Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taken paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10⁻³ g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers.

嵌段共聚物前药（BCP）由于自组装成定义明确的核-壳纳米颗粒以改善药代动力学，血液循环的稳定性而没有药物泄漏以及优化的生物分布，因此在纳米医学的临床翻译中引起了广泛的关注。然而，阻止药物特异性递送至肿瘤细胞的生理障碍的级联限制了最终的治疗功效。在本文中，我们报告了一种基于硫代内酯化学的稳健而简便的策略，以制造具有明确定义的BCP，并具有连续的肿瘤pH值促进细胞内在化和细胞内刺激反应性药物释放。通过一锅合成从临床使用的小分子抗癌药物中制备了一系列BCP。药物共轭硫代内酯的开环反应释放巯基经由通过氨解ñ - （3-氨基丙基） -咪唑，其进一步与聚（乙二醇）反应-嵌段-聚（甲基丙烯酸乙酯吡啶基二硫化物）（PEG-PDSEMA）以产生咪唑和二硫键并入过境点。以紫杉醇（PTX）为例，PTX BCP的载药量高（> 50％），临界胶束化浓度低（5×10 ^-3  g / L），可以在水溶液中自组装成胶束纳米颗粒。小尺寸（〜40 nm）。纳米颗粒显示出hypopermeable肿瘤高肿瘤积累和均匀分布通过系统管理。同时，咪唑基团赋予纳米颗粒肿瘤pH敏感的电荷从近乎中性转变为正电荷，从而促进了细胞内在化。癌细胞的细胞内谷胱甘肽（GSH）可以切割二硫键，从而加速细胞内活性PTX药物的释放。最后，PTX BCP纳米粒子治疗后完全消灭了高度侵袭性的鼠类乳腺癌4T1肿瘤和渗透性低的人胰腺腺癌BxPC3肿瘤。因此，基于硫代内酯化学的稳健而简便的制备策略代表了一种通过解决多种生理障碍来构建多功能BCP以获得更好疗效的有效方法。