title: Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates.
abstract: Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Jia
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhai
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006046:Gold / Q000737:chemistry*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D058726:Nanoconjugates; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D058726:Nanoconjugates; D006046:Gold; D017239:Paclitaxel