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Evaluations of combination MDR-1 gene silencing and paclitaxel administration in biodegradable polymeric nanoparticle formulations to overcome multidrug resistance in cancer cells

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Abstract

In this study, the effect of MDR-1 gene silencing, using small interfering RNA (siRNA), and paclitaxel (PTX) co-therapy in overcoming tumor multidrug resistance was examined. Poly(ethylene oxide)-modified poly(beta-amino ester) (PEO-PbAE) and PEO-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were formulated to efficiently encapsulate MDR-1 silencing siRNA and PTX, respectively. Upon administration in multidrug resistant SKOV3TR human ovarian adenocarcinoma cells, siRNA-mediated MDR-1 gene silencing was evident at 100 nM dose. Combination of MDR-1 gene silencing and nanoparticle-mediated delivery significantly influenced the cytotoxic activity of PTX in SKOV3TR cells similar to what was observed in drug sensitive SKOV3 cells. We speculate that the enhancement in cytotoxicity was due to an increase in intracellular drug accumulation upon MDR-1 gene silencing leading to an apoptotic cell-kill effect. Taken together, these preliminary results are highly encouraging for the development of combination nano-therapeutic strategies that combine gene silencing and drug delivery to provide more potent therapeutic effect, especially in refractory tumors.

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Acknowledgments

This study was supported by the Nanotechnology Platform Partnership grant (R01-CA119617) from the National Cancer Institute (NCI) of the U.S. National Institutes of Health. We deeply appreciate the assistance of Professor Robert Campbell and his lab members with the particle size, surface charge, and optical microscopy studies. Scanning electron microscopy was performed by Mr. William Fowle at the Electron Microscopy Center, Northeastern University (Boston, MA).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, 02115, USA

    Sunita Yadav, Lilian E. van Vlerken & Mansoor M. Amiji

  2. Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Steven R. Little

Authors
  1. Sunita Yadav
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  2. Lilian E. van Vlerken
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  3. Steven R. Little
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  4. Mansoor M. Amiji
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Correspondence to Mansoor M. Amiji.

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Yadav, S., van Vlerken, L.E., Little, S.R. et al. Evaluations of combination MDR-1 gene silencing and paclitaxel administration in biodegradable polymeric nanoparticle formulations to overcome multidrug resistance in cancer cells. Cancer Chemother Pharmacol 63, 711–722 (2009). https://doi.org/10.1007/s00280-008-0790-y

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  • DOI: https://doi.org/10.1007/s00280-008-0790-y

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