Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells

Authors

Georgette D. Kanmogne, University of Nebraska Medical CenterFollow
Sangya Singh, University of Nebraska Medical Center
Upal Roy, University of Nebraska Medical Center
Xinming Liu, University of Nebraska Medical Center
JoEllyn McMillan, University of Nebraska Medical Center, OmahaFollow
Santhi Gorantla, University of Nebraska Medical CenterFollow
Shantanu Balkundi, University of Nebraska Medical Center
Nathan Smith, University of Nebraska Medical CenterFollow
Yazen Alnouti, University of Nebraska Medical Center, OmahaFollow
Nagsen Gautam, University of Nebraska Medical Center, OmahaFollow
You Zhou, University of Nebraska - LincolnFollow
Larisa Poluektova, University of Nebraska Medical CenterFollow
Alexander Kabanov, University of Nebraska Medical Center
Tatiana Bronich, University of Nebraska Medical CenterFollow
Howard Gendelman, University of Nebraska Medical CenterFollow

Date of this Version

2012

Document Type

Article

Citation

International Journal of Nanomedicine 2012:7 2373–2388

Comments

© 2012 Kanmogne et al

Open access

http://dx.doi.org/10.2147/IJN.S29454

Abstract

Despite the successes of antiretroviral therapy (ART), HIV-associated neurocognitive disorders remain prevalent in infected people. This is due, in part, to incomplete ART penetration across the blood–brain barrier (BBB) and lymph nodes and to the establishment of viral sanctuaries within the central nervous system. In efforts to improve ART delivery, our laboratories developed a macrophage-carriage system for nanoformulated crystalline ART (nanoART) (atazanavir, ritonavir, indinavir, and efavirenz). We demonstrate that nanoART transfer from mononuclear phagocytes (MP) to human brain microvascular endothelial cells (HBMEC) can be realized through cell-to-cell contacts, which can facilitate drug passage across the BBB. Coculturing of donor MP containing nanoART with recipient HBMEC facilitates intercellular particle transfer. NanoART uptake was observed in up to 52% of HBMEC with limited cytotoxicity. Folate coating of nanoART increased MP to HBMEC particle transfer by up to 77%. To translate the cell assays into relevant animal models of disease, ritonavir and atazanavir nanoformulations were injected into HIV-1-infected NOD/scid-γ_c^null mice reconstituted with human peripheral blood lymphocytes. Atazanavir and ritonavir levels in brains of mice treated with folate-coated nanoART were three- to four-fold higher than in mice treated with noncoated particles. This was associated with decreased viral load in the spleen and brain, and diminished brain CD11b-associated glial activation. We postulate that monocyte-macrophage transfer of nanoART to brain endothelial cells could facilitate drug entry into the brain.