A Sequentially Responsive Nanosystem Breaches Cascaded Bio-barriers and Suppresses P‑Glycoprotein Function for Reversing Cancer Drug Resistance

• Published in: ACS applied materials & interfaces Vol. 12; no. 49; pp. 54343 - 54355
• Main Authors: Liu, Jia, Zhao, Lei, Shi, Lin, Yuan, Ye, Fu, Daan, Ye, Zhilan, Li, Qilin, Deng, Yan, Liu, Xingxin, Lv, Qiying, Cheng, Yanni, Xu, Yunruo, Jiang, Xulin, Wang, Guobin, Wang, Lin, Wang, Zheng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.12.2020
• Subjects: acidity; Adenosine Triphosphate - metabolism; Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; beta-Cyclodextrins - chemistry; Biological and Medical Applications of Materials and Interfaces; blood circulation; doxorubicin; Doxorubicin - chemistry; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Carriers - metabolism; Drug Liberation; Drug Resistance, Neoplasm - drug effects; drug therapy; Female; glutathione; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Mice; Mice, Inbred BALB C; multiple drug resistance; Nanoparticles - chemistry; Nanoparticles - metabolism; neoplasms; P-glycoproteins; polymers; Polymers - chemistry; Porosity; porous media; silica; Silicon Dioxide - chemistry; Tissue Distribution; toxicity; multidrug resistance; mesoporous silica nanoparticles; drug delivery; sequentially responsive; charge reversal
• ISSN: 1944-8244; 1944-8252; 1944-8252
• DOI: 10.1021/acsami.0c13852

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-b-PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based carriers (MSNs-SS-Py), and cationic β-cyclodextrin-PEI (CD-PEI) gatekeepers. The PEG-b-PLLDA corona makes RCMSNs stealthy with prolonged blood circulation time. Once tumors are reached, extracellular acidity degrades PEG-b-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 in vitro. Importantly, in preclinical tumor models, DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic toxicity, demonstrating their potential of clinical translation.