CORE-TO-SURFACE POLYMERIZATION FOR THE SYNTHESIS OF STAR POLYMERS AND USES THEREOF
20190030067 ยท 2019-01-31
Inventors
Cpc classification
C08G61/08
CHEMISTRY; METALLURGY
C08F222/404
CHEMISTRY; METALLURGY
C08F222/404
CHEMISTRY; METALLURGY
C08G2261/1426
CHEMISTRY; METALLURGY
C08G2261/418
CHEMISTRY; METALLURGY
C08G2261/3225
CHEMISTRY; METALLURGY
A61K31/787
HUMAN NECESSITIES
International classification
Abstract
Disclosed are methods, compositions, reagents, systems, and kits to prepare star polymers, as well as compositions and uses thereof. Various embodiments show that synthesis of these polymers contain low metal concentration to provide polymers for diverse biomedical applications including in vivo applications.
Claims
1. A star polymer formed from two or more of olefin metathesis polymerization reactions with a metal complex; provided that the metal concentration of the star polymer is less than about 450 ppm.
2-35. (canceled)
36. The star polymer of any one of claim 1, wherein the backbone polymeric arms are of Formula (I): ##STR00040## or a salt thereof, wherein: G.sup.A is 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, L.sup.4, L.sup.A, and L.sup.B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, 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 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, optionally substituted thio, a structure of Formula (I), and a bond to the polymeric core as described herein; n is an integer between 5 and 10000, inclusive; y is an integer between 1 and 20, inclusive; A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, and 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 thio; and B is hydrogen, an agent as described herein, or a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da.
37-76. (canceled)
77. The star polymer of claim 1, wherein the polymeric core is of Formula (II): ##STR00041## or a salt thereof, wherein: G.sup.A is 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.3, and L.sup.4, is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof; each of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is 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, optionally substituted thio, a structure of Formula (I), and a structure of Formula (II); and b and c are independently an integer between 1 and 10000, inclusive.
78-80. (canceled)
81. A method of preparing a star polymer of any one of claim 1, the method comprising the step of forming the star polymer via polymerization reactions.
82-93. (canceled)
94. A method of preparing a ring-opening metathesis polymerization-in brush-arm star polymer (ROMP-in BASP), the method comprising the steps of: (a) providing a macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; and (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP.
95-102. (canceled)
103. A method of preparing a ring-opening metathesis polymerization-out brush-arm star polymer (ROMP-out BASP), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; and (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP.
104-113. (canceled)
114. A method of preparing a brush-arm star polymer gel (BASP gel), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a first crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP; (h) providing a second crosslinker comprising one or more reactive moieties; and (i) reacting the ROMP-out BASP provided in step (g) and the crosslinker provided in step (h) under conditions suitable to effect a polymerization reaction and yield a BASP gel.
115-145. (canceled)
146. A pharmaceutical composition comprising a star polymer of claim 1, and a pharmaceutically acceptable excipient.
147. (canceled)
148. A kit comprising a star polymer of claim 1, and instructions for use.
149. A method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 146.
150. A method of preparing a surface-functionalized ring-opening metathesis polymerization-out brush-arm star polymer (ROMP-out BASP), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP; and (h) providing a surface capping reagent comprising one or more reactive moieties; and (i) reacting the ROMP-out BASP with the surface capping reagent in step (h) under conditions suitable to effect a polymerization reaction and yield a surface-functionalized ROMP-out BASP.
151-174. (canceled)
175. A pharmaceutical composition comprising a star polymer prepared by a method of claim 81, and a pharmaceutically acceptable excipient.
176. A pharmaceutical composition comprising a star polymer prepared by a method of claim 94, and a pharmaceutically acceptable excipient.
177. A pharmaceutical composition comprising a star polymer prepared by a method of claim 103, and a pharmaceutically acceptable excipient.
178. A pharmaceutical composition comprising a star polymer prepared by a method of claim 114, and a pharmaceutically acceptable excipient.
179. A method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 175.
180. A method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 176.
181. A method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 177.
182. A method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 178.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0160] The accompanying drawings, which constitute a part of this specification, illustrate several exemplary embodiments of the invention and together with the description, serve to explain certain principles of the invention. The embodiments disclosed in the drawings are exemplary and do not limit the scope of this disclosure.
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DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0181] The present disclosure provides methods, compounds, particles (e.g., nanoparticles, microparticles), compositions, systems, reagents, and kits focused on the synthesis and uses of star polymers. In certain embodiments, the star polymers are brush-arm star polymers (BASPs). In certain embodiments, the brush-arm star polymers are comprised of brush-arm polymers containing polymeric sidechains covalently linked to a polymeric core via crosslinkers.
[0182] In certain embodiments, the present disclosure describes methods to prepare star polymers. In certain embodiments, the methods provide ROMP-in BASPs. In certain embodiments, the methods provide ROMP-out BASPs. In certain embodiments, the methods provide BASP gels. In certain embodiments, the methods utilize one or more olefin metathesis polymerization reactions to prepare the star polymers. In certain embodiments, the olefin metathesis polymerization reaction is performed with a metal complex. In certain embodiments, the methods comprise a purification step to remove the metal.
[0183] In certain embodiments, the present disclosure describes methods to prepare surface-functionalized ROMP-out BASP. In certain embodiments, a surface-functionalized ROMP-out BASP is formed from reacting a ROMP-out BASP with a surface capping reagent. In certain embodiments, a surface-functionalized ROMP-out BASP is formed from reacting a ROMP-out BASP capped by a surface capping reagent containing an activated ester or activated carbonate with a nucleophile.
