CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China; Department of Pharmacology, Xin Hua University of Anhui, Hefei, Anhui 230088, China.
Biomaterials. 2018 Feb;154:261-274. doi: 10.1016/j.biomaterials.2017.11.006. Epub 2017 Nov 9.
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. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10 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（BCPs）由于能够自组装成具有良好定义的核壳纳米粒子，从而改善药代动力学、在血液循环中稳定而无药物泄漏，并优化生物分布，因此在纳米医学的临床转化中引起了相当大的关注。然而，一系列针对药物特异性递送到肿瘤细胞的生理屏障限制了最终的治疗效果。在此，我们报告了一种基于硫内酯化学的稳健且简便的策略，用于构建具有顺序肿瘤 pH 促进细胞内化和细胞内刺激响应药物释放的良好定义的 BCP。通过一锅法从临床使用的小分子抗癌药物合成了一系列 BCP。通过 N-(3-氨基丙基)-咪唑的氨解，药物偶联的硫内酯的开环反应释放巯基，然后进一步与聚（乙二醇）-嵌段-聚（吡啶二硫代乙基甲基丙烯酸酯）（PEG-PDSEMA）反应生成含咪唑和二硫键的 BCP。以紫杉醇（PTX）为例，PTX BCP 表现出高载药量（>50%）和低临界胶束浓度（5×10 g/L），可在水溶液中自组装成具有小尺寸（约 40nm）的胶束纳米粒子。通过全身给药，纳米粒子在低渗透性肿瘤中具有高肿瘤积累和均匀分布。同时，咪唑基团赋予纳米粒子肿瘤 pH 敏感的电荷从近中性到正的转变，从而促进细胞内化。二硫键可以被癌细胞内的谷胱甘肽（GSH）裂解，从而加速细胞内活性 PTX 药物的释放。最后，经过 PTX BCP 纳米粒子治疗后，高度侵袭性的小鼠乳腺癌 4T1 肿瘤和低渗透性的人胰腺腺癌 BxPC3 肿瘤完全被消融。因此，基于硫内酯化学的稳健且简便的制备策略代表了一种通过解决多种生理屏障来构建更好治疗效果的多功能 BCP 的有效方法。
