P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells

Author:

Navarro Gemma1,Sawant Rupa R1,Biswas Swati1,Essex Sean1,Tros de Ilarduya Conchita2,Torchilin Vladimir P

Affiliation:

1. Center for Pharmaceutical Biotechnology & Nanomedicine, Northeastern University, Boston, MA 02115, USA

2. Department of Pharmacy & Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080 Pamplona, Spain

Abstract

Aims: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs. Method: We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells. Results: The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells. Discussion: The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells.

Publisher

Future Medicine Ltd

Subject

Development,General Materials Science,Biomedical Engineering,Medicine (miscellaneous),Bioengineering

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