Brush-Arm Star Polymers (BASPs)
[0184] One aspect of the present disclosure relates to star polymers (i.e., ROMP-in BASPs, ROMP-out BASPs, and BASP gels) formed from two or more olefin metathesis polymerization reactions with a metal complex; provided that the metal concentration of the star polymer is less than about 450 ppm. In certain embodiments, the metal of the metal complex is a transition metal. In certain embodiments, the transition metal is ruthenium. In certain embodiments, the ruthenium concentration of the star polymer is less than about 400 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 350 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 300 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 250 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 200 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 150 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 100 ppm. In certain embodiments, the ruthenium concentration of the star polymer is less than about 50 ppm. In certain embodiments, the ruthenium concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0185] In certain embodiments, the transition metal is osmium. In certain embodiments, the osmium concentration of the star polymer is less than about 450 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 400 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 350 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 300 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 250 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 200 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 150 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 100 ppm. In certain embodiments, the osmium concentration of the star polymer is less than about 50 ppm. In certain embodiments, the osmium concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0186] In certain embodiments, the transition metal is molybdenum. In certain embodiments, the molybdenum concentration of the star polymer is less than about 450 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 400 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 350 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 300 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 250 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 200 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 150 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 100 ppm. In certain embodiments, the molybdenum concentration of the star polymer is less than about 50 ppm. In certain embodiments, the molybdenum concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0187] In certain embodiments, the transition metal is tungsten. In certain embodiments, the tungsten concentration of the star polymer is less than about 450 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 400 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 350 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 300 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 250 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 200 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 150 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 100 ppm. In certain embodiments, the tungsten concentration of the star polymer is less than about 50 ppm. In certain embodiments, the tungsten concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0188] In certain embodiments, the transition metal is cobalt. In certain embodiments, the cobalt concentration of the star polymer is less than about 450 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 400 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 350 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 300 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 250 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 200 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 150 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 100 ppm. In certain embodiments, the cobalt concentration of the star polymer is less than about 50 ppm. In certain embodiments, the cobalt concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0189] In certain embodiments, the transition metal is vanadium. In certain embodiments, the vanadium concentration of the star polymer is less than about 450 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 400 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 350 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 300 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 250 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 200 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 150 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 100 ppm. In certain embodiments, the vanadium concentration of the star polymer is less than about 50 ppm. In certain embodiments, the vanadium concentration of the star polymer is below the detectable limit measurable by inductively coupled plasma mass spectrometry (ICP-MS).
[0190] In certain embodiments, the star polymer comprises a polymeric core of repeating units covalently linked to backbone polymeric arms of repeating units each covalently linked to polymeric sidechains. In certain embodiments, the star polymer contains one type of polymeric sidechain. In certain embodiments, the star polymer contains different types of polymeric sidechains. In certain embodiments, the polymeric sidechains can be a natural or synthetic polymer. In certain embodiments, the polymeric sidechains are each independently selected from the group consisting of polyethers, polyesters, polyacrylamides, polycarbonates, polysiloxanes, polyfluorocarbons, polysulfones, and polystyrenes.
[0191] In certain embodiments, the star polymer contains one type of polymeric sidechain. In certain embodiments, the star polymer contains two types of polymeric sidechains. In certain embodiments, the star polymer contains three types of polymeric sidechains, In certain embodiments, the star polymer contains four types of polymeric sidechains. In certain embodiments, the star polymer contains five types of polymeric sidechains. In certain embodiments, the star polymer contains six types of polymeric sidechains. In certain embodiments, the star polymer contains seven types of polymeric sidechains. In certain embodiments, the star polymer contains eight types of polymeric sidechains. In certain embodiments, the star polymer contains nine types of polymeric sidechains. In certain embodiments, the star polymer contains ten types of polymeric sidechains.
[0192] In certain embodiments, the polymeric sidechain is a polyether sidechain. In certain embodiments, the polyether sidechains are 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, the polyether sidechains are polyethylene glycol (PEG). In certain embodiments, the polyethylene glycol sidechains have a molecular weight ranging from about 200 g/mol to about 6000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 200 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 1000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 1500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 2000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 2500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 3000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 3500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 4000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 4500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 5000 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 5500 g/mol. In certain embodiments, the polyethylene glycol sidechains have a molecular weight about 6000 g/mol.
[0193] In certain embodiments, the polymeric sidechain is a polyester sidechain. In certain embodiments, the polyester sidechains are 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).
[0194] In certain embodiments, the polymeric sidechain is a polyacrylamide sidechain. In certain embodiments, the polyacrylamide sidechains are poly(N-alkylacrylamide) sidechains.
[0195] In certain embodiments, the polymeric sidechain is a polycarbonate sidechain. In certain embodiments, the polycarbonate sidechains are selected from the group consisting of poly(bisphenol A carbonate), poly[bisphenol A carbonate-co-4,4-(3,3,5-trimethylcyclohexylidene)diphenol carbonate], and poly(propylene carbonate).
[0196] In certain embodiments, the polymeric sidechain is a polysiloxane sidechain. In certain embodiments, the polysiloxane sidechain is of the formula:
##STR00008##
wherein:
[0197] R.sup.1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted alkoxy;
[0198] R.sup.2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted alkoxy; and
[0199] q is an integer between 1 and 1000, inclusive.
[0200] In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.2 is optionally substituted alkyl. In certain embodiments, q is an integer between 1 and 100, inclusive. In certain embodiments, the polysiloxane is polydimethylsiloxane (PDMS). In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight ranging from about 200 g/mol to about 6000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 200 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 1000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 1500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 2000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 2500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 3000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 3500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 4000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 4500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 5000 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 5500 g/mol. In certain embodiments, the polydimethylsiloxane sidechains have a molecular weight about 6000 g/mol.
[0201] In certain embodiments, the polymeric sidechain is a polyfluorocarbon sidechain. In certain embodiments, the polyfluorocarbon sidechains are selected from the group consisting of poly(chlorotrifluoroethylene), poly(ethylene-co-tetrafluoroethylene), poly(tetrafluoroethylene), poly(tetrafluoroethylene-co-perfluoro(propylvinyl ether)), poly(vinylidene fluoride), and poly(vinylidene fluoride-co-hexafluoropropylene).
[0202] In certain embodiments, the polymeric sidechain is a polysulfone sidechain. In certain embodiments, the polysulfone sidechains are selected from the group consisting of poly[1-[4-(3-carboxy-4-hydroxyphenylazo)benzenesulfonamido]-1,2-ethanediyl, sodium salt], poly(1-hexadecene-sulfone), poly(oxy-1,4-phenylenesulfonyl-1,4-phenylene), poly(oxy-1,4-phenylenesulfonyl-1,4-phenylene), and polyphenylsulfone.
