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

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, 68198, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2009; 183(1):661-9. DOI: 10.4049/jimmunol.0900274
Source: PubMed


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.

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    • "Notwithstanding, he noted, as did several other speakers on the day, that the hypothesis that the CNS serves as a reservoir site for HIV remains to be conclusively proven. Were this found to be the case, the issue of achieving effective antiretroviral CNS penetrance would be important and Dr Margolis highlighted some research directed towards providing cART via nanoformulations to enhance their CNS levels (Dou et al. 2009). The issue of establishing an ideal model to study HIV persistence in different tissues including the brain was discussed (Dinoso et al. 2009). "
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    • "Additionally, these immune cells possess the ability to readily migrate across the BBB or at least transfer their drug content to endothelial cells at the BBB, as recently shown in vitro (Figure 5).106 The previous possibilities have been systematically explored by investigators at the Nebraska Medical Center, Omaha, NE, USA.103–109 Drug incorporation into cells was performed by simply incubating cells with particles in culture media for 8–12 hours, followed by cell washing and removal of free drug. Researchers observed that nanoformulated indinavir could be delivered into the brain of an HIV-1 encephalitis rodent model up to around 20-fold higher levels when incorporated into bone marrow-derived macrophages after a single dose administered intravenously.109 "
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