Study On Synthesis And Properties Of Dual Enzyme Responsive Linear And Star-Shaped Poly (D,L-Lactic Acid)-b-Poly(N-Vinylpyrrolidone) Copolymers

Compared with linear polymers,star-shaped polymers have a wide application prospect in intelligent drug delivery systems,especially in controlling and targeting drug delivery carriers,due to their unique three-dimensional topological structure and low hydrodynamic volume.Enzymes are biocatalysts and play an important role in the regulation of cell and tissue metabolism,while the occurrence of some human diseases is often caused by the abnormal expression of specific enzymes.Due to its good biocompatibility and high selectivity,enzyme-responsive polymer micelles can achieve targeted drug release according to the overexpression of enzymes in specific sites.At present,there are few reports on the research of the dual enzyme responsive star-shaped block copolymers.In this thesis,dual enzyme responsive linear and star-shaped copolymers were synthesized and their enzymatic response behavior was studied.The synthesis is divided into two parts:（1）Poly（N-vinylpyrrolidone）-b-poly（D,L-lactic acid）copolymers（PNVP-Phe-Lys-b-PDLLA）with a phenylalanyl-lysine（Phe-Lys）dipeptide linkage were synthesized by combining xanthate-regulated reversible addition-fracture chain transfer（MADTX/RAFT）radical polymerization,ring-opening polymerization（ROP）and azido-acetyl"click reaction"（Cu AAC）;（2）Three star-shaped block copolymers（S-（PDLLA-Phe-Lys-b-PNVP）₄）with various hydrophilic/hydropholic ratios based on PNVP and PDLLA with a Phe-Lys dipeptide linkage were synthesized by a combination of the MADTX/RAFT polymerization and ring opening polymerization（ROP）using"core first"method.The structure and molecular weight of the synthesized linear and star shaped copolymers were characterized and analyzed by ¹H NMR spectra and gel permeation chromatography（GPC）,which proved that the target product were successfully synthesized.The self-assembly behavior in aqueous solution and enzymatic responsive properties of the linear and star-shaped copolymers were studied by ¹H NMR spectra,fluorescence,transmission electron microscopy（TEM）and particle size analyzer.The results showed that linear and star-shaped copolymers could self-assemble into spherical micelles in aqueous solution.The critical micelle concentration（CMC）of star-shaped copolymers increased with the increase of the proportion of hydrophilic segments,but were lower than those of linear copolymers,showing good stability.The copolymer micelles can loaded the lipophilic dye Nile red and anticancer drug apigenin.After the addition of protease K or trypsin respectively,the copolymer micelles can disassemble and release the encapsulated the small molecules.Morever,after the addition of trypsin and protease K simultaneously,the micelles disassembly of the micelles was accelerated.Star-shaped copolymer micelles have higher drug loading capacity and loading efficiencies than linear copolymer micelles,but are more stable,and the release rate of the encapsulated drug is slower.