, T.sup.2 is optionally substituted amino. In certain embodiments, T.sup.2 is optionally substituted thiol. In certain embodiments, both T.sup.1 and T.sup.2 are hydrogen.

[0211] In certain embodiments, the copolymer of Formula (I) is of Formula (I-e):

##STR00047##

[0212] In certain embodiments, the copolymer of Formula (I) is of the following formula:

##STR00048##

[0213] As generally defined herein, each of L.sup.A, L.sup.B, and L.sup.C is independently a linker selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted alkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is optionally substituted C.sub.1-20 alkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is optionally substituted C.sub.1-6 alkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is unsubstituted C.sub.1-6 alkylene. For example, in certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is of the formula:

##STR00049##

In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted heteroalkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is optionally substituted C.sub.1-20 heteroalkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is optionally substituted C.sub.1-6 heteroalkylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is substituted C.sub.1-6 heteroalkylene. For example, in certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is of the formula:

##STR00050##

As a further example, in certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C is of the formula:

##STR00051##

In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted carbocyclylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted heterocyclylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted arylene. In certain embodiments, at least one of L.sup.A, L.sup.B, and L.sup.C comprises optionally substituted heteroarylene.

[0214] In certain embodiments, L.sup.A comprises optionally substituted alkylene. In certain embodiments, L.sup.A is optionally substituted C.sub.1-20 alkylene. In certain embodiments, L.sup.A is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.A is unsubstituted C.sub.1-6 alkylene. For example, in certain embodiments, L.sup.A is of the formula:

##STR00052##

In certain embodiments, L.sup.A comprises optionally substituted heteroalkylene. In certain embodiments, L.sup.A is optionally substituted C.sub.1-20 heteroalkylene. In certain embodiments, L.sup.A is optionally substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.A is substituted C.sub.1-6 heteroalkylene. For example, in certain embodiments, L.sup.A is of the formula:

##STR00053##

As a further example, in certain embodiments, L.sup.A is of the formula:

##STR00054##

In certain embodiments, L.sup.A comprises optionally substituted carbocyclylene. In certain embodiments, L.sup.A comprises optionally substituted heterocyclylene. In certain embodiments, L.sup.A comprises optionally substituted arylene. In certain embodiments, L.sup.A comprises optionally substituted heteroarylene.

[0215] In certain embodiments, L.sup.B comprises optionally substituted alkylene. In certain embodiments, L.sup.B is optionally substituted C.sub.1-20 alkylene. In certain embodiments, L.sup.B is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.B is unsubstituted C.sub.1-6 alkylene. For example, in certain embodiments, L.sup.B is of the formula:

##STR00055##

In certain embodiments, L.sup.B comprises optionally substituted heteroalkylene. In certain embodiments, L.sup.B is optionally substituted C.sub.1-20 heteroalkylene. In certain embodiments, L.sup.B is optionally substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.B is substituted C.sub.1-6 heteroalkylene. For example, in certain embodiments, L.sup.B is of the formula:

##STR00056##

As a further example, in certain embodiments, L.sup.B is of the formula:

##STR00057##

In certain embodiments, L.sup.B comprises optionally substituted carbocyclylene. In certain embodiments, L.sup.B comprises optionally substituted heterocyclylene. In certain embodiments, L.sup.B comprises optionally substituted arylene. In certain embodiments, L.sup.B comprises optionally substituted heteroarylene.

[0216] In certain embodiments, L.sup.C comprises optionally substituted alkylene. In certain embodiments, L.sup.C is optionally substituted C.sub.1-20 alkylene. In certain embodiments, L.sup.C is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.C is unsubstituted C.sub.1-6 alkylene. For example, in certain embodiments, L.sup.C is of the formula:

##STR00058##

In certain embodiments, L.sup.C comprises optionally substituted heteroalkylene. In certain embodiments, L.sup.C is optionally substituted C.sub.1-20heteroalkylene. In certain embodiments, L.sup.C is optionally substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.C is substituted C.sub.1-6 heteroalkylene. For example, in certain embodiments, L.sup.C is of the formula:

##STR00059##

As a further example, in certain embodiments, L.sup.C is of the formula:

##STR00060##

In certain embodiments, L.sup.C comprises optionally substituted carbocyclylene. In certain embodiments, L.sup.C comprises optionally substituted heterocyclylene. In certain embodiments, L.sup.C comprises optionally substituted arylene. In certain embodiments, L.sup.C comprises optionally substituted heteroarylene.

