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.

紫杉醇是使用最广泛的抗癌药之一，但副作用强，生物利用度低限制了其临床疗效。肿瘤微环境反应性前药的使用有望解决这些问题，而智能连接对于实现紫杉醇从此类前药在肿瘤中的有效释放至关重要。在本文中，基于酸响应性丙酮的无环缩酮键用于构建具有不同长度的聚乙二醇（PEG）的紫杉醇前药。紫杉醇的聚乙二醇化丙酮基无环缩酮连接前药（PKPs）自组装成在正常生理环境中稳定但在肿瘤的弱酸性环境中迅速释放出紫杉醇的纳米颗粒。PEG的长度对PKP纳米颗粒的尺寸和临界胶束浓度有相当大的影响，从而影响前药对PKP纳米粒子的水解动力学，药代动力学，生物分布和抗肿瘤活性。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抗紫杉醇的优异抗肿瘤功效。我们的结果表明，基于无环缩酮的前药可用于开发酸响应性抗癌纳米药物。