The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance. Issue 31 (17th June 2020)

• Record Type: Journal Article
• Authors: Jiang, Yuqian; Wang, Zheng; Duan, Wei; Liu, Lingyan; Si, Mahan; Chen, Xiaoyuan; Fang, Chen-Jie
• Is Part Of: Nanoscale. Volume 12:Issue 31(2020)
• Page Start: 16451
• Page End: 16461
• Publication Date: 2020-06-17
• Subjects: Nanoscience -- Periodicals; Nanotechnology -- Periodicals; 620.505
• DOI: 10.1039/d0nr03226c
• Languages: English
• ISSNs: 2040-3364

Abstract

Abstract : The critical size of Au nanoparticles for overcoming multi-drug resistance was identified to be between 4.1 nm and 5.4 nm. 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.