In this study, to enhance the therapeutic function and reduce the side-effects of doxorubicin (DOX), a biodegradable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer–DOX conjugate has been prepared through reversible addition fragmentation chain transfer (RAFT) polymerization and conjugation chemistry, and the anticancer agent DOX was covalently linked to the polymeric vehicle through a pH-responsive hydrazone bond. The cellular mechanisms of the conjugate were explored, and the therapeutic indexes were studied as well. The high molecular weight (MW) polymeric conjugate (94 kDa) was degraded into products with low MW (45 kDa) in the presence of lysosomal cathepsin B and also showed pH-responsive drug release behavior. In vitro cellular mechanism studies revealed that the polymeric conjugate was uptaken by the 4T1 cells, leading to cell apoptosis and cytotoxicity to cancer cells, while the polymeric conjugate demonstrated excellent in vivo biosafety even at a high dose. Compared to free DOX, the conjugate has a much longer half-life in pharmacokinetics and accumulates in tumors with a much higher amount. The conjugate therefore has a much greater in vivo anticancer efficacy against 4T1 xenograft tumors and shows subtle side-effects, which were confirmed via tumor size and weight, immunohistochemistry and histological studies. Overall, this polymeric conjugate may be used as an enzyme/pH-sensitive anticancer agent.

中文翻译：

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酶/ pH敏感的多HPMA-DOX偶联物可作为生物相容性有效的抗癌药†

在这项研究中，为了增强治疗功能并减少阿霉素（DOX）的副作用，已通过可逆加成断裂链转移（RAFT）制备了可生物降解的N-（2-羟丙基）甲基丙烯酰胺（HPMA）聚合物-DOX共轭物。聚合和共轭化学，抗癌剂DOX通过pH响应键共价连接到聚合物载体上。探索了缀合物的细胞机制，并研究了治疗指标。在溶酶体组织蛋白酶B的存在下，高分子量（MW）聚合物共轭物（94 kDa）被降解为低MW（45 kDa）的产物，并且还显示出pH响应的药物释放行为。体外细胞机制研究表明，聚合物结合物被4T1细胞摄取，导致细胞凋亡和对癌细胞的细胞毒性，而聚合物结合物即使在高剂量下也表现出出色的体内生物安全性。与游离的DOX相比，结合物在药代动力学中具有更长的半衰期，并且在肿瘤中的蓄积量要高得多。因此，该缀合物对4T1异种移植肿瘤具有更大的体内抗癌功效，并显示出微妙的副作用，这些副作用已通过肿瘤大小和重量，免疫组织化学和组织学研究得到了证实。总体而言，该聚合物缀合物可以用作酶/ pH敏感的抗癌剂。