Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS

J Immunol. 2009 Jul 1;183(1):661-9. doi: 10.4049/jimmunol.0900274. Epub 2009 Jun 17.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Availability
  • Bone Marrow Cells / pathology
  • Bone Marrow Cells / virology
  • Brain / pathology
  • Brain / virology*
  • Cell Movement
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Administration Schedule
  • Encephalitis, Viral / drug therapy*
  • Encephalitis, Viral / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / growth & development
  • Humans
  • Indinavir / administration & dosage*
  • Indinavir / pharmacokinetics
  • Macrophages / pathology
  • Macrophages / transplantation*
  • Macrophages / virology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Nanocapsules / administration & dosage*
  • Severe Combined Immunodeficiency / drug therapy*
  • Severe Combined Immunodeficiency / virology
  • Virus Replication / drug effects

Substances

  • Nanocapsules
  • Indinavir

Grants and funding