Fabrication And Study Of GSH-Responsive Diselenide-Containing Micelles In Drug Delivery

Nowadays Chemotherapy has become the main method to cure cancer in clinical. However, owing to the drug resistance of cancer cells, nonspecific adsorption in blood circulation and some others, chemotherapy usually had fearful side effects and low drug bioactivity. Recently, stimuli-responsive amphiphilic polymers have been increasingly attractive in drug delivery system, such as pH, temperature, or external triggers like light irradiation or magnetic fields, to trigger and realize the release of encapsulated drugs. Among these, the reduction drug delivery systems which are stimuli-response to glutathione(GSH) have been made for cancer cure due to the big difference between normal issue and tumor issue. This paper in view of reducing GSH high expression in tumor cells, two GSH-responsive micelles are prepared. 1. GSH-responsive poly(ethylene glycol)-b-poly(L-lactide) micelles containing diselenide bonds for effective drug deliveryGSH-responsive polymers have emerged as promising drug carriers for cancer therapy due to their excellent properties. They could release drug in a rapid and control behavior with the tumor reducing environment. Recently, the diselenide bond has appeared as a novel reduction-sensitive linkage. In this study, we synthesized an amphiphilic poly(ethylene glycol)-b-poly(L-lactide) drug delivery linked with diselenide bond and used it to load anti-tumor drug, docetaxel(DTX), to form the GSH-responsive micelles. The GSH-responsive micelles showed a rapid response to GSH, which lead to a fast release of DTX in the presence of GSH. On the contrary, less than 40% of DTX was released from the micelles in more than 72 h under the normal condition. The DTX-loaded micelles showed a significant inhibition effect to MCF-7 cells due to their GSH-responsibility. In addition considering the clinical applications of these drug delivery through intravenous injection, we also studied the blood compatibility by the hemolysis analysis, activated partial thromboplastin time, prothrombin time and thromboelastography assays. These results confirmed that the GSH-responsive micelles showed good blood safety, suggesting a potential application in cancer therapy. 2. GSH-responsive prodrug micelles containing diselenide bonds for synergistic effect in cancer therapyCancer is one of the three commom causes of death in the world, and chemotherapy turns out to be a major base of cancer cure. The use of a single drug usually fails to reach an effective result due to the drug resistance in tumor cells. Nowadays co-delivery of multifunctional agents to achieve synergistic effect attracts variety of interests. In this work, to overcome the drug resistance and to enhance the loading efficiency, a novel camptothecin(CPT) prodrug micelles containing diselenide bonds were fabricated. The designed prodrug comprised covalent conjugation with two CPT as hydrophobic block and poly(ethylene glycol) as hydrophilic block via diselenide linker. Drug loading capacity of this prodrug could reach 18.3%. In addition, the obtained prodrug can form micelles in aqueous solutions and is used to load another antitumor drug, curcumin(CUR) with 2.3% of the loading efficiency. The CUR-loaded micelles showed a significant inhibition effect to MCF-7 cells due to the synergistic effect of CPT and CUR. These results indicate that the GSH-responsive prodrug show excellent anticancer effect.