title: 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, 68198, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Dou
authors.forename: Cassi B
authors.initials: CB
authors.lastname: Grotepas
authors.forename: JoEllyn M
authors.initials: JM
authors.lastname: McMillan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Destache
authors.forename: Mahesh
authors.initials: M
authors.lastname: Chaubal
authors.forename: Jane
authors.initials: J
authors.lastname: Werling
authors.forename: James
authors.initials: J
authors.lastname: Kipp
authors.forename: Barrett
authors.initials: B
authors.lastname: Rabinow
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D001682:Biological Availability; D001854:Bone Marrow Cells / Q000473:pathology / Q000821:virology; D001921:Brain / Q000473:pathology / Q000821:virology*; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008264:Macrophages / Q000473:pathology / Q000637:transplantation* / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D053769:Nanocapsules / Q000008:administration & dosage*; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D053769:Nanocapsules; D019469:Indinavir