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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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Submitted March 24, 2006
Accepted June 8, 2006
Development of a macrophage-based nanoparticle system for anti-retroviral drug delivery
Huanyu Dou, Christopher J Destache, Justin R Morehead, R L Mosley, Michael D Boska, Jeffrey Kingsley, Santhi Gorantla, Larisa Poluektova, Jay A Nelson, Mahesh Chaubal, Jane Werling, James Kipp, Barrett Rabinow, and Howard E Gendelman*
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center
Creighton University School of Pharmacy and Health Professions
Baxter Healthcare Corporation
* Corresponding author; email: hegendel{at}unmc.edu.
Abstract
Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of anti-retroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow derived macrophages (BMM) was developed. Drug distribution and disease outcomes were assessed in immune competent and HIV-1 infected humanized mice, respectively. In the former, NP-IDV formulation contained within BMM was adoptively transferred. After a single administration, single photon emission computed tomography, histology and RP-HPLC demonstrated robust lung, liver, and spleen BMM and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 µM for 2 weeks. NP-IDV BMM 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 BMM as a carrier, is effective and warrants consideration for human testing.
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