用于肿瘤治疗的酶/pH敏感的支化聚合物–阿霉素偶联物（英文）

Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment

本文设计了一种可生物降解的、肿瘤环境敏感的药物释放系统,以达到安全、高效治疗癌症的目的.我们利用单体N-(1,3-二羟基-2-丙基)甲基丙烯酰胺,通过可逆加成-断裂链转移聚合方法制备了含有对肿瘤细胞内组织蛋白酶B敏感的GFLG肽段的支化聚合物–药物偶联物.阿霉素通过pH敏感的腙键偶联到支化聚合物骨架上.支化聚合物药物偶联物可自组装形成纳米粒,平均粒径约为103 nm.连接到聚合物载体的阿霉素可在酸性环境中释放.较高分子量(M_W, 220 kDa)的含有GFLG连接的支化聚合物—阿霉素偶联物可在组织蛋白酶B的作用下降解为低分子量聚合物片段(<40 kDa).支化偶联物通过内吞途径进入细胞,然后释放抗癌药物,进而对肿瘤细胞引起明显的细胞毒性。偶联物的血液循环时间显著延长,使得阿霉素在肿瘤部位大量蓄积. 4T1荷瘤小鼠体内抗肿瘤实验表明,支化偶联物的抗肿瘤效果优于游离阿霉素.此外,体重测量和组织形态学检查的结果表明支化偶联物对正常组织的毒性很低.因此,这种对细胞内的酶和肿瘤组织或细胞内的酸性pH具有响应性的支化聚合物给药系统在肿瘤靶向治疗中具有一定的前景.

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.