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Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors

Gene Therapy volume 22, pages 257–266 (2015)Cite this article

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Abstract

Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here we evaluated phospholipid-modified, low-molecular-weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model. Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation. Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts. Weekly injection of siRNA nanopreparations and Dox for up to 5 weeks sensitized the tumors to otherwise non-effective doses of Dox and decreased the tumor volume by threefold vs controls. This therapeutic improvement in response to Dox was attributed to the significant, sequence-specific P-gp downregulation in excised tumors mediated by the DOPE-PEI formulations.

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Acknowledgements

This study was supported with the NIH grant U54CA151881 to VT.

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  1. S Essex and G Navarro: These authors contributed equally to this work.

Authors and Affiliations

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

    S Essex, G Navarro, P Sabhachandani, A Chordia, M Trivedi, S Movassaghian & V P Torchilin

  2. Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

    V P Torchilin

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  1. S Essex
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Essex, S., Navarro, G., Sabhachandani, P. et al. Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors. Gene Ther 22, 257–266 (2015). https://doi.org/10.1038/gt.2014.97

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