[0203] In certain embodiments, the polymeric sidechain is a polystyrene sidechain. In certain embodiments, the polystyrene sidechain is polystyrene (PS). In certain embodiments, the polystyrene sidechains have a molecular weight ranging from about 200 g/mol to about 6000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 200 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 1000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 1500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 2000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 2500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 3000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 3500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 4000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 4500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 5000 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 5500 g/mol. In certain embodiments, the polystyrene sidechains have a molecular weight about 6000 g/mol.
[0204] In certain embodiments, the backbone polymeric arms of Formula (I-b):
##STR00009##
or a salt thereof, wherein:
[0205] G.sup.A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof;
[0206] each of L.sup.1, L.sup.2, L.sup.3, L.sup.4, L.sup.A, and L.sup.B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
[0207] each of T.sup.1 and T.sup.2 is 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, optionally substituted thio, a structure of Formula (I), and a bond to the polymeric core as described herein;
[0208] n is an integer between 5 and 10000, inclusive;
[0209] y is an integer between 1 and 20, inclusive;
[0210] A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, and 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 thio;
[0211] each B independently is hydrogen, an agent as described herein, or a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da; and
[0212] m is an integer between 2 and 10, inclusive.
[0213] In certain embodiments, the backbone polymeric arms are of Formula (I-ab):
##STR00010##
or a salt thereof.
[0214] In certain embodiments, the backbone polymeric arms are of Formula (I):
##STR00011##
or a salt thereof, wherein:
[0215] G.sup.A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof;
[0216] each of L.sup.1, L.sup.2, L.sup.3, L.sup.4, L.sup.A, and L.sup.B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
[0217] each of T.sup.1 and T.sup.2 is 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, optionally substituted thio, a structure of Formula (I), or a bond to the polymeric core as described herein;
[0218] n is an integer between 5 and 10000, inclusive;
[0219] y is an integer between 1 and 20, inclusive;
[0220] A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, and is 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 thio; and
B is hydrogen, an agent as described herein, or a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da. In certain embodiments, y is 1. In certain embodiments, y is an integer between 2 and 20, inclusive. In certain embodiments, G.sup.A is optionally substituted carbocyclylene, optionally substituted heterocyclylene, or a combination thereof. In certain embodiments, each of L.sup.1 and L.sup.3 is optionally substituted alkenylene.
[0221] In certain embodiments, the backbone polymeric arm is of Formula (I-a):
##STR00012##
or a salt thereof. In certain embodiments, L.sup.2 is optionally substituted alkylene or optionally substituted heteroalkylene. In certain embodiments, L.sup.A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, or optionally substituted heteroarylalkylene. In certain embodiments, L.sup.B is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted heteroarylene, or optionally substituted heteroarylalkylene. In certain embodiments, L.sup.2 is optionally substituted heteroalkylene; L.sup.A is optionally substituted heteroarylalkylene; and L.sup.B is optionally substituted heteroalkylene. In certain embodiments, L.sup.4 is of formula:
##STR00013##
wherein: a is an integer between 1 and 100, inclusive. In certain embodiments, L.sup.4 is of formula:
##STR00014##
wherein: a is an integer between 1 and 100, inclusive. In certain embodiments, n is an integer between 10 and 1000, inclusive. In certain embodiments, n is an integer between 10 and 100, inclusive. In certain embodiments, n is an integer between 20 and 60, inclusive. In certain embodiments, each of T.sup.1 and T.sup.2 is independently hydrogen, optionally substituted aryl, a structure of Formula (I), or a bond to the polymeric core as described herein. In certain embodiments, B is a hydrogen. In certain embodiments, B is an agent selected from the group consisting of a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent), drug, protein, polynucleotide, imaging agent, biopolymer, polymer, small molecule, large molecule, amino acid, polysaccharide, or lipid.
[0222] In certain embodiments, the backbone polymeric arm is of formula:
##STR00015##
wherein:
[0223] p is an integer between 1 and 10, inclusive;
[0224] n is an integer between 5 and 10000, inclusive; and
[0225] z is an integer between 1 and 100, inclusive.
[0226] In certain embodiments, the backbone polymeric arm is of formula:
##STR00016##
wherein n is an integer between 5 and 10000, inclusive.
[0227] In certain embodiments, the backbone polymeric arm is of formula:
##STR00017##
wherein:
[0228] p is an integer between 1 and 10, inclusive;
[0229] n is an integer between 5 and 10000, inclusive; and
[0230] z is an integer between 1 and 100, inclusive.
[0231] In certain embodiments, the backbone polymeric arm is of formula:
##STR00018##
wherein n is an integer between 5 and 10000, inclusive.
[0232] In certain embodiments, the backbone polymeric arm is of formula:
##STR00019##
wherein:
[0233] p is an integer between 1 and 10, inclusive;
[0234] n is an integer between 5 and 10000, inclusive; and
[0235] z is an integer between 1 and 100, inclusive.
[0236] In certain embodiments, the backbone polymeric arm is of formula:
##STR00020##
wherein n is an integer between 5 and 10000, inclusive.
[0237] In certain embodiments, the polymeric core is of Formula (II):
##STR00021##
or a salt thereof, wherein:
[0238] G.sup.A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof;
[0239] each of L.sup.1, L.sup.3, and L.sup.4, is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
[0240] each of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is 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, optionally substituted thio, a structure of Formula (I), or a structure of Formula (II); and
[0241] b and c are independently an integer between 1 and 10000, inclusive. In certain embodiments, each of T.sup.1, T.sup.2, T.sup.3 and T.sup.4 is independently a structure of Formula (I) or a structure of Formula (II).
[0242] In certain embodiments, the polymer core is of formula:
##STR00022##
In certain embodiments, each instance of n can be independently an integer between 1 and 10000, inclusive.
[0243] In certain embodiments, the polymeric core is of formula:
##STR00023##
In certain embodiments, each instance of n can be independently an integer between 1 and 10000, inclusive.
[0244] In certain embodiments, at least one backbone polymeric arm contains B, wherein B is an agent selected from the group consisting of a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent), drug, protein, polynucleotide, imaging agent, biopolymer, polymer, small molecule, large molecule, amino acid, polysaccharide, or lipid. In certain embodiments, B is a small molecule, wherein the small molecule is a boronic acid.
[0245] In certain embodiments, an agent is a pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent), diagnostic agent, prophylactic agent, drug, protein, peptide, polynucleotide, imaging agent, biopolymer, polymer, small molecule, large molecule, amino acid, polysaccharide, or lipid.
