Preparation And Characteristics Of Amphiphlic Caprolactone Copolymers And Their Micelles For Drug Delivery

Aliphatic polyesters especially poly(ε-caprolactone), poly(glycolide), poly(lactic acid) and their copolymers have been recently received much attention due to their biodegradability and biocompatibility. These polymers have found wide applications in tissue engineering scaffolds, suture, implants and drug delivery vehicles. However, these aliphatic polyesters have their limitations in terms of high hydrophobicity, semicrystalline properties and lacking of functional groups. Through tailoring the main chain structures or incorporating functional pendent groups, biodegradable polyesters are enabled to possess versatile properties, such as hydrophilicity and enhanced biodegradability and mechanical properties, to meet the requirements in different biomedical fields.Amphiphilic copolymers can self-assemble into micelles in aqueous solution through the hydrophobic interactions among the core-forming segments. The hydrophobic inner core serves as a container for hydrophobic drugs, and the outer shell composed of hydrophilic polymers maintains a hydration barrier to provide colloidal stability. These micelles possess several unique features, such as enhancing the aqueous solubility of drugs, prolonging the circulation time, improving the preferential accumulation at tumor sites by the enhanced permeability and retention (EPR) effect, and reducing systemic side effects. Polymeric micelles have been developed for potential application as a delivery vehicle for drugs.In this dissertation, a series of amphiphilic caprolactone copolymers with a comb or linear-comb architecture are designed and prepared by making use of the copolymerization of a functionalized caprolactone monomer. The drug-loading and in vitro drug-release properties of the polymeric micelles of the amphiphilic copolymers are investigated.Chapter one presents a detailed review of recent progress in aliphatic biodegradable polyesters used in drug delivery systems.In chapter two, linear-comb copolymers of s-caprolactone were synthesized by using a functionalized ε-caprolactone monomer,4-(2-benzoxyethoxy)-s-caprolactone (BECL), bearing a pendant benzyl-protected hydroxyl group. First, block copolymer PEG-b-P(CL-co-BECL) was synthesized by ROP of CL and BECL with poly(ethylene glycol) monomethyl ether (PEG) as a macroinitiator. Then, the protecting benzyl groups were removed by catalyzed hydrogenation to afford block copolymer PEG-b-P(CL-co-HECL) with hydroxyl pendant groups. Finally, grafting polymerization of CL on the hydroxyl copolymer afforded the amphiphilic linear-comb block copolymers PEG-b-P[CL-co-(HECL-g-PCL-PCL)]. The molecular weights determined by1H NMR and GPC were in good agreement with the theoretical values calculated on the basis of the feed ratio. These amphiphilic copolymers formed micellar structures in aqueous solution by a dialysis method. The size of micelles increased firstly, and then decreased with the increment of the hydrophobic block. The morphology of micelles verified by TEM was spherical shape. The in vitro drug release behavior of the polymeric micelles was investigated with prednisone acetate as a model drug. The drug loading content increased along with the increase of the hydrophobic block. Release rate decreased as increasing content of hydrophobic segment incorporated in copolymers.In chapter three, a novel hydroxyl polyester, P(CL-co-HECL) was successfully synthesized through copolymerization of BECL with CL followed by deprotection reaction of the benzyl groups by catalyzed hydrogenation. Then, the comb polyesters were synthesized through graft copolymerization of CL on P(CL-co-BECL). The biodegradable amphiphilic comb-like copolyester, P[CL-co-(HECL-g-PCL-PEG)] were synthesized by the coupling reaction of chloroformate activated methoxy poly(ethylene glycol) with the pendant hydroxyl groups of P[CL-co-(CL-g-HEPCL)]. The graft copolymers were characterized by1H NMR and GPC. These amphiphilic copolymers formed spherical micelles in aqueous media. The size of the micelles increased with the increment of the hydrophobic content. The in vitro drug release behavior of anticancer drug DOX in the polymeric micelles was investigated. MTT assay for cytotoxicity of the comb amphiphilic copolymers suggested these man-sized micellar particles are biocompatible. In chapter four, novel amphiphilic triblock copolyesters PHECL-b-PCL-b-PHECL with hydrophilic hydroxyl polyester blocks were designed and synthesized. First, the PCL-diol macroinitiators were synthesized through bulk polymerization of CL with1,6-hexanediol as the initiator and Sn(Oct)2as the catalyst. Then, amphiphilic triblock copolyesters PHECL-b-PCL-b-PHECL were synthesized through polymerization of BECL with PCL-diol as the initiator followed by a hydrogenolytic deprotection reaction with Pd/C as a catalyst. The amphiphilic triblock polymers were characterized by1H NMR, GPC and water contact angle. The hydrophilic property of the amphiphilic triblock copolyester can be tuned by varying the HECL and CL block length. These amphiphilic copolymers can form micelles in aqueous solution. The morphology of micelles verified by TEM was spherical shape. The amphiphilic triblock copolymers may have potential applications in drug delivery.In chapter five, homopolymer PEEGE was prepared by anionic polymerization, then the hydroxyl group on the back bone were recovered after hydrolysis. Linear polyglycidols were used as macroinitiators for the ring-opening polymerization of CL. The biodegradable amphiphilic graft copolyester, LPG-g-(PCL-PEG) were synthesized by the coupling reaction of chloroformate activated methoxy poly(ethylene glycol) with the pendant hydroxyl groups of LPG. The comb-like copolymers were characterized by1H NMR and GPC. These amphiphilic copolymers formed spherical micelles. The size of micelles increased with the increment of the hydrophobic content, and the critical micelle concentrations decreased with the increment of the hydrophobic content. The in vitro drug release behavior was investigated. The drug loading content increased along with the increase of the hydrophobic content. Release rate decreased as increasing content of hydrophobic segment incorporated in the copolymers.