Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 1 2011

Fingerprint

efavirenz
Ritonavir
Macrophages
Indinavir
Monocytes
Surface-Active Agents
Zonula Occludens-2 Protein
Brain
Surface active agents
Pharmaceutical Preparations
Occludin
Tight Junction Proteins
Pharmacokinetics
Fluconazole
Cytotoxicity
Electric Impedance
Suspensions
Tumor Necrosis Factor-alpha
Physical properties
Proteins

Keywords

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

ASJC Scopus subject areas

  • Biomedical Engineering
  • Toxicology

Cite this

Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage. / Bressani, Rafael F.; Nowacek, Ari S.; Singh, Sangya; Balkundi, Shantanu; Rabinow, Barrett; McMillan, JoEllyn M; Gendelman, Howard Eliot; Kanmogne, Georgette D.

In: Nanotoxicology, Vol. 5, No. 4, 01.12.2011, p. 592-605.

Research output: Contribution to journalArticle

Bressani, Rafael F. ; Nowacek, Ari S. ; Singh, Sangya ; Balkundi, Shantanu ; Rabinow, Barrett ; McMillan, JoEllyn M ; Gendelman, Howard Eliot ; Kanmogne, Georgette D. / Pharmacotoxicology of monocyte-macrophage nanoformulated antiretroviral drug uptake and carriage. In: Nanotoxicology. 2011 ; Vol. 5, No. 4. pp. 592-605.
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