title: One-Step Self-Assembling Nanomicelles for Pirarubicin Delivery To Overcome Multidrug Resistance in Breast Cancer.
abstract: Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by P-glycoprotein (P-gp). Here we report a targeted delivery system to carry pirarubicin (THP) to MDR breast cancer both in vitro and in vivo. PEG-derivatized vitamin E (PAMV6) amphiphiles loaded with THP were self-assembled in a single step. The PAMV6micelles showed unimodal size distribution and high drug loading efficiency. Cytotoxicity of PAMV6/THP was higher than that of free THP on MCF-7/ADR cells but comparable to that of THP on MCF-7 cells. PAMV6/THP was able to reverse MDR more than free THP in MCF-7/ADR cells, likely reflecting the remarkably higher intracellular THP concentration in micelle-treated cells and PAMV6-mediated inhibition of P-gp activity. PAMV6/THP micelles were internalized into MCF-7/ADR cells via macropinocytosis and caveolin-mediated endocytosis, further avoiding P-gp-mediated efflux. Mechanistic studies revealed that blank PAMV6micelles inhibited P-gp activity but did not affect P-gp expression, by significantly reducing mitochondrial membrane potential and slightly decreasing intracellular ATP levels. In a nude mouse xenograft model, PAMV6/THP led to much greater THP accumulation in tumors and much slower tumor growth than free THP. At the same time, PAMV6/THP was associated with significantly less severe bone marrow suppression and organ toxicity than free THP. Our results indicate that this PAMV6-based micelle system holds promise for combating MDR in cancer therapy.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Qinhui
authors.initials: Q
authors.lastname: Liu
authors.forename: Wenyao
authors.initials: W
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zou
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.forename: Shihai
authors.initials: S
authors.lastname: Cheng
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Su
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University , Chengdu 610041, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008823:Micelles; D004317:Doxorubicin; D000255:Adenosine Triphosphate; C027260:pirarubicin
keywords: P-gp inhibitor; PAMV6 copolymer; multidrug resistance; nanomicelles; pirarubicin