Biswas, S. (Swati)

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    P-glycoprotein silencing with siRNA delivered by DOPEmodified PEI overcomes doxorubicin resistance in breast cancer cells
    (Future Medicine, 2012) Navarro, G. (Gemma); Biswas, S. (Swati); Essex, S. (Sean); Tros-de-Ilarduya, C. (Conchita); Torchilin, V.P. (Vladimir P.); Sawant, R.R. (Rupa R.)
    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.