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Humanized Mice as a Platform for the Development of Long-Acting Nanoformulated Antiretroviral Therapy

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Humanized Mice for HIV Research

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Abstract

Cell-carried nanoformulations of antiretroviral therapy (nanoART) were pioneered at the University of Nebraska Medical Center. The platform utilizes monocyte-macrophages as Trojan Horses for drug delivery to human immunodeficiency viral reservoirs. This includes virus target cells, tissues, and subcellular organelles where the virus completes its life cycle. Particles manufactured with polymer excipients are coated with sugars or peptides, facilitating particle cell uptake and sequestration. The intent, overall, is to use cells as drug depots and endosomes as storage centers for particle-associated and free bioactive medicines. The latter contains drugs that are dissociated from particles over periods of days to weeks. Parenteral administration of nanoART produced drug concentrations in the reticuloendothelial system above the effective dose 50 with limited systemic toxicities. Antiretroviral responses were realized through studies of human immunodeficiency virus type one (HIV-1) infected humanized mice. The results showed that weekly parenteral administration of nanoART could reduce plasma virus to at or below five viral copies/ml. Targeting of the nanoART to monocyte-macrophages enabled “best” pharmacokinetic (PK) outcomes. These studies could lead to improved drug compliance, diminished viral resistance, and facilitation of virus reservoir reductions.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, 68198-5880, Omaha, NE, USA

    JoEllyn M. McMillan & Howard E. Gendelman

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  1. JoEllyn M. McMillan
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  2. Howard E. Gendelman
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Correspondence to Howard E. Gendelman .

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Editors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Larisa Y. Poluektova

  2. Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    J. Victor Garcia

  3. Research Center for AIDS Laboratory of Viral Pathogenesis, Kyoto University Institute for Virus Research, Sakyo-ku, Japan

    Yoshio Koyanagi

  4. Division of Hematology, University Hospital Zürich, Zürich, Switzerland

    Markus G. Manz

  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Andrew M. Tager

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McMillan, J., Gendelman, H. (2014). Humanized Mice as a Platform for the Development of Long-Acting Nanoformulated Antiretroviral Therapy. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_30

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