title: Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage.
abstract: Limitations inherent to antiretroviral therapy (ART) in its pharmacokinetic properties remain despite over 15 years of broad use. Our laboratory has pioneered a means to improve ART delivery through monocyte-macrophage carriage of nanoformulated drug-encapsulated particles (nanoART). To this end, our prior works sought to optimize nanoART size, charge, and physical properties for cell uptake and antiretroviral activities. To test the functional consequences of indinavir, ritonavir, and efavirenz formulations we investigated relationships between human monocyte and macrophage cytotoxicities and nanoART dose, size, surfactant, and preparation. Wet-milled particles were more cytotoxic to monocytes-macrophages than those prepared by homogenization; with concurrent induction of tumor necrosis factor-alpha. Interestingly, pure suspensions of indinavir and ritonavir at 0.5 mM, and efavirenz at 0.1 mM and 0.5 mM also proved cytotoxic. Individual surfactants and formulated fluconazole neither affected cell function or viability. Although nanoART did not alter brain tight junction proteins ZO-2 and occludin, 0. 5mM ritonavir formulations did alter brain transendothelial electric resistance. These results underscore the potential importance of evaluating the physicochemical and functional properties of nanoART before human evaluations.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Bressani
authors.forename: Ari S
authors.initials: AS
authors.lastname: Nowacek
authors.forename: Sangya
authors.initials: S
authors.lastname: Singh
authors.forename: Shantanu
authors.initials: S
authors.lastname: Balkundi
authors.forename: Barrett
authors.initials: B
authors.lastname: Rabinow
authors.forename: Joellyn
authors.initials: J
authors.lastname: McMillan
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Georgette D
authors.initials: GD
authors.lastname: Kanmogne
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D044966:Anti-Retroviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D053769:Nanocapsules / Q000737:chemistry / Q000633:toxicity*; D062793:Occludin; D062827:Zonula Occludens-2 Protein
chemical_list: D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D008565:Membrane Proteins; D053769:Nanocapsules; C568985:OCLN protein, human; D062793:Occludin; C569046:TJP2 protein, human; D062827:Zonula Occludens-2 Protein