title: Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo.
abstract: Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University , Chengdu, Sichuan, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Cao
authors.forename: Jingwen
authors.initials: J
authors.lastname: Luo
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D044182:Benzylisoquinolines / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004655:Emulsions; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods; D009336:Necrosis; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D004655:Emulsions; D008055:Lipids; C514835:bromotetrandrine; C009438:tetrandrine; D004317:Doxorubicin
keywords: P-glycoprotein inhibitor; biodistribution; doxorubicin; lipid nanoemulsions; multidrug resistance; pharmacokinetics