[0246] In certain embodiments, the agent is a pharmaceutical agent. In certain embodiments the pharmaceutical agent is a therapeutic agent, a diagnostic agent, or a prophylactic agent. In certain embodiments, the therapeutic agent is an anti-cancer agent. Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon , interferon ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent) docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca.sup.2+ ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN, AZD2171), dasatinib (SPRYCEL, BMS-354825), erlotinib (TARCEVA), gefitinib (IRESSA), imatinib (Gleevec, CGP57148B, STI-571), lapatinib (TYKERB, TYVERB), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA), semaxanib (semaxinib, SU5416), sunitinib (SUTENT, SU11248), toceranib (PALLADIA), vandetanib (ZACTIMA, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN), bevacizumab (AVASTIN), rituximab (RITUXAN), cetuximab (ERBITUX), panitumumab (VECTIBIX), ranibizumab (Lucentis), nilotinib (TASIGNA), sorafenib (NEXAVAR), everolimus (AFINITOR), alemtuzumab (CAMPATH), gemtuzumab ozogamicin (MYLOTARG), temsirolimus (TORISEL), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine. In certain embodiments, the anti-cancer agent is paclitaxel.
[0247] In certain embodiments, the agent is an anti-hypertension agent. Exemplary anti-hypertension agents include, but are not limited to, amiloride, amlodipine, atenolol, azilsartan, benazepril, bendroflumethiazide, betaxolol, bisoprolol, bucindolol, bumetanide, candesartan, captopril, carteolol, carvedilol, chlorothiazide, chlorthalidone, cilnidipine, clevidipine, diltiazem, doxazosin, enalapril, epitizide, eplerenone, eprosartan, ethacrynic acid, felodipine, Fimasartan, fosinopril, furosemide, hydrochlorothiazide, indapamide, indoramin, irbesartan, isradipine, labetalol, lercanidipine, levamlodipine, lisinopril, losartan, methyclothiazide, metolazone, metoprolol, moexipril, nadolol, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, olmesartan, oxprenolol, penbutolol, perindopril, pindolol, phenoxybenzamine, phentolamine, polythiazide, prazosin, propranolol, quinapril, ramipril, spironolactone, telmisartan, terazosin, timolol, tolazoline, torsemide, trandolapril, triamterene, valsartan, and verapamil. In certain embodiments, the anti-hypertension agent is telmisartan.
[0248] Exemplary diagnostic agents include, but are not limited to, fluorescent molecules; gases; metals; imaging agents, such as commercially available imaging agents used in positron emissions tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents, such as magnetic-resonance signal enhancing agents, X-ray attentuatung agents, ultrasound scattering agent, and ultrasound frequency shifting agents. Examples of suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and x-ray imaging include iodine-based materials. In certain embodiments, the diagnostic agent is used in magnetic resonance imaging (MRI), such as iron oxide particles or gadolinium complexes. Gadolinium complexes that have been approved for clinical use include gadolinium chelates with DTPA, DTPA-BMA, DOTA and HP-DO3A which are reviewed in Aime, et al. (Chemical Society Reviews (1998), 27:19-29), the entire teachings of which are incorporated herein by reference.
[0249] In certain embodiments, the diagnostic agent is a metal, inorganic compound, organometallic compound, organic compound, or salt thereof. In certain embodiments, the imaging agent contains a metal selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bohrium, hassium, meitnerium, gadolinium, gallium, thallium, and barium. In certain embodiments, the diagnostic agent is an organic compound. In certain embodiments, the diagnostic agent is metal-free. In certain embodiments, the diagnostic agent is a metal-free organic compound.
[0250] In certain embodiments, the imaging agent is a magnetic resonance imaging (MRI) agent. In certain embodiments, the MRI agent is gadolinium. In certain embodiments, the MRI agent is a nitroxide radical-containing compound.
[0251] In certain embodiments, the imaging agent is a nuclear medicine imaging agent. In certain embodiments, the nuclear medicine imaging agent is selected from the group consisting of .sup.64Cu diacetyl-bis(N.sup.4-methylthiosemicarbazone) (.sup.64Cu-ASTM), .sup.18F-fluorodeoxyglucose (FDG), .sup.18F-fluoride, 3-deoxy-3-.sup.18F-fluorothymidine (FLT), .sup.18F-fluoromisonidazole (FMISO), gallium, technetium-99m, and thallium.
[0252] In certain embodiments, the imaging agent is radiographic imaging agent. In certain embodiments, the radiographic imaging agent is selected from the group consisting of barium, gastrografin, and iodine contrast agent.
[0253] In certain embodiments, the imaging agent is a radical-containing compound. In certain embodiments, the imaging agent is a nitroxide radical-containing compound. In certain embodiments, the imaging agent or diagnostic agent is of the formula:
##STR00024##
[0254] In certain embodiments, the imaging agent or diagnostic agent is an organic compound. In certain embodiments, the imaging agent is a salt of an organic compound. In certain embodiments, the imaging agent or diagnostic agent is of the formula:
##STR00025##
[0255] In certain embodiments, the diagnostic agent may comprise a fluorescent molecule, a metal chelate, a contrast agent, a radionuclide, or a positron emission tomography (PET) imaging agent, an infrared imaging agent, a near-IR imaging agent, a computer assisted tomography (CAT) imaging agent, a photon emission computerized tomography imaging agent, an X-ray imaging agent, or a magnetic resonance imaging (MRI) agent.
[0256] In some embodiments, the diagnostic agent is a fluorescent molecule. In some embodiments, the fluorescent molecule comprises an acridine dye, a cyanine dye, a rhodamine dye, a BODIPY dye, a fluorescein dye, a dansyl dye, an Alexa dye, an atto dye, a quantum dot, or a fluorescent protein. In some embodiments, the fluorescent molecule is a cyanine dye (e.g., Cy3, Cy 3.5, Cy5, Cy5.5, Cy7, or Cy7.5).
[0257] In some embodiments, the diagnostic agent is an MRI agent (e.g., a contrast agent). Examples of suitable materials for use as MRI agents (e.g., contrast agents) include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium.
[0258] In some embodiments, the diagnostic agent is a CAT imaging agent or an X-ray imaging agent. Examples of materials useful for CAT and X-ray imaging include iodine-based materials.
