Despite the recent advances of controlled polymerization methods over the last decades, the lack of backbone degradability of well‐defined polymers remains a major synthetic challenge that limits the full exploitation of polymer–drug conjugates (PDCs) in clinical practice. Here, we report the copolymerization of a cyclic ketene acetal (CKA) and a vinyl‐based drug‐monomer as a proof‐of‐concept approach to prepare model polyester‐based prodrugs via reversible addition‐fragmentation chain‐transfer (RAFT) polymerization. We demonstrate the versatility of the system toward backbone degradability and control over the chain length while maintaining both low dispersity (Đ_M) and homogenous distribution of degradation points along the main polymer chain. The resulting PDCs exhibit unique self‐assembly properties and potent cytotoxicity against pancreatic cancer cells. A methacrylate prodrug is copolymerized with a CKA co‐monomer using RAFT polymerization producing a backbone degradable PDC with well‐defined molecular structure. The resulting PDC undergoes controlled backbone degradation and produces by‐products of narrow dispersity and low toxicity. In addition, it is demonstrated that the insertion of degradation segments does not affect the cytotoxic properties of the PDC under in vitro conditions.

中文翻译：

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可逆的加成-断裂链转移聚合合成的定义明确的骨架可降解聚合物-药物共轭物

尽管最近几十年来控制聚合方法取得了最新进展，但定义良好的聚合物缺乏主链可降解性仍然是一个主要的合成挑战，这限制了临床实践中聚合物-药物缀合物（PDC）的充分利用。在这里，我们报告了环烯酮缩醛（CKA）和乙烯基类药物单体的共聚，这是概念验证方法，可逆加成-断裂链转移（RAFT）聚合制备基于聚酯的模型前药。我们证明该系统对骨干降解性和控制链长的多功能性，同时保证了低分散性（DJ_中号）和降解点沿主聚合物链的均匀分布。所得的PDC具有独特的自组装特性和对胰腺癌细胞的强大细胞毒性。使用RAFT聚合将甲基丙烯酸酯前药与CKA共聚单体共聚，产生具有明确分子结构的骨架可降解PDC。产生的PDC受到受控的主链降解，并产生分散性窄和毒性低的副产物。另外，已证明降解片段的插入在体外条件下不影响PDC的细胞毒性。