Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells.
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.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. gkanmogne@unmc.edu
Georgette D
GD
Kanmogne
Sangya
S
Singh
Upal
U
Roy
Xinming
X
Liu
Joellyn
J
McMillan
Santhi
S
Gorantla
Shantanu
S
Balkundi
Nathan
N
Smith
Yazen
Y
Alnouti
Nagsen
N
Gautam
You
Y
Zhou
Larisa
L
Poluektova
Alexander
A
Kabanov
Tatiana
T
Bronich
Howard E
HE
Gendelman
D000328:Adult; D000818:Animals; D044966:Anti-Retroviral Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D015658:HIV Infections; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D012157:Mononuclear Phagocyte System / Q000166:cytology / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019438:Ritonavir / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013154:Spleen / Q000821:virology; D014018:Tissue Distribution; D019562:Viral Load / Q000187:drug effects
D044966:Anti-Retroviral Agents; D004337:Drug Carriers; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D005492:Folic Acid; D019438:Ritonavir