Journal
BIOMATERIALS SCIENCE
Volume 7, Issue 10, Pages 4260-4272Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c9bm00797k
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Funding
- Natural Science Foundation of China [81603046, 81673368, 81703446]
- Independent Innovation Foundation of Higher Education of China [2016JCTD109, 2016YXMS140, 2016YXMS147]
- National Postdoctoral Program for Innovative Talents [BX201600057]
- China Postdoctoral Science Foundation [2017M612474]
- Fundamental Research Funds for the Central Universities [HUST: 2018JYCXJJ008]
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Hypoxia, acidosis and high level of glutathione (GSH) are characteristic abnormalities of the tumor microenvironment (TME), which promote tumor progression, metastasis, and resistance to therapies. Previous attempts to improve therapeutic efficacy were limited to modifying individual TME elements. In this study, we proposed a comprehensive TME modulation strategy that modifies multiple elements of the TME in order to enhance cisplatin anticancer efficacy. To do so, we prepared biocompatible lipid-coated CaO2/cisplatin nanoparticles (LipoCaO(2)/DDP) by the reverse microemulsion method. We imbued CaO2 with the following reverse-TME properties: O-2 generation, increased pH value in tumor cells, and oxidation of intracellular glutathione. In vitro experiments showed that LipoCaO(2)/DDP could deplete GSH for preventing the binding of GSH to cisplatin. Simultaneously, CaO2 could significantly downregulate multidrug resistance-associated protein 2 (MRP2) by O-2-dependent hypoxia-inducible factor 1 (HIF-1) inactivation. Hence, the complete drug-efflux pathway was blocked, and the anticancer effect of cisplatin was enhanced both in vitro and in vivo. Herein, we not only demonstrated the GSH depletion capacity of CaO2 for the first time, but also provided a new comprehensive therapeutic strategy to overcome therapeutic resistance caused by multiple factors in the TME.
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