Polyphosphoesters-based Ramdom Copolymers With Multifunctional Pendant Groups For Drug And Gene Delivery

Polyphosphoesters (PPEs), a class of polyesters with repeating phosphoesterlinkages in the backbone, have excellent biocompatibility and biodegradability. Thepentavalent phosphorus atoms in the backbone allow the introduction of variousfunctional molecules as pendant groups, resulting in adjustable water solubility andbioactivity of polymers. Acidic or basic conditions, as well as phosphoesterase I existedin the cytosome or subcellular regions of human cells, can accelerate the degradation ofPPEs. And the degradation products have little effect on local pH. Relying on theadvantages mentioned above, PPEs have received growing attention in biomedicalapplications.This thesis aims at preparing biocompatible and biodegradable copolymers based onPPEs via ring opening polymerization (ROP). Thiol-ene addition reaction was employedto introduce bioactive molecules to the polymers as pendant groups. The chemicalstructures and properties of copolymers were characterized and further studied as drugcarrier.The main contents of this dissertation are listed as follows:(1) Poly(CL-co-OPEA) copolymers were synthesized via a random ROP reaction of2-(2-oxo-1,3,2-dioxaphospholoyloxy) ethyl acrylate (OPEA) and-caprolactone (-CL)and using BzOH as the initiator and Sn(Oct)2as the catalyst; and then, galactosamine(Gal) was covalently conjugated with the polyphosphoester units via a combination ofphotoinduced thiol-ene reaction and amidation reaction and poly(CL-co-OPEA-Gal) wasobtained. The1H NMR,31P NMR and GPC were used to prove the successful synthesisof above products. And the biocompatibility of random copolymers with or without Galmodification was demonstrated by MTT assay. (2) Gal modified random copolymers poly(CL-co-OPEA-Gal) were researched forhepatoma-targeting delivery of anti-cancer drug doxorubicin (DOX). Amphiphilicpoly(CL-co-OPEA-Gal) could self-assemble into micelles in aqueous solution, withhydrophobic PCL segments as the core and hydrophilic polyphosphoester parts as theshell. DOX was then encapsulated into the biocompatible micelles to formhepatoma-targeting drug delivery system. Poly(CL-co-OPEA) without Gal was used ascontrol for subsequent characterizations. The morphology, particle size and particle sizedistribution of blank micelles and drug loaded micelles were measured by TEM and DLS.The pH-responsive release behavior of drug loaded micelles was studied through in vitroDOX release experiments. The cellular uptake of drug loaded micelles was evaluated,which confirmed the cellular uptake-enhancement function of Gal by HepG2cells. Thehepatoma-targeting behavior was also supported by MTT assays which indicated thatdrug loaded micelles exhibited high antitumor efficacy against HepG2cells.(3) MePEG-b-P(CL-co-OPEA) copolymers were synthesized via ROP reaction ofOPEA and-CL using MePEG2000as the initiator and Sn(Oct)2as the catalyst;2-mercaptoacetic acid was used to react with the carbon-carbon double bonds viathiol-ene reaction to obtain MePEG-b-P(CL-co-OPEA-COOH); and then, histamine (His)was conjugated to the pendant groups in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andN-hydroxysuccinimide via amidation reaction and give MePEG-b-P(CL-co-OPEA-His).1H NMR and GPC were used to prove the successful synthesis of above products. Andthe biocompatibility of MePEG-b-P(CL-co-OPEA-His) was demonstrated by MTT assay.This His modified copolymer can be developed as gene carrier to improve the efficiencyof transfection because of the proton buffering effect of His.