Bioreducible Micelles with Endosomal Buffering and Multidrug Resistance-Reversing Function Enhance Anti-Tumor Efficacy of Doxorubicin.
The clinical success of anthracyclines-containing chemotherapy for breast cancer is mainly restricted by cardiac damage and the development of multidrug resistance (MDR). For efficient reversal of drug resistance, doxorubicin (DOX) loaded multifunctional bioreducible micelles were constructed from a new amphiphilic copolymer consisting of polyethylene glycol and poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-histamine and characterized. The introduction of imidazole group endowed the micelles with endosomal buffering capacity and improved the endosomal escape. The reduction-responsiveness of the micelles promoted DOX release. The activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme, were also inhibited by the micelles. The accumulation of DOX in tumor after intravenous administration of the drug-loading micelles was increased in drug resistant tumor-bearing mice. These results indicated that the micelle was a promising drug delivery system for MDR cancer therapy.
Qi
Q
Yin
Jianan
J
Shen
Haijun
H
Yu
Yongzhuo
Y
Huang
Zhiwen
Z
Zhang
Yaping
Y
Li
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D011992:Endosomes / Q000737:chemistry*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D010316:Particle Size; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008823:Micelles; D053769:Nanocapsules; D004317:Doxorubicin