[0259] In some embodiments, the diagnostic agent is a PET imaging agent. Examples of suitable PET imaging agents include compounds and compositions comprising the positron emitting radioisotopoes .sup.18F, .sup.15O, .sup.13N, .sup.11C, .sup.82Rb, .sup.64Cu, and .sup.68Ga, e.g., fludeoxyglucose (18F-FDG), .sup.68Ga-DOTA-psuedopeptides (e.g., .sup.68Ga-DOTA-TOC), .sup.11C-metomidate, .sup.11C-acetate, .sup.11C-methionine, .sup.11C-choline, .sup.18F-fluciclovine, .sup.18F-fluorocholine, .sup.18F-fluorodeoxysorbitol, .sup.18F-3-fluoro-3-deoxythymidine, .sup.11C-raclopride, and .sup.18F-desmethoxyfallypride.
[0260] In some embodiments, the diagnostic agent is a near-IR imaging agent. Examples of near-IR imaging agents include Pz 247, DyLight 750, DyLight 800, cyanine dyes (e.g., Cy5, Cy5.5, Cy7), AlexaFluor 680, AlexaFluor 750, IRDye 680, IRDye 800CW, and Kodak X-SIGHT dyes.
[0261] In some embodiments, the agent can be a radionuclide, e.g., for use as a therapeutic, diagnostic, or prognostic agents. Among the radionuclides used, gamma-emitters, positron-emitters, and X-ray emitters are suitable for diagnostic and/or therapy, while beta emitters and alpha-emitters may also be used for therapy. Suitable radionuclides for forming use with various embodiments of the present disclosure include, but are not limited to, .sup.123I, .sup.125I, .sup.130I, .sup.131I, .sup.133I, .sup.135I, .sup.47Sc, .sup.72As, .sup.72Sc, .sup.90Y, .sup.88Y, .sup.97Ru, .sup.100Pd, .sup.101mRh, .sup.119Sb, .sup.128Ba, .sup.197Hg, .sup.211At, .sup.212Bi, .sup.212Pb, .sup.109Pd, .sup.111In, .sup.67Ga, .sup.68Ga, .sup.67Cu, .sup.75Br, .sup.77Br, .sup.99mTc, .sup.14C, .sup.13N, .sup.15O, .sup.32P, .sup.33P, or .sup.18F.
[0262] Prophylactic agents that can be included in the conjugates of the disclosure include, but are not limited to, antibiotics, nutritional supplements, and vaccines. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts. Prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, Freund's adjuvant.
Methods for Preparing Brush-Arm Star Polymers (BASPs)
[0263] Another aspect of the present disclosure relates to methods of preparing a star polymer comprising forming a star polymer via polymerization reactions and a step to remove the metal complex performing the polymerization reaction. In certain embodiments, the methods are utilized to prepare ROMP-in BASPs. In certain embodiments, the methods are utilized to prepare ROMP-out BASPs. In certain embodiments, the methods are utilized to prepare BASP gels. In certain embodiments, the polymerization reactions are olefin metathesis polymerization reactions. In certain embodiments, the polymerization reactions are ring-opening metathesis polymerization (ROMP).
[0264] In general, the methods of preparing a star polymer comprise the step of forming the star polymer via polymerization reactions. In certain embodiments, the method further comprises the step of purifying the star polymer via addition of an additive, dialysis, and/or lyophilization to produce a BASP with a metal concentration less than about 450 ppm.
[0265] In certain embodiments, the star polymers are formed from two or more of olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form two olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form three olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form four olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form five olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form six olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form seven olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form eight olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form nine olefin metathesis polymerization reactions. In certain embodiments, the star polymers are formed form ten olefin metathesis polymerization reactions. In certain embodiments, the olefin metathesis polymerization reaction is a ring-opening metathesis polymerization reaction.
[0266] In certain embodiments, the polymerization reaction comprises the steps of: (a) providing a macromonomer comprising one or more polymeric sidechains and one more reactive moieties; and (b) reacting the macromonomer provided in step (a) under conditions suitable to effect a polymerization reaction and yield a star polymer. In certain embodiments, the reactive moieties are olefins. In certain embodiments, the polymerization reactions comprise reacting the macromonomers in the presence of a metal complex. In certain embodiments, the metal complex is a transition metal complex. In certain embodiments, the transition metal is selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bohrium, hassium, and meitnerium. In certain embodiments, the transition metal complex is a ruthenium complex. In certain embodiments, the transition metal complex is a molybdenum complex. In certain embodiments, the transition metal complex is a zirconium complex. In certain embodiments, the transition metal complex is selected from the group consisting of ruthenium salts, bis(cyclopentadienyl)dimethylzirconium(IV), dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine) ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene) (tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), dichloro(3-methyl-2-butenylidene)bis (tricyclopentylphosphine)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (Grubbs C571), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) (Grubbs I), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine) ruthenium(II) (Grubbs II), and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromopyridine)ruthenium(II) (Grubbs III). In certain embodiments, the polymerization initiator is of the formula:
##STR00026##
[0267] In certain embodiments, the additive allows for the removal of metal byproducts. In certain embodiments, the additive is selected from a group consisting of DMSO, triphenylphosine oxide, lead tetraacetate (Pb(OAc).sub.4), activated carbon, mesoporous silicates, isocyanides, and trishydroxymethylphosphine. In certain embodiments, the additive is trishydroxymethylphosphine. In certain embodiments, the reactions to form BASPs were quenched with an organic compound. In certain embodiments, the organic compound is ethyl vinyl ether. In certain embodiments, the reactions were quenched with a drop of ethyl vinyl ether and then were dialyzed against water for 1 day before lyophilization after addition of trishydroxymethylphosphine and DMSO. After the preparation of BASP gels, the gels were swollen in ethyl vinyl ether, trishydroxymethylphosphine, and water before lyophilization. Ruthenium concentrations were determined by inductively coupled mass spectrometry (ICP-MS) using a calibration curve derived from Grubbs III.
[0268] In certain embodiments, the present disclosure describes a method of preparing a ring-opening metathesis polymerization-in brush-arm star polymer (ROMP-in BASP), the method comprising the steps of: (a) providing a macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; and (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP. In certain embodiments, the method further comprises the step of purifying the ROMP-in BASP via addition of an additive, dialysis, and/or lyophilization to produce a BASP with a metal concentration less than about 450 ppm.
