Zhong Haiping, Mu Jingqing, Du Yanyan, Xu Zunkai, Xu Yang, Yu Na, Zhang Shubiao, Guo Shutao
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 Biotechnology and Bioresources Utilization of Ministry of Education , Dalian Minzu University , Dalian 116600 , China.
Biomacromolecules. 2020 Feb 10;21(2):803-814. doi: 10.1021/acs.biomac.9b01493. Epub 2020 Jan 29.
Nucleoside analogue drugs are widely used in cancer therapy and antiviral therapy, while fast metabolism, drug resistance, and severe side effects significantly limit their clinical applications. To address these issues, a variety of ester- and amide-linked prodrugs and their nanoparticulate formulations have been devised. However, most of these prodrugs suffer from inefficient transformation to native drugs in tumor. Here, we report an approach to conjugate gemcitabine, a kind of anticancer nucleoside drug and widely used to treat cancers, to polyketal backbone via pH-sensitive ketal linkage, and prepared gemcitabine-containing polyketal prodrug nanoparticles with minimal drug release under physiological conditions and acid-triggerable release of native gemcitabine. Intracellular and intratumoral degradation of the pH-sensitive gemcitabine-containing polyketal prodrug and incorporation of gemcitabine into DNA were confirmed by confocal microscopy using EdU, an analogue of gemcitabine. One single intravenous injection of these gemcitabine-containing polyketal prodrug nanoparticles demonstrated notable anticancer efficacy in the A2780 ovarian xenograft tumor model with increased survival rate and good safety. Our approach can be adopted for other diol nucleoside analogues to synthesize pH-sensitive nucleoside-polyketal prodrugs for developing anticancer and antiviral formulations.
核苷类似物药物广泛应用于癌症治疗和抗病毒治疗，然而其快速代谢、耐药性和严重的副作用显著限制了它们的临床应用。为了解决这些问题，人们设计了多种酯键和酰胺键连接的前药及其纳米颗粒制剂。然而，这些前药中的大多数在肿瘤中向天然药物的转化效率低下。在此，我们报道了一种通过pH敏感的缩酮键将吉西他滨（一种抗癌核苷药物，广泛用于治疗癌症）与聚缩酮主链偶联的方法，并制备了含吉西他滨的聚缩酮前药纳米颗粒，其在生理条件下药物释放极少，且能在酸性条件下触发天然吉西他滨的释放。使用吉西他滨类似物EdU通过共聚焦显微镜证实了含pH敏感的吉西他滨的聚缩酮前药在细胞内和肿瘤内的降解以及吉西他滨掺入DNA。单次静脉注射这些含吉西他滨的聚缩酮前药纳米颗粒在A2780卵巢异种移植肿瘤模型中显示出显著的抗癌疗效，提高了生存率且安全性良好。我们的方法可用于其他二醇核苷类似物，以合成pH敏感的核苷 - 聚缩酮前药，用于开发抗癌和抗病毒制剂。
