Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage
| Autor: | JoEllyn M McMillan, Barrett E. Rabinow, Sangya Singh, Ari S. Nowacek, Shantanu Balkundi, Howard E. Gendelman, Rafael Bressani, Georgette D. Kanmogne |
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| Rok vydání: | 2010 |
| Předmět: |
Pharmacotoxicology
Efavirenz Anti-HIV Agents Cell Survival Biomedical Engineering Pharmacology Biology Zonula Occludens-2 Protein Toxicology Occludin Monocytes Article chemistry.chemical_compound Nanocapsules Pharmacokinetics Indinavir medicine Humans Cells Cultured Nanoart Macrophages Monocyte Endothelial Cells Membrane Proteins virus diseases medicine.anatomical_structure Anti-Retroviral Agents chemistry Blood-Brain Barrier Immunology Ritonavir medicine.drug |
| Zdroj: | Nanotoxicology. 5:592-605 |
| ISSN: | 1743-5404 1743-5390 |
| DOI: | 10.3109/17435390.2010.541292 |
| Popis: | 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, structure, 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 significantly 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 0.5mM, and efavirenz at 0.1mM and 0.5mM 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 importance of evaluating the physicochemical and functional properties of nanoART before human evaluations. |
| Databáze: | OpenAIRE |
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