Reversing Chemotherapy Resistance by a Synergy between Lysosomal pH-Activated Mitochondrial Drug Delivery and Erlotinib-Mediated Drug Efflux Inhibition

• Published in: ACS applied materials & interfaces Vol. 13; no. 25; pp. 29257 - 29268
• Main Authors: Cheng, Furong, Pan, Qingqing, Gao, Wenxia, Pu, Yuji, Luo, Kui, He, Bin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-06-2021
• Subjects: Biological and Medical Applications of Materials and Interfaces; chemotherapy resistance; nanoparticles; doxorubicin; charge reversal; mitochondrial targeting
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c03196

Mitochondrial drug delivery has attracted increasing attention in various mitochondrial dysfunction-associated disorders such as cancer owing to the important role of energy production. Herein, we report a lysosomal pH-activated mitochondrial-targeting polymer nanoparticle to overcome drug resistance by a synergy between mitochondrial delivery of doxorubicin (DOX, an anticancer drug) and erlotinib-mediated inhibition of drug efflux. The obtained nanoparticles, DE-NPs could maintain negative charge and have long blood circulation while undergoing charge reversal at lysosomal pH after internalization by cancer cells. Thereafter, the acidity-activated polycationic and hydrophobic polypeptide domains boost lysosomal escape and mitochondrial-targeting drug delivery, leading to mitochondrial dysfunction, ATP suppression, and cell apoptosis. Moreover, the suppressed ATP supply and erlotinib enabled dual inhibition of drug efflux by DOX-resistant MCF-7/ADR cells, leading to significantly augmented intracellular DOX accumulation and a synergistic anticancer effect with a 17-fold decrease of IC50 relative to DOX. In vivo antitumor study demonstrates that DE-NPs efficiently suppressed the tumor burden in MCF-7/ADR tumor-bearing mice and led to negligible toxicity. This work establishes that a combination of mitochondrial drug delivery and drug efflux inhibition could be a promising strategy for combating multidrug resistance.