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Effective down-regulation of breast cancer resistance protein (BCRP) by siRNA delivery using lipid-substituted

Hamidreza Montazeri Aliabadi1, Breanne Landry, Parvin Mahdipoor

  • 1Department of Chemical & Material Engineering, University of Alberta, Edmonton, AB, Canada.

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V
|February 8, 2012
PubMed

Insights

Lipid-modified polyethyleneimine (PEI) effectively delivers siRNA to reduce Breast Cancer Resistance Protein (BCRP) expression. This enhances cancer cell sensitivity to chemotherapy drugs like mitoxantrone.

Area of Science:

  • Biotechnology
  • Nanomedicine
  • Cancer Research

Background:

  • Breast Cancer Resistance Protein (BCRP, ABCG2) contributes to multidrug resistance in cancer.
  • Small interfering RNA (siRNA) can down-regulate BCRP, but requires efficient intracellular delivery systems.
  • Effective siRNA carriers must achieve intracellular delivery with minimal toxicity.

Purpose of the Study:

  • To evaluate lipid-substituted low molecular weight polyethyleneimine (PEI) as a carrier for BCRP siRNA delivery.
  • To investigate the structure-function relationship of lipophilic substitutions for enhanced siRNA delivery and BCRP down-regulation.

Main Methods:

  • Synthesis and characterization of various lipid-substituted low molecular weight (2kDa) PEI polymers.
  • Structure-function studies assessing siRNA delivery efficiency and BCRP gene silencing.
  • Evaluation of drug-resistant cell sensitization to mitoxantrone following BCRP down-regulation.

Main Results:

  • siRNA delivery efficiency significantly increased with lipid substitution (C8-C18).
  • BCRP silencing correlated with polymer delivery efficiency and lasted approximately 5 days.
  • BCRP down-regulation sensitized cells to mitoxantrone, reducing IC(50) by ~14-fold, with effects lasting 14 days.

Conclusions:

  • Lipid-modified low molecular weight PEI is a feasible carrier for functional siRNA delivery.
  • The extent and nature of lipid substitution are critical for effective siRNA delivery and BCRP down-regulation.
  • This approach shows promise for overcoming multidrug resistance in cancer therapy.

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