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The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance

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Abstract

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.

Graphical abstract: The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance

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Supplementary files

Article information


Submitted
24 Apr 2020
Accepted
31 May 2020
First published
04 Jun 2020

Nanoscale, 2020, Advance Article
Article type
Paper

The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance

Y. Jiang, Z. Wang, W. Duan, L. Liu, M. Si, X. Chen and C. Fang, Nanoscale, 2020, Advance Article , DOI: 10.1039/D0NR03226C

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