Zhong Haiping, Li Xingwei, Yu Na, Zhang Xi, Mu Jingqing, Liu Tao, Yuan Bo, Yuan Xiaoyong, Guo Shutao
Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University Tianjin 300071 China
Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital Tianjin 300020 China.
Chem Sci. 2023 Mar 17;14(14):3789-3799. doi: 10.1039/d3sc00550j. eCollection 2023 Apr 5.
The maintenance of robust ratiometric loading of dual therapeutic agents and fine-tuning release kinetics for consistent and optimization of combination effects is vital for discovering new anticancer drug combinations and remains challenging. Smart nanomedicine strategies have been investigated for this purpose, but most of the reported strategies focus either on ratiometric delivery or on unimodal sequential release of the two different agents, which hampers effective optimization of combination effects. Herein we report a sequential drug release system based on nanoformulated mutual prodrugs constructed by the formation of ketal linkages with different acid sensitivities, thus enabling the acid-triggered release of two anticancer drugs, paclitaxel and gemcitabine, in various sequences. We found that in several cell lines, the sequence of drug release substantially affected the combination effects; specifically, in A549 cells, time-staggered release profiles showed enhanced synergistic effects relative to those of a simultaneous release profile. Moreover, assessment of the antitumor efficacy of the nanoformulations in A549 xenograft models indicated that the best therapeutic effects were obtained with time-staggered release profiles, which was consistent with the results. Our strategy for precisely controlled sequential drug release can be expected to facilitate the screening of optimal drug combinations and maximize combination effects both and .
维持两种治疗药物的稳健比例加载以及微调释放动力学以实现联合效应的一致性和优化，对于发现新的抗癌药物组合至关重要且仍具挑战性。为此人们研究了智能纳米药物策略，但大多数已报道的策略要么侧重于比例递送，要么侧重于两种不同药物的单峰顺序释放，这阻碍了联合效应的有效优化。在此，我们报告了一种基于纳米制剂互变异构体的顺序药物释放系统，该互变异构体通过形成具有不同酸敏感性的缩酮键构建而成，从而能够以各种顺序实现酸触发的两种抗癌药物紫杉醇和吉西他滨的释放。我们发现，在几种细胞系中，药物释放顺序显著影响联合效应；具体而言，在A549细胞中，相对于同时释放模式，时间交错释放模式显示出增强的协同效应。此外，对纳米制剂在A549异种移植模型中的抗肿瘤疗效评估表明，时间交错释放模式获得了最佳治疗效果，这与结果一致。我们精确控制顺序药物释放的策略有望促进最佳药物组合的筛选，并在体内和体外最大化联合效应。