[0269] In certain embodiments, the present disclosure describes a method of preparing a ring-opening metathesis polymerization-out brush-arm star polymer (ROMP-out BASP), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; and (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP. In certain embodiments, the method further comprises the step of purifying the ROMP-out BASP via addition of an additive, dialysis, and/or lyophilization to produce a BASP with a metal concentration less than about 450 ppm.
[0270] In certain embodiments, the present disclosure describes a method of preparing a brush-arm star polymer gel (BASP gel), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a first crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP; (h) providing a second crosslinker comprising one or more reactive moieties; and (i) reacting the ROMP-out BASP provided in step (g) and the crosslinker provided in step (h) under conditions suitable to effect a polymerization reaction and yield a BASP gel. In certain embodiments, the method further comprises the step of purifying the BASP gel via addition of an additive, dialysis, and/or lyophilization to produce a BASP with a metal concentration less than about 450 ppm.
[0271] In certain embodiments, the present disclosure describes a method of preparing a surface-functionalized ring-opening metathesis polymerization-out brush-arm star polymer (ROMP-out BASP), the method comprising the steps of: (a) providing a first macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (b) providing a metal complex; (c) reacting the macromonomer provided in step (a) and the metal complex provided in step (b) under conditions suitable to yield a polymer; (d) providing a crosslinker comprising one or more reactive moieties; (e) reacting the polymer provided in step (c) and the crosslinker provided in step (d) under conditions suitable to effect a polymerization reaction and yield a ROMP-in BASP; (f) providing a second macromonomer comprising one or more polymeric sidechains and one or more reactive moieties; (g) reacting the ROMP-in BASP provided in step (e) and the macromonomer provided in step (f) under conditions suitable to effect a polymerization reaction and yield a ROMP-out BASP; and (h) providing a surface capping reagent comprising one or more reactive moieties; and (i) reacting the ROMP-out BASP with the surface capping reagent in step (h) under conditions suitable to effect a polymerization reaction and yield a surface-functionalized ROMP-out BASP. In certain embodiments, the method further comprises the step of purifying the surface-functionalized ROMP-out BASP via addition of an additive, dialysis, and/or lyophilization to produce a BASP with a metal concentration less than about 450 ppm.
[0272] In certain embodiments, the method of preparing a surface-functionalized ROMP-out BASP further comprises a step of performing a nucleophilic substitution reaction. In certain embodiments, surface-functionalized ROMP-out BASP is prepared by reacting a nucleophile with a surface-functionalized ROMP-out BASP containing activated esters or activated carbonates.
[0273] In certain embodiments, the nucleophile is selected from the group consisting of halides, Grignard reagents, organolithium reagents, acetylides, enols, enolates, water, hydroxide anion, alkoxide anions, hydrogen peroxide, molecules containing an alcohol group, molecules containing a carboxylate anion, hydrogen sulfide, salts of hydrogen sulfide, thiols, thiolate anions, anions of thiolcarboxylic acids, anions of dithiocarbonates, anions of dithiocarbamates, ammonia, azide, amines, molecules containing an amino group, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, and amides. In certain embodiments, the nucleophile is a molecule containing an amino group.
[0274] In certain embodiments, the methods of preparing a star polymer include the use of a solvent. In certain embodiments, the solvent used to prepare the star polymer can be polar or non-polar, and/or protic or aprotic. In certain embodiments, the methods of preparing a star polymer include the use of more than one solvent. Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexanes, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethylsulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene. In certain embodiments, the solvent used to prepare the star polymer is tetrahydrofuran. In certain embodiments, the solvent used to prepare the star polymer is dichloromethane.
[0275] In certain embodiments, the methods of preparing a star polymer require at least one macromonomer. In certain embodiments, the methods of preparing a star polymer utilize the same macromonomer. In certain embodiments, the methods of preparing a star polymer utilize at least two different macromonomers. In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of Formula (III):
##STR00027##
or a salt thereof, wherein:
[0276] each of L.sup.2, L.sup.4, L.sup.A, and L.sup.B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
[0277] y is an integer between 1 and 20, inclusive;
[0278] A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, and 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 thio; and
[0279] B is a hydrogen, pharmaceutical agent (e.g., a therapeutic agent, a diagnostic agent, or a prophylactic agent), a drug, a protein, a polynucleotide, an imaging agent, a biopolymer, a polymer, a small molecule, a large molecule, an amino acid, a polysaccharide, a lipid, or a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da.
[0280] In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of Formula (III-b):
##STR00028##
or a salt thereof, wherein:
[0281] each of L.sup.2, L.sup.4, L.sup.A, and L.sup.B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
[0282] y is an integer between 1 and 20, inclusive;
[0283] A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, or 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 thio;
[0284] each B is independently hydrogen, pharmaceutical agent, a drug, a protein, a polynucleotide, an imaging agent, a biopolymer, a polymer, a small molecule, a large molecule, an amino acid, a polysaccharide, a lipid, or polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da; and
[0285] m is an integer between 2 and 10, inclusive.
[0286] In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00029##
wherein: p is an integer between 1 and 10 inclusive; and z is an integer between 1 and 100, inclusive. In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00030##
[0287] In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00031##
wherein: p is an integer between 1 and 10, inclusive; and z is an integer between 1 and 100, inclusive. In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00032##
[0288] In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00033##
wherein: p is an integer between 1 and 10, inclusive; and z is an integer between 1 and 100, inclusive. In certain embodiments, the methods of preparing a star polymer utilize the macromonomer of formula:
##STR00034##
[0289] In certain embodiments, the methods of preparing a star polymer require at least one crosslinker. In certain embodiments, the crosslinker is of Formula (IV):
##STR00035##
or a salt thereof, wherein
[0290] L.sup.4 is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof. In certain embodiments, the crosslinker is of formula:
##STR00036##
[0291] In certain embodiments, the methods of preparing a star polymer require at least one surface capping reagent. In certain embodiments, the surface capping reagent contains an activated ester or activated carbonate. In certain embodiments, the surface capping reagent is of the formula:
##STR00037##
or a salt thereof, wherein: X is CH.sub.2, NR.sup.3, or O; wherein R.sup.3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; Y is activating group; and z is an integer between 1 and 100, inclusive. In certain embodiments, the surface capping reagent is of the formula:
##STR00038##
or a salt thereof. In certain embodiments, the surface capping reagent is of the formula:
##STR00039##
or a salt thereof. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6. In certain embodiments, z is 7. In certain embodiments, z is 8. In certain embodiments, z is 9. In certain embodiments, z is 10. In certain embodiments, z is an integer between 11 and 100, inclusive.
