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 Blood, 15 October 2006, Vol. 108, No. 8, pp. 2827-2835.
Prepublished online as a Blood First Edition Paper on June 29, 2006; DOI 10.1182/blood-2006-03-012534.

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PHAGOCYTES

Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery

Huanyu Dou, Christopher J. Destache, Justin R. Morehead, R. Lee Mosley, Michael D. Boska, Jeffrey Kingsley, Santhi Gorantla, Larisa Poluektova, Jay A. Nelson, Mahesh Chaubal, Jane Werling, James Kipp, Barrett E. Rabinow, and Howard E. Gendelman

From the Center for Neurovirology and Neurodegenerative Disorders, the Departments of Pharmacology and Experimental Neuroscience, Radiology, Internal Medicine, and Pediatrics, University of Nebraska Medical Center, Omaha; Creighton University School of Pharmacy and Health Professions, Omaha, NE; and Baxter Healthcare, Round Lake, IL.

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 µM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4+ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.


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