Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China..
J Control Release. 2020 Oct 10;326:265-275. doi: 10.1016/j.jconrel.2020.07.022. Epub 2020 Jul 17.
Paclitaxel is one of the most widely used anticancer agents, but strong side effects and low bioavailability limit its clinical efficacy. The use of tumor microenvironment-responsive prodrugs is promising to solve these problems, and a smart linkage is crucial to achieve the efficient release of paclitaxel from such prodrugs in tumor. Herein, an acid-responsive acetone-based acyclic ketal linkage is used to construct paclitaxel prodrugs with different length of poly(ethylene glycol) (PEG). The PEGylated acetone-based acyclic-ketal-linked prodrugs of paclitaxel (PKPs) self-assembled into nanoparticles that were stable in normal physiological environment but released paclitaxel rapidly in mildly acidic environment in tumor. The length of PEG had considerable impact on size and critical micelle concentration of PKP nanoparticles, thereby affecting prodrug hydrolysis kinetics, pharmacokinetics, biodistribution, and antitumor activity for PKP nanoparticles. In an A2780 xenograft mouse model, PKP nanoparticles displayed improved pharmacokinetics and superior antitumor efficacy against Taxol. Our results demonstrate that acyclic-ketal-based prodrugs are useful for the development of acid-responsive anticancer nanomedicines.
紫杉醇是应用最广泛的抗癌药物之一，但强烈的副作用和低生物利用度限制了其临床疗效。使用肿瘤微环境响应前药有希望解决这些问题，而智能连接对于从这些前药中高效释放紫杉醇至关重要。在这里，我们使用酸响应的丙酮基无环缩酮键来构建具有不同长度聚乙二醇（PEG）的紫杉醇前药。聚乙二醇化的丙酮基无环缩酮连接的紫杉醇前药（PKP）自组装成纳米颗粒，在正常生理环境中稳定，但在肿瘤中轻度酸性环境中迅速释放紫杉醇。PEG 的长度对 PKP 纳米颗粒的大小和临界胶束浓度有很大的影响，从而影响前药的水解动力学、药代动力学、生物分布和 PKP 纳米颗粒的抗肿瘤活性。在 A2780 异种移植小鼠模型中，PKP 纳米颗粒显示出改善的药代动力学和对紫杉醇的优越抗肿瘤功效。我们的结果表明，无环缩酮基前药可用于开发酸响应型抗癌纳米药物。
