Therapeutic application of unmodified camptothecin (CPT) is severely restricted by its extremely low water solubility and the instability of active lactone ring. In this study, a redox-sensitive CPT-OA conjugate containing the disulfide bond (CPT-SS-OA) was used to deliver the lactone-stabilized CPT for the improved antitumor efficacy. A non-sensitive CPT-OA was used as control to illuminate the role of disulfide bond. Both CPT-SS-OA and CPT-OA formulated in cremophor EL micelles (CM) displayed multiple therapeutic advantages: small diameter (∼14 nm), efficient cellular internalization, prolonged blood circulation, and favorable biodistribution. However, only CPT-SS-OA/CM achieved the superior chemotherapeutic efficacy over CPT solution in the Lewis lung carcinoma (LLC) cancer xenograft, which was ascribed to the accelerated release of the active lactone CPT responding to the elevated reductive glutathione in tumor cells. Such redox-sensitive lipophilic prodrugs represent an effective alternative strategy for the delivery of CPT in the active lactone form. This strategy can be used for other chemically unstable chemotherapeutant for the improved therapeutic efficacies.

中文翻译：

---

氧化还原敏感的亲脂性前药：提供不稳定的化疗剂以改善癌症治疗。


未修饰的喜树碱（CPT）因其极低的水溶性和活性内酯环的不稳定性而严重限制其治疗应用。在这项研究中，使用含有二硫键的氧化还原敏感的喜树碱-OA缀合物（CPT-SS-OA）来传递内酯稳定的喜树碱，以提高抗肿瘤功效。使用不敏感的 CPT-OA 作为对照来阐明二硫键的作用。以 Cremophor EL 胶束 (CM) 配制的 CPT-SS-OA 和 CPT-OA 均具有多种治疗优势：直径小（~14 nm）、有效的细胞内化、延长血液循环和良好的生物分布。然而，在 Lewis 肺癌 (LLC) 癌症异种移植物中，只有 CPT-SS-OA/CM 取得了优于 CPT 溶液的化疗效果，这归因于活性内酯 CPT 响应肿瘤细胞中还原性谷胱甘肽升高而加速释放。 。这种氧化还原敏感的亲脂性前药代表了以活性内酯形式递送喜树碱的有效替代策略。该策略可用于其他化学不稳定的化疗药物以提高治疗效果。