[0217] In certain embodiments of the invention, a triblock bottlebrush copolymer of Formula (I) is of Formula (I-d):

##STR00061##

wherein all of A are of one of the following formulae:

##STR00062##

all of B are of one of the following formulae:

##STR00063##

and
all of C are of one of the following formulae:

##STR00064##

provided that A, B, and C are of different formula.

[0218] In certain embodiments of the invention, a triblock bottlebrush copolymer of Formula (I) is of Formula (I-e):

##STR00065##

wherein all of -L.sup.A-A are of one of the following formulae:

##STR00066##

all of -L.sup.B-B are of one of the following formulae:

##STR00067##

and
all of -L.sup.C-C is are one of the following formulae:

##STR00068##

provided that -L.sup.A-A, -L.sup.B-B, and -L.sup.C-C are of different formula.

[0219] In certain embodiments of the invention, a triblock bottlebrush copolymer of Formula (I) is of the formula:

##STR00069##

wherein all of -L.sup.A-A are of one of the following formulae:

##STR00070##

[0220] all of -L.sup.B-B are of one of the following formulae:

##STR00071##

and
all of -L.sup.C-C are of one of the following formulae:

##STR00072##

provided that -L.sup.A-A, -L.sup.B-B, and -L.sup.C-C are of different formula.

[0221] In certain embodiments, group A is a polyester group, group B is a polyether group, and group C is a polyacrylamide group. For instance, in certain embodiments, group A is PLA, group B is PEG, and group C is PNIPAM. In certain embodiments, group A is a polyacrylamide group, group B is a polyester group, and group C is a polyether group. For example, in certain embodiments, group A is PNIPAM, group B is PLA, and group C is PEG. In certain embodiments of the triblock bottlebrush copolymers described herein, one of group A, B, or C is replaced by a different polymer group.

[0222] In certain embodiments, each of group A is PLA; each of group B is PEG; and each of group C is PNIPAM; and the triblock bottlebrush copolymer of Formula (I) is of Formula (II):

##STR00073##

wherein T.sup.1, T.sup.2, L.sup.1, L.sup.2, L.sup.3, L.sup.4, L.sup.A, L.sup.B, L.sup.C, G.sup.A, G.sup.B, G.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0223] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-a):

##STR00074##

wherein T.sup.1, T.sup.2, L.sup.A, L.sup.B, L.sup.C, G.sup.A, G.sup.B, G.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0224] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-b):

##STR00075##

wherein T.sup.1, T.sup.2, L.sup.A L.sup.B, L.sup.C, G.sup.A, G.sup.B, G.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0225] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-c):

##STR00076##

wherein T.sup.1, T.sup.2, L.sup.A L.sup.B, L.sup.C, X.sup.A, X.sup.B, X.sup.C, A.sup.R, B.sup.R, C.sup.R, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0226] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-d):

##STR00077##

wherein T.sup.1, T.sup.2, L.sup.A, L.sup.B, L.sup.C, A.sup.R, B.sup.R, C.sup.R, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0227] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-e):

##STR00078##

wherein T.sup.1, T.sup.2, L.sup.A L.sup.B, L.sup.C, A.sup.R, B.sup.R, C.sup.R, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0228] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-f):

##STR00079##

wherein T.sup.1, T.sup.2, L.sup.A, L.sup.B, L.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0229] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of Formula (II-g):

##STR00080##

wherein L.sup.A, L.sup.B, L.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0230] In certain embodiments, the triblock bottlebrush copolymer of Formula (II) is of the following formula:

##STR00081##

wherein L.sup.A, L.sup.B, L.sup.C, R.sup.O, R.sup.C, n, m, p, s, r, and q are as defined herein.

[0231] For example, in certain embodiments, a triblock bottlebrush copolymer is of the following formula:

##STR00082##