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ACS Appl Mater Interfaces. 2017 Dec 20;9(50):43498-43507. doi: 10.1021/acsami.7b14577. Epub 2017 Dec 7.

Mitochondrial-Targeting Lonidamine-Doxorubicin Nanoparticles for Synergistic Chemotherapy to Conquer Drug Resistance.

Author information

1
Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University , Suzhou, Jiangsu 215123, P.R. China.
2
School of Engineering, Institute for Bioengineering, University of Edinburgh , Edinburgh EH9 3JL, United Kingdom.

Abstract

Lonidamine (LND) can act on mitochondria and inhibit energy metabolism in cancer cells and therefore has been used together with chemotherapy drugs for synergistically enhanced therapeutic efficacy. However, its use is hindered by the poor solubility and slow diffusion in the cytoplasm. To address these problems, we designed and prepared aqueous dispersible nanoparticles (NPs) containing integrated components including triphenylphosphine (TPP) to target the mitochondria of cells and LND and doxorubicin (DOX) for synergistic cancer treatment and conquering drug resistance. This design allows the NPs to concentrate in the mitochondria of cells, solve the low solubility of LND, and contain very high load of LND and DOX in comparison with previously reported drug-delivery systems based on various carrier nanomaterials. Detailed mechanism studies reveal that TPP-LND-DOX NPs could induce significant reactive oxygen species production, mitochondrial membrane potential decrease, and mitochondrial apoptosis pathway, thereby leading to great cytotoxicity in cancer cells. In vivo anticancer activities indicate that TPP-LND-DOX NPs exhibit the highest efficacy in tumor inhibition among all tested groups and show high effectiveness in drug-resistant model. This work demonstrates the potential use of our TPP-LND-DOX NPs to jointly promote the mitochondria apoptosis pathway and contribute to conquer drug resistance in cancer therapy.

KEYWORDS:

chemotherapy; drug resistance; lonidamine; mitochondria targeting; triphenylphosphine

PMID:
29171954
DOI:
10.1021/acsami.7b14577
[Indexed for MEDLINE]

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