Compositions and Kits
[0292] Another aspect of the present disclosure relates to compositions and kits containing a star polymer. In certain embodiments, the present disclosure describes a pharmaceutical composition comprising a star polymer, wherein the metal concentration is less than about 450 ppm, and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure describes a pharmaceutical composition comprising a therapeutically effective amount of a star polymer. In certain embodiments, the present disclosure describes a kit comprising a star polymer, wherein the metal concentration is less than about 450 ppm, or a composition described herein, and instructions for use.
[0293] Compositions described herein can be prepared by any method known in the art. In general, such preparatory methods include bringing the star polymer described herein into association 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.
[0294] 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 pharmaceutical 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 one-half or one-third of such a dosage.
[0295] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated 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.
[0296] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical 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.
[0297] Although the descriptions of compositions provided herein are principally directed to pharmaceutical 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 pharmaceutical 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.
[0298] The star polymers and compositions provided herein can be administered by any 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. Specifically contemplated routes are 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). In certain embodiments, the polymer or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
[0299] The exact amount of a polymer 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 compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound or polymer described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
[0300] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical 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.
[0301] The star polymer or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (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 (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the star polymer or 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 star combination described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) 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.
[0302] Also encompassed by the disclosure are kits. The kits provided may comprise a star polymer or pharmaceutical composition described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or star polymer described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
[0303] In certain embodiments, the kits are comprised of a star polymer described herein and instructions for use. In certain embodiments, the kits are comprised of a composition described herein and instructions for use. In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein 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. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
Methods of Treatment
[0304] Another aspect of the present disclosure relates to methods of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a star polymer or a composition described herein. In particular, the star polymers and compostions described herein are useful for in vivo applications because the metal concentration has been reduced to a safe range to be used in a subject.
[0305] In certain embodiments, a method of treating or preventing a disorder, disease, or condition comprising administering to a subject in need thereof a therapeutically effective amount of a star polymer or a composition described herein.
[0306] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. 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 some embodiments, 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 (e.g., transgenic mice and transgenic pigs).
[0307] In certain embodiments, the disorder, disease, or condition is selected from a group consisting of genetic diseases, dermatological conditions, proliferative diseases (e.g., cancer), liver diseases, spleen diseases, gastrointestinal diseases, lung diseases, hematological diseases, neurological diseases, painful conditions, psychiatric disorders, metabolic disorders, cardiovascular diseases, infectious diseases (e.g., bacterial infections, viral infections), and fibrotic conditions.
EXAMPLES
[0308] In order that the present disclosure 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 compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
Example 1: General Procedure for Synthesis of ROMP-Out BASP
Step 1: ROMP-in
[0309] To 21 mL vials charged with a Teflon-lined white cap was added PEG 3k MM (12.9 mg, 10 equiv). Care was taken to ensure the solid white PEG 3k MM (3244 g/mol) was added to the bottom of the vial and did not stick to the side and/or top of the vial. A stirbar was added to one of the two vials. Another 1 mL vial charged with a Teflon-lined white cap was charged with Acetal XL (35.7 mg; MW=580.6 g/mol). The vials were then brought into a N.sub.2 filled glovebox, whereupon anhydrous 1,4-dioxane (65 uL) was added via a micropipetter. Care was taken to ensure the solvent was added directly to the bottom of the vial on top of the white solid rather than down the side of the vial. The vial was capped and stirred gently (100-150 rpm) until the resulting viscous solution was homogenous. The vial can also be gently rolled between ones fingers to help facilitate dissolution of PEG 3k MM. Next, a stock solution of Grubbs III (20 mg/mL in anhydrous 1,4-dioxane) was generated by adding 1,4-dioxane (320 uL) to a 4 mL vial containing Grubbs III (6.4 mg; 726 g/mol). A portion of the dark green Grubbs III stock solution was added to a gently stirred (100-150 ppm) solution of PEG 3k MM (14.4 uL, final concentration PEG 3k MM=0.05 M) via micropipetter; the tip of the pipette was placed below the surface of the viscous reaction medium. The solution immediately turned from colorless to dark green (very briefly after addition of Grubbs III) to brown. The reaction was capped and stirred for 20 min before beginning Step 2. Meanwhile, a stock solution (0.1 M) of Acetal XL was made by dissolving the solid in anhydrous 1,4-dioxane (614 uL). Vortexing is required to fully dissolve Acetal XL, however the solution will eventually become homogenous.
Step 2: Crosslinking
[0310] After the reaction time of the first polymerization (Step 1) reached 20 min, the cap of the reaction vial was removed. A 250 uL microsyringe was charged with a solution of Acetal XL (40 uL). The microsyringe was positioned just above the top of the gently stirring (100-150 rpm) reaction medium; one drop was dispensed directly into the reaction every ca. 5-6 sec. Once all of the crosslinker has been added, the reaction vial was capped and stirring continued for ca. 100 min before beginning Step 3. Meanwhile, the second vial of PEG 3k MM was dissolved in anhydrous 1,4-dioxane (40 uL, 0.1 M).
Step 3: ROMP-Out
[0311] After the crosslinking step reached ca. 100 min, the next portion of PEG 3k MM solution was added as a single stream via microsyringe (placed below the level of the reaction solution) from a stock solution of MM (at a concentration between 0.05M-0.1M). The density of the MM must be taken into account to track the volume change, which can by measured by observing the volume change of a stock solution. The reaction was allowed to proceed for 1 h, and quenched with a drop or two of ethyl vinyl ether. The quenched reaction mixture was capped and stirred for ca. 15-20 min.
