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A novel nanoparticle formulation overcomes multiple types of membrane efflux pumps in human breast cancer cells

Preethy Prasad1, Ji Cheng, Adam Shuhendler

  • 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada, M5S 3M2.

Drug Delivery and Translational Research
|March 20, 2015
PubMed

Insights

This study shows that polymer lipid hybrid nanoparticles (PLNs) can overcome multidrug resistance (MDR) in cancer cells by targeting multiple drug efflux pumps. Co-loading Doxorubicin and Mitomycin C into PLNs significantly enhances their effectiveness against resistant cancer cells.

Area of Science:

  • Nanotechnology in Medicine
  • Cancer Biology
  • Drug Delivery Systems

Background:

  • Multidrug resistance (MDR) in cancer limits chemotherapy efficacy.
  • Overexpression of membrane drug efflux pumps (e.g., P-gp, MRP1, BCRP) is a key MDR mechanism.
  • Previous work demonstrated polymer lipid hybrid nanoparticles (PLNs) circumvent P-glycoprotein (P-gp) resistance.

Purpose of the Study:

  • Evaluate PLN system's ability to overcome multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP) overexpression.
  • Assess synergistic effects of co-encapsulated doxorubicin (Dox) and mitomycin C (MMC) in MDR cancer cell lines.
  • Investigate PLN system's potential to overcome multiple efflux pump-mediated drug resistance.

Main Methods:

  • Utilized human breast cancer cell lines MCF7 VP (MRP1+) and MCF7 MX (BCRP+).
  • Measured in vitro cellular uptake, intracellular trafficking, and cytotoxicity of Dox, MMC, or Dox-MMC loaded PLNs.
  • Employed clonogenic assay and median effect analysis for cytotoxicity assessment.
  • Visualized intracellular trafficking using fluorescently labeled PLNs.

Main Results:

  • PLN encapsulation significantly enhanced cancer cell kill compared to free drugs for single agents.
  • Dox-Doxorubicin-Mitomycin C co-loaded PLNs were 20-30 times more effective in killing MDR cells than free drugs.
  • Co-encapsulated Dox-MMC within PLNs demonstrated superior efficacy over single-agent encapsulated PLNs.
  • Microscopic analysis confirmed perinuclear localization of PLNs, suggesting effective intracellular delivery.

Conclusions:

  • The PLN system effectively overcomes MRP1 and BCRP mediated multidrug resistance in cancer cells.
  • Co-delivery of Doxorubicin and Mitomycin C via PLNs exhibits significant synergistic cytotoxicity against MDR cancer cells.
  • PLNs represent a promising strategy to enhance anticancer drug efficacy by overcoming multiple drug efflux pump mechanisms at reduced drug doses.

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