Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo

Mol Pharm. 2015 Jan 5;12(1):274-86. doi: 10.1021/mp500637b. Epub 2014 Dec 12.

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.

Keywords: P-glycoprotein inhibitor; biodistribution; doxorubicin; lipid nanoemulsions; multidrug resistance; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Apoptosis
  • Benzylisoquinolines / chemistry*
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Doxorubicin / chemistry*
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Emulsions
  • Female
  • Humans
  • Lipids / chemistry
  • Mice
  • Mice, Nude
  • Nanomedicine / methods
  • Necrosis
  • Neoplasm Transplantation
  • Rats
  • Rats, Wistar
  • Tissue Distribution

Substances

  • Antineoplastic Agents
  • Benzylisoquinolines
  • Emulsions
  • Lipids
  • bromotetrandrine
  • tetrandrine
  • Doxorubicin