Synthesis And Multifunctional Modification Of Amphiphilic Copolyester Based On Polyphosphoesters

Polyphosphoester （PPE） is a class of biodegradable polymers with repeatedphosphoester bonds in the backbone. Due to the pentavalency of the phosphorous atomsin main chain, the pendant groups in PPE can be readily modified functionally andallowed the conjugation of bioactive molecules, resulting in all kinds of functionalpolyphosphoesters. Meanwhile, considered the properties of biocompatibility, cellularaffinity and capability of cell membrane permeability, PPE has gained more and moreattentions in biomedical applications.This dissertation is part of the National Natural Science Foundation of China“Design and Research of Functional Polymer Carriers based on Phosphoester（21074078）”. We designed to prepare a kind of amphiphilic polyesters with acryloyl inpendant groups of polyphosphoester. The polyesters would have good biocompatibility,full biodegradability and multifunctional modification. Both Michael-type additionreaction and thiol-ene reaction methods were utilized to modify the pendant groups ofthe polyesters. A series of biodegradable copolyesters with various functionalizedpendant groups were synthesized. The chemical structures and properties of thesecopolyesters were characterized. In addition, these copolyesters were further used asdrug delivery carries, and their biophysical properties were evaluated.The main contents and conclusions of this dissertation are summarized in threeparts:（1） Preparing cyclic phosphoester monomer [2-（2-oxo-1,3,2-dioxaphospholoyloxy）ethyl acrylate]（OPEA） with acryloyl in pendant group.Poly（ε-caprolactone）（PCL-OH） with hydroxyl group in the end of the chain wasutilized as macroinitiator and Sn（Oct）₂was used as the catalyst. The parent diblockcopolymer PCL-b-POPEA was synthesized via ring-opening polymerization （ROP）. Therefore, the diblock copolymer had good biocompatibility and full biodegradability.In this work, we firstly introduced carbon carbon double bond （C=C） intopolyphosphoester segment, and then the carbon carbon double bond could further reactwith mercaptans via Michael-type addition reaction, resulting in a series offunctionalized block copolymers bearing diverse side groups （e.g. hydroxyl, carboxyl,amine, and amino acid）. The chemical structures of these block copolymers werecharacterized by NMR spectroscopy (¹H NMR,¹³C NMR and³¹P NMR), gelpermeation chromatography （GPC）, and fourier transform infrared spectrometer （FT-IR）.In vitro cytotoxicity test by3-（4,5）-dimethylthiahiazo （-z-y1）-3,5-di-phenytetrazoliumromide （MTT） assay indicated that all the copolyesters possessed goodbiocompatibility, which measured up to the expected results.（2） Discussions of self-assembly behaviors of amphiphilic block copolymersPCL-b-POPEA in aqueous solution. The block copolymers assembled micellarnanoparticles with PCL as nucleus and POPEA as shell materials. The morphology, sizeand size distribution of the self-assembly nanoparticles of PCL-b-POPEA blockcopolymers were determined by transmission electron microscopy （TEM） andhigh-performance particle size instrument （HPPS）. Due to the good biocompatibilityand full biodegradability, the micellar nanoparticles were used as drug delivery carries.Initial drug loading and release studies using Doxorubicin （DOX） as a model drugdemonstrated a faster release in the presence of phosphodiesterase I as compared to thesystem without enzyme. Moreover, it was found that DOX-loaded nanoparticlesdisplayed higher inhibition to KB cells proliferation in comparison with DOX in freeform.（3） Random copolymers P（CL-co-OPEA） with acryloyl group were synthesizedvia ROP by mixed monomers of ε-caprolactone （ε-CL） and cyclic phosphoestermonomer OPEA. Benzyl alcohol was used as initiator and Sn（Oct）2was used as thecatalyst. Carboxyl groups were introduced to pendant groups of the random copolymersby thiol-ene reaction. Then galactosamine can be further conjugated topolyphosphoester segment of the random copolymer by the amidation reaction. NMRand GPC analyzed the chemical structures of these random copolymers. It was proved by¹H NMR spectroscopy that carboxyl groups appeared in the pendant groups in thepolyphosphoester segment and the conjugation with amino of galactosamine. As a result,this kind of random copolymers would self-assemble into micellar nanoparticles andtarget to cancer cells.