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Polymer-surfactant nanoparticles for improving oral bioavailability of doxorubicin

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Abstract

The oral bioavailability of several clinically relevant drugs is compromised because of their limited absorption across the gastrointestinal tract. Active efflux of the drug by transporters such as P-glycoprotein (P-gp) present on the luminal side of the intestinal epithelial cells limits drug absorption. Encapsulation of drugs in nanoparticles can reduce transporter-mediated efflux and increase drug absorption. The purpose of this manuscript is to determine if the bioavailability of doxorubicin, a P-gp substrate, could be increased by encapsulation in nanoparticles. We synthesized polymer-surfactant nanoparticles comprised of a sodium alginate core complexed with doxorubicin and stabilized by the surfactant Aerosol OT (AOT). Encapsulation of doxorubicin in nanoparticles improved its transport across cell monolayers as evidenced by Transwell® studies. Drug uptake studies were carried out in cells overexpressing P-gp and those with basal levels of P-gp. These studies revealed that AOT inhibited P-gp activity and improved drug uptake in P-gp expressing cells by ~5-6-fold. Increase in drug uptake was found only in cells expressing P-gp and was limited to P-gp substrates. We also determined the in vivo oral bioavailability of the nanoparticle formulation of doxorubicin in mice. Doxorubicin delivered in the form of nanoparticles had a higher bioavailability relative to that with the free drug. This study shows that the oral bioavailability of P-gp substrates such as doxorubicin can be enhanced by delivering them in AOT-alginate nanoparticles.

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    Authors and Affiliations

    1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN, 55455, USA

      Ameya R. Kirtane, Garvey Liu & Jayanth Panyam

    2. Wayzata High School, Plymouth, MN, USA

      Priyanka Narayan

    3. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

      Jayanth Panyam

    Authors
    1. Ameya R. Kirtane
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    2. Priyanka Narayan
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    3. Garvey Liu
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    4. Jayanth Panyam
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    Correspondence to Jayanth Panyam.

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    Ameya R. Kirtane and Priyanka Narayan have contributed equally to this work.

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    Kirtane, A.R., Narayan, P., Liu, G. et al. Polymer-surfactant nanoparticles for improving oral bioavailability of doxorubicin. Journal of Pharmaceutical Investigation 47, 65–73 (2017). https://doi.org/10.1007/s40005-016-0293-5

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    • DOI: https://doi.org/10.1007/s40005-016-0293-5

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