Step 4: Workup and Purification
[0312] Before purification, the tip of a pipette was used to remove a small portion of the reaction mixture for GPC and DLS analysis (one pipette for GPC and one pipette for DLS). The pipette was either rinsed with either 0.025 M LiBr in DMF (GPC: 400-500 uL, filtered through 0.45 um PTFE filter) or nanopure milliQ water (DLS: 1 mL) into clean vials. Before dialysis, if scavenging additives are to be added to the reaction, add 250 uL of tetramethylhydroxyphospine (THMP) (M in milliQ H.sub.2O) and 250 uL of DMSO to the reaction mixture. If scavenging additives are not going to be used, add 500 uL of milliQ water. Transfer the mixture to regenerated cellulose dialysis tubing (Spectrum Labs, 8 kDa MWCO). Dialyze against milliQ water for 1 d; add fresh water after ca. 1-2 h, after ca. 12 h, and after another ca. 8-10 h. Once the dialysis is complete, transfer the contents of the dialysis tubing into a clean vial and lyophilize for at least 1 d.
Example 2: Surface Functionalization for the Synthesis of ROMP-Out BASP
[0313] Perform Step 1 and Step 2 as described in Example 1.
Step 3: ROMP-Out and Capping
[0314] After the crosslinking step reached ca. 100 min, the next portion of PEG 3k MM solution was added as a single stream via microsyringe (placed below the level of the reaction solution) from a stock solution of MM (at a concentration between 0.05M-0.1M). The density of the MM must be taken into account to track the volume change, which can by measured by observing the volume change of a stock solution. The reaction was allowed to proceed for 1 h. Nb-PNP (2 equiv, 0.05-0.1 M) was added in 1,4 dioxane and the mixture was stirred for ca. 20 min. The vial was then removed from the glovebox, uncapped, and 2 drops of ethyl vinyl ether were added. The reaction was capped and stirred for ca. 15-20 min. A suitable benzylic amine (i.e. benzyl amine or another benzylic amine with a functionalized aryl ring, 5 equiv) was added in equal volume DMSO. The reaction was stirred for 48 h at r.t. Progress was monitored by measuring the amount of p-nitrophenol in the reaction mixture and quantifying by LC/MS against a standard calibration curve. After completion of the reaction, a drop or two of ethyl vinyl ether are added to quench the reaction. The quenched reaction mixture was capped and stirred for ca. 15-20 min.
[0315] Perform Step 4 as described in Example 1.
Discussion
[0316] In order to investigate selective BASP uptake by cells, 7-20-X-PNP and/or 10-10-X-PNP BASPs were treated with a suitable nucleophile that could mediate cell uptake (i.e. a targeting ligand) (The notation used in the figures is m.sub.1-n-m.sub.2, where m.sub.1 is equivalents of ROMP-in macromonomer relative to the metal complex capable of initiating ROMP (Grubbs III), n is equivalents of crosslinker, and m.sub.2 equivalents of ROMP-out macromonomer). Prior work from the Kataoka laboratory on nanostructures containing phenyl boronic acids showed their propensity for highly selective sialic acid binding. Sialic acid, the fundamental unit of sialylated glycans, is commonplace on the surface of cancerous tissues. Therefore, BASPs labeled with phenyl boronic acids would be expected to be up-taken more readily than their unlabeled RO-BASP analogs in cancer cells. Nickel-catalyzed Miyura borylation of readily accessible 4-chlorobenzyl(N-Boc-amine) with tetrahydroxydiboron afforded the putative aryl boronic acid, which was deprotected with TFA to afford Cap-B(OH).sub.2 in 34% yield over three steps. Treatment of crude 7-20-7-2PNP and 10-10-10-2PNP with excess Cap-B(OH).sub.2 (5 equiv relative to Nb-PNP used) and DIPEA (5 equiv) in DMSO (equal volume based on reaction mixture volume) afforded boronic acid functionalized BASPs 7-20-7-2BA and 10-10-10-2BA with 99% conversion based on p-nitrophenol production measured by HPLC analysis (
[0317] In addition to the functionalized 7-20-7-2BA and 10-10-10-2BA polymers, 7-20-0, 10-10-0, 7-20-7, and 10-10-10 architectures were also synthesized; all polymers incorporated 1 mol % Cy5.5-MM to facilitate in vitro analysis. Importantly, no differences in hydrodynamic diameter (D.sub.h) were observed between any of the structures as determined by dynamic light scattering. To begin to assess the effects of BASP architecture on cell uptake, A549 cells were incubated in DMEM (37 C., 5% CO.sub.2) with the various polymers for 1 h, 6 h, or 24 h. Subsequent analysis by flow cytometry revealed striking differences in cell uptake at each time point that depended on architecture, stoichiometry, and functionality. In all cases, 10-10-X BASPs were uptaken more readily than 7-20-X BASPs, presumably due to the more hydrophilic nature of the former structures that contain a larger PEG/crosslinker ratio (
[0318] Flow cytometry results were also corroborated by fluorescence microscopy (
[0319] While the effects of aryl boronic acids on receptor-mediated cellular uptake in polymers are well studied, this phenomenon required confirmation. To start, there was no significant difference in uptake between 10-10-10 and 10-10-10-2Bn; the presence of functionalized aryl carbamates did not lead to increased uptake over the course of 24 h. Furthermore, active transport of 7-20-7-2BA and 10-10-10-2BA was probed by incubation of all polymers for 1 h at 0 C. Significant differences in uptake were not observed between 7-20-7 and 7-20-7-2BA or 10-10-10 and 10-10-10-2BA at 0 C. On the other hand, statistically significant differences (P<0.0001) in uptake were seen for both pairs at 37 C. Compared to uptake levels at 0 C., the increase in uptake for the unfunctionalized polymers at 37 C. was significantly less (ca. 2-3) than that of the boronic acid-functionalized polymers (ca. 6-7); decreased rates of active transport (compared to passive transport) at colder temperatures further corroborated our other evidence for receptor-mediated transport of 7-20-7-2BA and 10-10-10-2BA.
[0320] With numerous BASPs in hand, the effects of polymer architecture (i.e. bottlebrush polymer vs. BASP) on cell uptake were investigated. One could imagine functionalizing a bottlebrush with aryl boronic acids in a fashion analogous to the BASP functionalizing described in
EQUIVALENTS AND SCOPE
[0321] 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.
[0322] 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.
[0323] 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.
[0324] 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.
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