title: The co-delivery of a low-dose P-glycoprotein inhibitor with doxorubicin sterically stabilized liposomes against breast cancer with low P-glycoprotein expression.
abstract: BACKGROUND
  P-glycoprotein (P-gp) inhibitors are usually used to treat tumors that overexpress P-gps. However, most common types of breast cancers, such as Luminal A, are low-P-gp expressing, at least during the initial phases of treatment. Therefore, it would be interesting to know if P-gp inhibitors are still useful in treating low-P-gp-expressing tumors.
  
  
  METHODS
  In the study reported here, the human breast-cancer cell line MCF-7, chosen as a model of Luminal A, was found to be low-P-gp expressing. We designed a novel doxorubicin (DOX) sterically stabilized liposome system co-loaded with the low-dose P-gp inhibitor cyclosporine A (CsA) (DOX/CsA/SSL).
  
  
  RESULTS
  The co-delivery system showed good size uniformity, high encapsulation efficiency, and a desirable release profile. The cell-uptake and cytotoxicity studies demonstrated that CsA could significantly enhance the intracellular accumulation and toxicity of free DOX and the liposomal DOX in MCF-7 cells. The confocal microscopy and in vivo imaging study confirmed the intracellular and in vivo targeting effect of DOX/CsA/SSL, respectively. Finally, the in vivo study proved that DOX/CsA/SSL could achieve significantly better antitumor effect against MCF-7 tumor than controls, without inducing obvious systemic toxicity.
  
  
  CONCLUSIONS
  This study demonstrated that the co-delivery of a low-dose P-gp inhibitor and liposomal DOX could improve the therapy of low-P-gp-expressing cancer, which is of significance in clinical tumor therapy.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People's Republic of China.
authors.forename: Meiwan
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Xiucong
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Medical and Healthy Analytical Center, Peking University, Beijing, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms; D016572:Cyclosporine; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D008081:Liposomes; D004317:Doxorubicin; D016572:Cyclosporine
keywords: antitumor activity; cyclosporine A; liposomes; low-P-gp-expressing tumor; targeted delivery
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