Synthesis And Construction Of Drug Delivery Systems From Novel Biodegradable Poly (Ethylene Glycol)-polylactide Diblock Copolymers

With the development of modern medicine,biodegradable polymers have been widely used in drug delivery systems.They have received great attention because of their good biocompatibility and biodegradability.Polylactide(PLA),polyglycolic acid(PGA),poly(?-caprolactone)(PCL)and their copolymers with poly(ethylene glycol)(PEG)have been used in the biomedical field,including wound closure,tissue repair,tissue regeneration,tissue engineering scaffolds and drug delivery systems.Filomicelles prepared from amphiphilic block copolymers have been widely studied as drug carriers.The nanoscale of the filomicelles has high permeability and retention effect(EPR effect),which can reduce the phagocytosis of the reticuloendothelial system(RES)and facilitate its circulation in the blood.Therefore,it is of great significance to study amphiphilic copolymer filomicelles for sustained drug delivery.The aim of this work was to study biodegradable filomicelles prepared from PLA-PEG diblock copolymers for drug delivery system.A series of PLA-PEG diblock copolymers were synthesized by ring-opening polymerization of L-lactide using monomethoxy PEG as macroinitiator and zinc lactate as catalyst.Filomicelles were prepared from the resulting copolymers by co-solvent evaporation method.It was confirmed that the structure of the self-assembled aggregate mainly depends on the hydrophilic/hydrophobic balance of the amphiphilic copolymer,and the filomicelles was obtained by the copolymer having a longer PLLA block.In order to prepare micelles with a faster degradation rate,PGA component was introduced into the PLLA-PEG backbone.The results showed that the PLGA-PEG self-assembled micelles were spherical,since the addition of PGA component may destroy the regularity of the PLA-PEG chain structure.However,PLGA-PEG micelles have nanostructures and can still be further studied as drug carriers.Various aspects of biocompatibility were considered,including MTT assay,agar diffusion test,release of cytokines,hemolytic test,dynamic clotting time,protein adsorption in vitro,and zebrafish embryonic compatibility in vivo.The combined results revealed that the PLA-PEG and PLGA-PEG micelles present good cytocompatibility and hemocompatibility in vitro.Moreover,the cumulative effects of micelles throughout embryos deveploping stages have no toxicity in vivo.A hydrophobic anticancer drug,cycloprotoberberine derivative A35,was successfully loaded in PLA-PEG filomicelles by co-solvent evaporation or membrane hydration methods with high encapsulation efficiency(above 88%).Berberine(BBR)was studied for comparison.In both methods,PLA-PEG filomicelles were prepared with a theoretical loading of 5%,10%and 20%.Physical stability studies indicated that BBR/A35-loaded filomicelles were more stable when stored at 4~oC than at 25~oC.Compared with BBR-loaded filomicelles,A35-loaded filomicelles exhibited higher antitumor activity.At the same drug concentrations,free drug solutions exhibit higher antitumor activity than drug loaded micelle solutions,which could be assigned to the slow drug release process for the latter.