Construction Of Redox Sensitive Cross-linked Lipoic Acid Nano-carrier And Study On Targeted Anti-tumor Effect

Tumor targeted chemotherapy means targeted delivery chemotherapy drugs to the tumor site using nano-technology to maximize the efficacy while reducing the toxic effects of chemotherapy drugs.The key of tumor nano-targeted therapy is nano-carrier materials.Good nano-carrier material should protect the drug from premature release in systemic circulation but release the drug immediately when they reach the targeted site.Therefore,it is very important to develop a new type and high quality nanocarrier material.Based on the microenvironment of tumor cells and related research,a new type of biodegradable polymer carrier material,crosslinked lipoic acid,was synthesized.The composition of this material is simple and the preparation process is controllable.Meanwhile,it has good stability,low toxicity,the tumor microenvironment sensitive drug release,and economy.Therefore,it has the the potential for commercialization.In vitro and in vivo studies have shown that the carrier material can efficiently deliver chemotherapeutic drugs targeted to the tumor site,and then the material itself degraded to maintain low toxicity.In the first part of this project,the five-membered rings of lipoic acid were catalyzed by cysteine to cross-link itself and the conditions of cross-linking were screened.The lipoic acid nanoparticles were prepared by ultrasonic emulsification method.The synthesis of the carrier material was confirmed by UV and GPC.The results showed that the size of the nanoparticles were about 110 nm and the zeta potention is about-35 mv.TEM figure showed a nearly spherical shape.The stability of the nanoparticles was very good,and the amount of drug loaded was 4.51% ± 0.49%,and the drug release showed tumor microenvironment sensitivity.In the second part of this study,the in vitro cytological evaluation of lipoic acid nanoparticles was carried out.Lung cancer A549 cells were used as target cells.The results showed that blank nanomaterials had lower cytotoxicity and 10-fold higher cell uptakethan DTX.The clathrin and plasma membrane-mediated endocytosis were the mainly cell uptake pathway,and cell uptake localization study showed that lipoic acid nanoparticles can be partially escape lysosomes.CCK-8,apoptosis and cycle studies confirmed that the in vitro tumor cell killing efficacy of the nanoparticles containing docetaxel was enhanced,and its IC50 value was decreased to 79.62 ng/ml as DTX group was 277.84 ng / ml and PLGA-DTX nanoparticles was 135.61 ng / ml.In the third part of this study,lipoic acid nanoparticles were studied in vivo.The results showed that lipoic acid nanoparticles had good tumor targeting properties,which could be accumulated in the tumor site after injection via the tail vein,and could effectively reduce the toxicity of spleen and lungs compared with PLGA nanoparticles.The antitumor efficacy of the nanoparticles was also enhanced.The tumor inhibition rate was increased from 64.8% to 81.62% compared with DTX group,and compared with PLGA-DTX nanoparticles group,the rate was increased from 76.96% to 64.8%.