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

Abstract

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.

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

“…Indeed, cell-based nanocarriers have been developed for not only cancer chemotherapy, but also a wide range of microbial infections (34)(35)(36). Macrophagebased nanomedicine delivery schemes may have several advantages over more conventional drug delivery, including enhanced cure rates, reduced side effects, increased drug stability, and effective subcellular targeting (26,27,37,38). Using macrophages as a nanocarriage vehicle can permit investigation of nanoATV entry, intracellular trafficking, and drug release kinetics.…”

“…Cell nuclei were counterstained with hematoxylin for 60 s. Images were taken using a Nikon TE300 microscope with a 40ϫ objective. Quantitation of immunostaining was performed by densitometry using ImagePro Plus, v. 4.0 (27).…”

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

“…4,11,12 Prior works demonstrated that such nanoART could be carried in monocyte-macrophages and reach viral sanctuaries. [11][12][13][14][15] These studies also showed that size, shape, and charge of crystalline indinavir (IDV), ritonavir (RTV), atazanavir (ATV), and efavirenz (EFV) affect uptake, release, cytotoxicities, and antiretroviral responses.…”

Anti-HIV-1 nanotherapeutics: promises and challenges for the future

“…26 Nano-ART can be taken up within minutes by circulating monocytes and released in tissues over a period of 2 weeks. [56][57][58][59][60] Theoretically, cell-based nano-ART would travel to sites of inflammation and release drug(s) slowly with limited tissue toxicities. Such a drug-delivery system can revolutionize HIV-1 therapeutics and can particularly target virus sequestration.…”

“…59 An elegant study using a nanosuspension of indinavir showed that macrophages loaded with this nanosuspension could bring about a measurable reduction in antiviral load in the brains of an HIV-infected rodent model. 56 Magnetic nanoformulations have been used for targeting active nucleotide analog reverse transcriptase inhibitors to the brain by application of an external magnetic force and thereby eliminating the brain HIV reservoirs. Our group has recently shown that conjugation with transferrin (Tf), allows antiretroviral drug-loaded nanoformulations to permeate across biological barriers such BBB via a receptor-mediated transport mechanism.…”