Li Yaqi, Sun Yixin, Wang Qing, Wang Shuo, Liu Cuiyun, Huang Yuetong, Zhong Wenxin, Wang Xiyan, Wang Wenjing, Zuo Shiyi, Shi Xianbao, Pu Xiaohui, Sun Jin, He Zhonggui, Sun Bingjun
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
School of Chemical Engineering, The University of Adelaide, Adelaide, South Australia 5005, Australia.
ACS Cent Sci. 2024 Nov 20;10(12):2253-2265. doi: 10.1021/acscentsci.4c01004. eCollection 2024 Dec 25.
Prodrug-based nanoassemblies are promising platforms for cancer therapy. Prodrugs typically consist of three main components: drug modules, intelligent response modules, and modification modules. However, the available modification modules are usually hydrophobic aliphatic side chains, which affect the activation efficiency of the prodrugs. Herein, hydrophilic ethylene glycol fragments were inserted between the modification modules and the response modules, and the important effects of hydrophilic fragments on the assembly, drug release, and therapeutic index of the prodrugs were investigated. Notably, the introduction of hydrophilic fragments affected the intermolecular forces of the prodrugs and increased the interaction of hydrogen bonding. In addition, hydrophilic fragments significantly improved the redox drug release profiles, which affected the therapeutic index of the prodrug nanoassemblies. PTX-SS-OA NPs with hydrophilic fragments exhibited increased redox sensitivity, enhanced cytotoxicity, and superior antitumor efficacy. In comparison, PTX-SS-OAL NPs without hydrophilic fragments showed limited redox sensitivity and cytotoxicity but displayed better safety. Overall, the hydrophilic fragment is a critical determinant in modulating the therapeutic index of the prodrug nanoassemblies, which contributes to the development of advanced prodrug nanodelivery systems.
基于前药的纳米组装体是很有前景的癌症治疗平台。前药通常由三个主要成分组成：药物模块、智能响应模块和修饰模块。然而，现有的修饰模块通常是疏水性脂肪族侧链，这会影响前药的活化效率。在此，将亲水性乙二醇片段插入修饰模块和响应模块之间，并研究了亲水性片段对前药的组装、药物释放和治疗指数的重要影响。值得注意的是，亲水性片段的引入影响了前药的分子间作用力并增加了氢键相互作用。此外，亲水性片段显著改善了氧化还原药物释放曲线，这影响了前药纳米组装体的治疗指数。具有亲水性片段的PTX-SS-OA纳米颗粒表现出更高的氧化还原敏感性、增强的细胞毒性和优异的抗肿瘤疗效。相比之下，没有亲水性片段的PTX-SS-OAL纳米颗粒显示出有限的氧化还原敏感性和细胞毒性，但具有更好的安全性。总体而言，亲水性片段是调节前药纳米组装体治疗指数的关键决定因素，这有助于先进前药纳米递送系统的开发。
