Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS

作     者：Rong Guoy Yang Longy Zhengze Lu Miao Deng Penghui He Man Li Qin He Rong Guo;Yang Long;Zhengze Lu;Miao Deng;Penghui He;Man Li;Qin He

作者机构：Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education MinistryWest China School of PharmacySichuan UniversityChengdu 610064China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第10期

页      面：1977-1988页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by Major Projects of the National Natural Science Foundation of China(81690261) Sichuan Science and Technology Program(2018RZ0136,China) 

主　　题：Gemcitabine TOS LMWH Tumor metastasis MMP-9 

摘      要：Chemotherapy agents have been widely used for cancer treatment,while the insolubility,instability and toxicity seriously restrict their ***,prodrug strategy was *** some prodrugs are still with poor solubility or stability,a synergy strategy is needed to enhance their ***(GEM)is a prescribed anticancer drug,however,the rapid clearance,growing resistance and serious side effects limit its clinical *** GEM with D-a-tocopherol succinate(TOS)is an effective solution,while the GEM-TOS(GT)is unstable in aqueous solution.D-a-Tocopherol polyethylene glycol succinate(TPGS)has been used to enhance the stability,but GT stabilized by TPGS(GTT)has limited effect on tumor *** metastases lead to high mortality in patients suffering from *** order to further achieve antimetastatic effect,an amphiphilic polymer(LT)was synthesized by connecting low-molecular-weight heparin(LMWH)with TOS,and eventually obtained desired selfdelivery micellar NPs(GLT)by co-assembly GT with *** GLT not only possessed excellent stability,but also inhibited the metastases by acting on different phases of the metastatic *** hydrophobic TOS inhibited the secretion of matrix metalloproteinase-9(MMP-9),the hydrophilic LMWH inhibited the interaction between tumor cells and *** a result,GLT reduced tumor cells entering the blood and implanting at the distant organs,leading to a much more excellent inhibitory effect on the lung metastasis than GEM and GTT.