Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage

Rafael F. Bressani, Ari S. Nowacek, Sangya Singh, Shantanu Balkundi, Barrett Rabinow, Joellyn McMillan, Howard E. Gendelman, Georgette D. Kanmogne

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)592-605
Number of pages14
JournalNanotoxicology
Volume5
Issue number4
DOIs
StatePublished - Dec 2011

Keywords

  • Antiretroviral therapy
  • Blood-brain barrier
  • Monocytes and macrophages
  • NanoART
  • Nanomedicine
  • Nanotoxicity
  • Pharmacotoxicology

ASJC Scopus subject areas

  • Biomedical Engineering
  • Toxicology

Fingerprint Dive into the research topics of 'Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage'. Together they form a unique fingerprint.

  • Cite this