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Enhancement of cisplatin efficacy by lipid-CaO 2 nanocarrier-mediated comprehensive modulation of the tumor microenvironment.
- Source :
-
Biomaterials science [Biomater Sci] 2019 Oct 01; Vol. 7 (10), pp. 4260-4272. Date of Electronic Publication: 2019 Aug 12. - Publication Year :
- 2019
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Abstract
- 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 CaO <subscript>2</subscript> /cisplatin nanoparticles (LipoCaO <subscript>2</subscript> /DDP) by the reverse microemulsion method. We imbued CaO <subscript>2</subscript> with the following reverse-TME properties: O <subscript>2</subscript> generation, increased pH value in tumor cells, and oxidation of intracellular glutathione. In vitro experiments showed that LipoCaO <subscript>2</subscript> /DDP could deplete GSH for preventing the binding of GSH to cisplatin. Simultaneously, CaO <subscript>2</subscript> could significantly downregulate multidrug resistance-associated protein 2 (MRP2) by O <subscript>2</subscript> -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 CaO <subscript>2</subscript> for the first time, but also provided a new comprehensive therapeutic strategy to overcome therapeutic resistance caused by multiple factors in the TME.
- Subjects :
- Animals
Cell Survival drug effects
Female
Glutathione metabolism
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Lipids administration & dosage
Mice, Inbred BALB C
Mice, Nude
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins genetics
Neoplasms drug therapy
Neoplasms metabolism
Neoplasms pathology
Oxygen metabolism
Tumor Burden drug effects
Tumor Microenvironment drug effects
Antineoplastic Agents administration & dosage
Cisplatin administration & dosage
Drug Carriers administration & dosage
Nanoparticles administration & dosage
Peroxides administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2047-4849
- Volume :
- 7
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biomaterials science
- Publication Type :
- Academic Journal
- Accession number :
- 31402373
- Full Text :
- https://doi.org/10.1039/c9bm00797k