![]() Side-chain protected Fmoc-amino acids, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HATU), O-benzotriazole- N,N,N′ ,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 4-dimethylaminopyridine (DMAP), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) were from AAPPTec (Louisville, KY). Exposure of the multiblock copolymer to papain, an enzyme with similar specificity as lysosomalcathepsin B, resulted in total biodegradation and formation of macromolecules with initial molecular weight. Addition of catalyst Cu(I)resulted in chain extension and formation of high molecular weight multiblock biodegradable HPMA copolymers. This feature makes the heterotelechelic polyHPMA a potentially biodegradable, long-circulation drug carrier. Unlike the reported “clickable” RAFT agents, the new CTA contains an enzyme-sensitive oligopeptide (GFLG) sequence. Post-polymerization modification of the other (non-alkynyl) chain-end with an azido-group was achieved by the reaction of the polymer with azido-modified initiator V-501 (diazido-V-501 4,4′-azobis(azidopropyl 4-cyanopentanoate)). A newly designed chain transfer agent (CTA-GFLG-alkyne) contains a degradable oligopeptide sequence, GFLG, and an alkyne group, which enabled a direct synthesis of alkyne-functionalized polyHPMA as well as HPMA copolymers with functional comonomers ( N-methacryloylglycylphenylalanylleucylglycyl thiazolidine-2-thione) or polymerizable derivatives of anticancer drugs ( N-methacryloylglycylphenylalanylleucylglycyl-gemcitabine). To this end, we synthesized α-azide, ω-alkyneheterotelechelic polyHPMA using RAFT polymerization. Herein we describe the synthesis of biodegradable, biocompatible high molecular weight HPMA copolymer drug carriers that will be long circulating in the vasculature leading to enhanced tumor accumulation. The emergence of living radical polymerization, especially reversible addition fragmentation chain transfer (RAFT) polymerization, provided a powerful tool to prepare polyHPMAs with well-defined structures as well as to introduce functional end-groups that can act as attachment points for various biomacromolecules. Experimental evidence suggests that the higher the molecular weight of HPMA copolymer-drug conjugates, the higher the tumor accumulation with concomitant increase in therapeutic efficacy. It is well known that accumulation of macromolecules in solid tumor is molecular weight-dependent. The necessity to limit the molecular weight distribution below the renal threshold (in order to secure elimination from the organism) resulted in short intravascular half-life and limited accumulation in the tumor. HPMA copolymer-anticancer drug conjugates have been evaluated in numerous cancer models and in clinical trials. Its physical properties and the synthetic flexibility have been proven to be very useful when combined with biological active agents. Poly (polyHPMA) is a nonimmunogenic, neutral, hydrophilic polymer currently employed in the delivery of anticancer drugs. The new synthetic method presented permits the synthesis of biocompatible, biodegradable high molecular weight HPMA copolymer-anticancer drug conjugates that possess long-circulation times and augmented accumulation in solid tumor tissue due to the enhanced permeability and retention effect. ![]() Similar results were obtained for copolymers of HPMA with N-methacryloylglycylphenylalanylleucylglycyl thiazolidine-2-thione and N-methacryloylglycylphenylalanylleucylglycyl-gemcitabine. Upon exposure to papain, these copolymers degraded into the initial blocks. Chain extension via click reaction resulted in high molecular weight multiblock copolymers. Post-polymerization modification with 4,4′-azobis(azidopropyl 4-cyanopentanoate)resulted in the formation of heterotelechelic HPMA copolymers containing terminal alkyne and azide groups. An enzyme-sensitive, alkyne-functionalized, chain transfer agent (CTA-GFLG-alkyne N α-(4-pentynoyl)-N δ-(4-cyano-4-(phenylcarbonothioylthio)pentanoyl-glycylphenylalanylleucylglycyl)-lysine) was synthesized and used to mediate the reversible addition-fragmentation chain-transfer (RAFT) polymerization and copolymerization of HPMA. A new strategy for the synthesis of biodegradable high molecular weight N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymeric carriers has been designed.
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