Key Laboratory of High Performance Polymer Material and Technology of Ministry of Education, Department of Polymer Science & Engineering, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210023, China.
ACS Appl Mater Interfaces. 2021 Dec 1;13(47):55851-55861. doi: 10.1021/acsami.1c16962. Epub 2021 Nov 17.
Temozolomide (TMZ) is a prodrug of 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC, short-lived) and used as a first-line therapy drug for glioblastoma multiforme (GBM). However, little progress has been made in regulating the kinetics of TMZ to MTIC degradation to improve the therapeutic effect, particularly in the case of TMZ-resistant GBM. In this work, we introduced a strategy to cage MTIC by N-acylation of the triazene moiety to boost the MTIC stability, designed a diblock copolymer-based MTIC prodrug installed with a disulfide linkage, and achieved self-assembled polymer micelles without the concern of MTIC leakage under physiological conditions. Polymer micelles could be induced to disassemble by stimuli factors such as glutathione (GSH) and visible light irradiation through thiol/sulfide exchange and homolytic sulfide scission mechanisms, which contributed to MTIC release in GSH-dependent and GSH-independent pathways. The in vitro results demonstrated that microenvironment-responsive polymeric micelles benefited the suppression of both TMZ-sensitive and TMZ-resistant GBM cells. The chemistry of polymer-MTIC prodrug provided a new option for TMZ-based glioma treatment.
替莫唑胺（TMZ）是 5-(3-甲基三嗪-1-基)咪唑-4-甲酰胺（MTIC，短寿命）的前体药物，用作多形性胶质母细胞瘤（GBM）的一线治疗药物。然而，在调节 TMZ 向 MTIC 降解的动力学以提高治疗效果方面，几乎没有取得进展，特别是在 TMZ 耐药的 GBM 中。在这项工作中，我们通过三嗪部分的 N-酰化引入了一种将 MTIC 笼封的策略，以提高 MTIC 的稳定性，设计了一种带有二硫键的基于两亲嵌段共聚物的 MTIC 前药，并在生理条件下实现了自组装聚合物胶束，而无需担心 MTIC 泄漏。聚合物胶束可以通过谷胱甘肽（GSH）和可见光照射等刺激因素诱导解组装，通过巯基/硫醚交换和均裂硫醚断裂机制促进 MTIC 的释放，这有助于 GSH 依赖和非依赖途径中的 MTIC 释放。体外结果表明，对微环境响应的聚合物胶束有利于抑制 TMZ 敏感和 TMZ 耐药的 GBM 细胞。聚合物-MTIC 前药的化学为基于 TMZ 的脑肿瘤治疗提供了新的选择。
