Study On Hypoxia Responsive Polymers And Their Self-assembled Micelles

In the treatment of cancer,radiotherapy,chemotherapy and local surgical resection are the most commonly used treatment methods.But many chemotherapy drugs have some limitations,such as low solubility,high toxicity and poor selectivity,which limit their clinical therapeutic effect on tumor.More and more researchers have discovered that the nano-drug carrier system not only increase the solubility of the drug in the blood,but also target the delivery of the drug to the location of the tumor.This is a key to cancer treatment.In order to decrease the toxic and side effects of anticancer drugs on human normal tissues and cells,and enhance the selectivity of drug release,this work focuses on the development of hypoxia-responsive nano-drug carrier system.Using cyclodextrin,a natural biological material,as the hydrophilic end of amphiphilic micelles,nitrobenzyl chloroformate as the hydrophobic end,polymer nitrobenzyl ester modified ?-cyclodextrin(?-CD-NBCF)was synthesized by ring opening reactions and amide reactions.And the micelles were selfassembled in aqueous solution by dialysis.Hydrogen nuclear magnetic resonance spectroscopy,infrared spectroscopy and gel permeation chromatography were used to characterize the polymer.Its CMC value is 7.83 mg/L measured by using pyrene as a probe.The research results show that the particle size of blank micelle ?-CD-NBCF is 123.6 nm,and the particle size of drug-loaded micelle DOX/?-CD-NBCF is 152.1 nm,with excellent drug loading(up to 11.3%).In vitro drug release experiments also show that it can avoid sudden release under normoxic condition and release DOX quickly under hypoxic condition.In order to improve the stability and drug-loading of polymer micelles,chitosan with a larger molecular weight was utilized as the hydrophilic end of the polymer,and nitrobenzyl chloroformate(NBCF)was also utilized as the response part of the polymer.And the amphiphilic hypoxia-responsive polymer nitrobenzyl ester modified chitosan(CS-NBCF)was synthesized.The results show that the micelle CS-NBCF has better performance in micelle stability,particle size distribution and drug loading.After loading the drug,CS-NBCF exhibit the better results than ?-CD-NBCF in releasing the drug in vitro,and it can release more than68% of the drug quickly under hypoxic condition,but it will not be released suddenly under normoxic condition.It can be found from the cytotoxicity experiment that the toxicity of the blank micelles is low,while DOX-loaded micelles take a good anti-cancer effect under hypoxic condition,and the cell inhibition rate of MCF-7 is high up to 63%.The in vitro cytotoxicity and cancer suppression tests show that amphiphilic hypoxia-responsive micelles have a good inhibitory effect on cancer cells.These results demonstrate that the hypoxiaresponsive polymeric micelles have the potential for anti-cancer drug carriers,which can provide new ideas for the research of controlled drug release systems.