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.

Keywords::

• NanoART
• pharmacotoxicology
• monocytes and macrophages
• blood-brain barrier
• antiretroviral therapy
• nanomedicine
• nanotoxicity

Acknowledgements

We thank Dr Han Chen and Dr You Zhou of the University of Nebraska-Lincoln electron microscopy core facility for assistance with the SEM analysis.

Declaration of interest: This work was supported by NIH grants RO1MH081780 (to GDK), 1P01DA028555-01, P01 NS043985 and P20 RR15635 (to HEG and GDK), 2R37 NS36126, PO1 NS31492, 2R01 NS034239, and P01MH64570 (to HEG). The authors report no conflict of interest. The authors are responsible for the content of the paper.