Abstract To cope with the poor aqueous solubility of withaferin A, a broad-spectrum anti-cancer agent effective against therapy-resistant cancers, a polymer-drug conjugate was synthesized via a grafting-from-drug approach. Modification of withaferin A at the C27-OH with a chain transfer agent (CTA) for reversible addition-fragmentation chain transfer (RAFT) polymerization through a degradable ester bond was achieved with excellent control on the regioselectivity via a PFP-ester transesterification route. Subsequent RAFT polymerization with the hydrophilic N,N-dimethylacrylamide yielded a fully water-soluble conjugate. A decreased cytotoxicity in vitro indicated that withaferin A exists as a prodrug in the conjugate form and requires hydrolysis of the ester to regain its activity.

中文翻译：

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通过药物功能化 RAFT CTA 方法制备水溶性 Withaferin A 聚合物前药

摘要 为了解决 withaferin A（一种对治疗耐药的癌症有效的广谱抗癌剂）水溶性差的问题，通过从药物接枝的方法合成了聚合物-药物偶联物。用链转移剂 (CTA) 在 C27-OH 处修饰 withaferin A，通过可降解的酯键实现可逆加成-断裂链转移 (RAFT) 聚合，并通过 PFP-酯酯转移途径对区域选择性进行了出色的控制。随后与亲水性 N,N-二甲基丙烯酰胺的 RAFT 聚合产生了完全水溶性的共轭物。体外细胞毒性降低表明，withaferin A 作为前药以缀合物形式存在，需要将酯水解以恢复其活性。