HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900274v1 183/1/661    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Dou, H. Articles by Gendelman, H. E. PubMed PubMed Citation Articles by Dou, H. Articles by Gendelman, H. E.

Macrophage Delivery of Nanoformulated Antiretroviral Drug to the Brain in a Murine Model of NeuroAIDS

Huanyu Dou^*, Cassi B. Grotepas^*, JoEllyn M. McMillan^*, Christopher J. Destache, Mahesh Chaubal, Jane Werling, Kipp James, Barrett Rabinow and Howard E. Gendelman^*,

^*Department of Pharmacology and Experimental Neuroscience and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198; School of Pharmacy and Health Professions Creighton University, Omaha, NE 68178; and Baxter Healthcare Corporation, Round Lake, IL 60073

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.

Address correspondence and reprint requests to Dr. Howard E. Gendelman, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: hegendel{at}unmc.edu.