Studies On The Fabrication And Performance Of Ph-responsive Micelles

In recent years,polymeric micelles self-assembled from amphiphilic copolymers as drug delivery system have made a remarkable progress.However,slow drug release from the micelles after their internalization into the tumor cells is one of the major drawbacks for their application in vivo.The research findings showed that stimuli-responsive polymeric micelles could accelerate the drug release in tumor cells.Anionic drug carriers are more biocompatible,degradable and less toxic than the cationic drug carriers.Moreover,the anionic micelles have an electrostatic absorption effect with the charged biological molecules,such as doxorubicin(DOX).Therefore,the anionic amphiphilic copolymers may have much more potential applications as the drug carrier.In this paper,the main contents are as follows:(1)Combination of ring-opening polymerization and click reaction,biodegradable copolymers bearing carboxylic groups of P(COOHCLCL)-PEG-P(COOHCLCL)were synthesized and characterized.The self-assembly behavior of these copolymers were studied by the evaporation and dialysis methods.The results showed that the micelles with small size,narrow size distribution and good stability.Compare with the PCL-PEG-PCL micelles,P(COOHCLCL)-PEG-P(COOHCLCL)polymeric micelles showed pH-responsive properties.The cytotoxicity results indicated that blank micelles were no significant cytotoxicity to L929 and Hela cells even at a high concentration of 0.8 mg/mL following 24 h incubation.Moreover,DOX-loaded micelles inhibited the growth of Hela cells remarkably,demonstrating its high efficiency of antitumor activity.The phagocytosis by murine peritoneal macrophage showed that the uptake probability of polymeric micelles was greatly reduced.Flow cytometry and inverted fluorescence microscope demonstrate the negative charged micelles although was not conductive to endocytosis,the enhanced intracellular release of DOX from micelles in hela cells also strengthened the intracellular fluorescence intensity.(2)Although the negative charged micelle has higher drug loading capacity,the drug release quickly at pH 7.4,and negative charged micelle was not conductive to endocytosis,which will reduce the bioavailability of the drug.So,we studied the mixed micelles of the anionic amphiphilic copolymer P(COOHCLCL)-PEG-P(COOHCLCL)and cationic amphiphilic copolymer PDMAEMA-PCL.The results showed that the mixed micelles with the weight ratio of 5:5 also have small particle size,narrow particle size distribution and good stability.In vitro cytotoxicity showed that the blank polymeric micelles were non-toxic and biocompatible to L929,Hela and MCF-7 cells when the concentration was below 0.08 mg/mL.However,DOX loaded micelles displayed strong toxicity to the Hela and MCF-7 cells even the concentration lower than 0.01 mg/mL.Interestingly,these experimental results showed that anionic copolymers could reduce the toxicity of cationic copolymer to a certain extent.