Preparation Of Oxaliplatin Loaded Sterically Stabilized And Targ Eted Liposomes, And Its Study On Antitumor Activity

This project aimes to develop a new type of Oxaliplatin-loaded sterically stabilized and targeted Liposome and investigate its anti-tumor effect on gastric caner cells. Gastric cancer is one of the most common malignant tumors of digestive tract. The current chemotherapeutic drug for gastric cancer is oxaliplatin, which gradually replaced the classical chemotherapy drug cisplatin due to its remarkable curative effect. But at the same time oxaliplatin also causes severe side effects on other organs. Besides, because of its short half-life time oxaliplatin cannot sustain cytotoxic effects on lesions, so that the survival rate of patients is not dramatically improved.As artificial double phospholipids, liposome is able to encapsulate drugs in the lipid bilayer, thus to stabilize drugs in vivo. The anti-tumor effect of drug-loaded liposome can be improved by adding sterically stabilized or targeted segment. Liposomes loaded with sterically stabilized fragment like polyethylene glycol(PEG) could avoid the attraction of reticuloendothelial system, so that the circulation time of liposomes in blood will be extended. It has been reported that, on the surface of gastric cancer cells estrogen receptor(ER) are over-expressed higher than in normal tissues, thus ER acts as a potential target for cancer targeted therapy. The drug-loaded liposomes modified with ER could specifically target tumor cells and further release chemotherapeutic drugs in cells.In this thesis we prepared different oxaliplatin loaded liposomes(conventional liposomes L-OXA, targeted liposomes ES-L-OXA, sterically stabilized liposomes SSL-OXA and sterically stabilized and targeted liposomes ES-SSL-OXA) via thin film hydration method. The characteristics of liposomes were studied by the detection of encapsulation efficiency, drug-loading capacity, Zeta potential, PDI and particle size. The results showed that the encapsulation rate of oxaliplatin liposomes was in the range of 46%~50% and the drug loading capacity was about 3%~4%. The sterically stabilized and targeted liposomes charged for-28.13±0.21 mV. Its PDI value was 0.162 + 0.007 and it suggested that it has good dispersion. The gastric cancer cells SGC-7901 were treated with free oxaliplatin and the four oxaliplatin loaded liposomes respectively. The results of this experiment explored that, the anti-tumor effect of drugs is concentration and time dependent and ES-SSL-OXA obtained the greatest anti-tumor effect. It has been observed that, after incubation for 2h the cells toke the highest dosis of liposomes, further, the cells still contained pretty much liposomes after 3h. This result confirmed that, liposomes could sustain in cells, especially ES-SSL-B due to its targeting property. The result of inhibition assay of cellular uptake indicated that, the cellular uptake of liposomes relied on estrogen receptor-mediated endocytosis and endocytosis and pinocytosis mediated by caveolin. ES-SSL-OXA can inhibit the tumor and treat them effectively through the in vivo antitumor test.In this thesis, the stable oxaliplatin liposomes were successfully prepared by thin film hydration method. Base on the results of the targeting and anti-tumor experiments, we suppose this new type of oxaliplatin liposomes could have a great development space as a new dosage form. This work also provides a new idea for the clinical treatment of gastric cancer.