Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
ACS Appl Mater Interfaces. 2020 Dec 9;12(49):54343-54355. doi: 10.1021/acsami.0c13852. Epub 2020 Nov 24.
Cancer chemotherapy is challenged by multidrug resistance (MDR) mainly attributed to overexpressed transmembrane efflux pump P-glycoprotein (P-gp) in cancer cells. Improving drug delivery efficacy while co-delivering P-gp inhibitors to suppress drug efflux is an often-used nanostrategy for combating MDR, which is however challenged by cascaded bio-barriers en route to cancer cells and P-gp inhibitors' adverse effects. To effectively breach the cascaded bio-barriers while avoiding P-gp inhibitors' adverse effects, a stealthy, sequentially responsive doxorubicin (DOX) delivery nanosystem (RCMSNs) is fabricated, composed of an extracellular-tumor-acidity-responsive polymer shell (PEG--PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based carriers (MSNs-SS-Py), and cationic β-cyclodextrin-PEI (CD-PEI) gatekeepers. The PEG--PLLDA corona makes RCMSNs stealthy with prolonged blood circulation time. Once tumors are reached, extracellular acidity degrades PEG--PLLDA, reversing nanosystem's surface charges to be positive, which drastically improves RCMSNs' tumor accumulation, penetration, and cellular internalization. Within cancer cells, CD-PEI gatekeepers detach to allow DOX unloading in response to intracellular acidity and glutathione and functionally act as a P-gp inhibitor, dampening P-gp's efflux activity by impairing ATP production. Thus, the resultant high-efficacy drug delivery along with reduced P-gp function cooperatively reverses MDR . Importantly, in preclinical tumor models, DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic toxicity, demonstrating their potential of clinical translation.
癌症化疗受到多药耐药性（MDR）的挑战，主要归因于癌细胞中过度表达的跨膜外排泵 P-糖蛋白（P-gp）。同时递送 P-gp 抑制剂以抑制药物外排来提高药物递送效率是一种常用的纳米策略，用于对抗 MDR，但在递送到癌细胞的过程中会遇到级联生物屏障的挑战，以及 P-gp 抑制剂的不良反应。为了有效地突破级联生物屏障，同时避免 P-gp 抑制剂的不良反应，设计了一种隐匿的、顺序响应的阿霉素（DOX）递送纳米系统（RCMSNs），由细胞外-肿瘤酸度响应性聚合物壳（PEG--PLLDA）、pH/还原双重响应介孔硅纳米粒子载体（MSNs-SS-Py）和阳离子β-环糊精-聚乙烯亚胺（CD-PEI）门控组成。PEG--PLLDA 冠使 RCMSNs 具有延长的血液循环时间，从而具有隐匿性。一旦到达肿瘤部位，细胞外酸度会降解 PEG--PLLDA，使纳米系统的表面电荷变为正电荷，从而极大地提高 RCMSNs 的肿瘤积累、穿透和细胞内化。在癌细胞内，CD-PEI 门控物脱落，以响应细胞内酸度和谷胱甘肽来实现 DOX 的卸载，并通过破坏 ATP 产生来发挥功能，充当 P-gp 抑制剂，抑制 P-gp 的外排活性。因此，高效的药物递送以及降低的 P-gp 功能协同作用逆转了 MDR。重要的是，在临床前肿瘤模型中，DOX@RCMSNs 有力地抑制了 MDR 肿瘤的生长，而没有引起全身毒性，表明了它们在临床转化方面的潜力。
