Journal
BIOMATERIALS
Volume 275, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2021.120891
Keywords
Furin-responsive; Aggregation; Chemoresistance; Autophagy inhibition; Macrophage polarization
Funding
- National Natural Science Foundation of China [81961138009]
- Research Funds of Sichuan Science and Technology Department [19YYJC2250]
- 111 Project [B18035]
- Fundamental of Research Funds for the Central University
- Key Research and Development Program of Science and Technology Department of Sichuan Province [2020YFS0570]
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The study developed a furin-responsive aggregated nanoplatform to address the challenges of insufficient drug accumulation and chemoresistance in cancer chemotherapy. By loading doxorubicin and hydroxychloroquine, the platform enhanced tumor cell sensitivity to chemotherapy drugs and exerted anti-tumor effects through macrophage polarization.
Insufficient drug accumulation and chemoresistance remain two major challenges in cancer chemotherapy. Herein, we designed a furin-responsive aggregated nanoplatform loaded with doxorubicin (DOX) and hydroxychloroquine (HCQ) (AuNPs-D&H-R&C) to combine chemotherapy, autophagy inhibition and macrophage polarization. AuNPs-D&H-R&C could passively target breast tumor via enhanced permeability and retention (EPR) effect after systemic administration and further aggregate together triggered by furin overexpressed in breast cancer. The in situ aggregations hindered the back-flow of NPs to the bloodstream and exocytosis of tumor cells, leading to enhanced drug accumulation within tumors. Moreover, upon exposure to acidic pH in the endosomes/ lysosomes, HCQ was efficiently released and it inhibited autophagy and thus restored the sensitivity of tumor cell to DOX. Meanwhile, autophagy inhibition could reprogram tumor-promoting M2-like TAMs to anti-tumor M1 phenotype, exerting a synergistic effect in overcoming chemoresistance. In vitro studies demonstrated the superiority of furin-triggered aggregated AuNPs delivery system in enhancing drug accumulation in breast tumor, compared with PEGlyated AuNPs. The co-delivery of DOX and HCQ showed much improved chemotherapeutic efficiency to chemoresistant MCF-7/ADR breast tumor, in large part due to macrophage polarization. In conclusion, we developed a stimulus-responsive delivery system and proposed a potential combination strategy to overcome chemoresistance in cancer chemotherapy.
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