It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer.Herein, a novel pH/enzyme sensitive dendritic pdi HPM...It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer.Herein, a novel pH/enzyme sensitive dendritic pdi HPMADOX conjugate was designed. di HPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic di HPMA polymer through a pH-sensitive hydrazone bond. The dendritic pdi HPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight（M_W, 220 kDa） was cleaved to release low MWsegments（〈40 kDa） in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4 T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.展开更多
基金supported by the National Natural Science Foundation of China (51673127 and 8162103)International Science and Technology Cooperation Program of China (2015DFE52780 and 81220108013)International Science and Technology Cooperation Program of Chengdu (2016-GH03-00005-HZ)
文摘It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer.Herein, a novel pH/enzyme sensitive dendritic pdi HPMADOX conjugate was designed. di HPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic di HPMA polymer through a pH-sensitive hydrazone bond. The dendritic pdi HPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight（M_W, 220 kDa） was cleaved to release low MWsegments（〈40 kDa） in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4 T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.
