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Small. 2019 Jun;15(24):e1901156. doi: 10.1002/smll.201901156. Epub 2019 May 9.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Author information

1
National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210093, China.
2
Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
3
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, Nanjing, 210009, China.
4
Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China.
5
State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China.

Abstract

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

KEYWORDS:

MOF-Fe2+; antitumor treatment; dichloroacetic acid; liposomes; oxidative stress

PMID:
31074196
DOI:
10.1002/smll.201901156

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