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

This Article Full Text 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 Citation Map 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 NeuroAIDS¹

Huanyu Dou^*, Cassi B. Grotepas^*, JoEllyn M. McMillan^*, Christopher J. Destache, Mahesh Chaubal, Jane Werling, James Kipp, Barrett Rabinow and Howard E. Gendelman^2,*,

^* 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P20RR 21937, P01 MH64570, and P01 NS43985 (to H.E.G.) from the National Institutes of Health.

² 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

³ Abbreviations used in this paper: MP, mononuclear phagocyte; MGC, multinucleated giant cell; BBB, blood-brain barrier; ART, antiretroviral therapy; MDM, monocyte-derived macrophage; BMM, bone marrow macrophage; NP, nanoparticle; IDV, indinavir; HIVE, HIV-1 encephalitis; Vim, vimentin; GFAP, glial fibrillary acidic protein; NF, neurofilament; p-NF, phosphorylated NF; CSF, cerebrospinal fluid; RP-HPLC, reverse phase HPLC.

⁴ The online version of this article contains supplemental material.