Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages.
Long-term antiretroviral therapy (ART) for human immunodeficiency virus type one (HIV-1) infection shows limitations in pharmacokinetics and biodistribution while inducing metabolic and cytotoxic aberrations. In turn, ART commonly requires complex dosing schedules and leads to the emergence of viral resistance and treatment failures. We posit that the development of nanoformulated ART could preclude such limitations and affect improved clinical outcomes. To this end, we wet-milled 20 nanoparticle formulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz, collectively referred to as "nanoART," then assessed their performance using a range of physicochemical and biological tests. These tests were based on cell-nanoparticle interactions using monocyte-derived macrophages and their abilities to uptake and release nanoformulated drugs and affect viral replication. We demonstrate that physical characteristics such as particle size, surfactant coating, surface charge, and most importantly shape are predictors of cell uptake and antiretroviral efficacy. These studies bring this line of research a step closer to developing nanoART that can be used in the clinic to affect the course of HIV-1 infection.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA. anowacek@unmc.edu
Ari S
AS
Nowacek
Shantanu
S
Balkundi
JoEllyn
J
McMillan
Upal
U
Roy
Andrea
A
Martinez-Skinner
R Lee
RL
Mosley
Georgette
G
Kanmogne
Alexander V
AV
Kabanov
Tatiana
T
Bronich
Howard E
HE
Gendelman
D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D003521:Cyclopropanes; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D010316:Particle Size; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D055672:Static Electricity; D013501:Surface-Active Agents / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D013501:Surface-Active Agents; D000069446:Atazanavir Sulfate; D019469:Indinavir; C098320:efavirenz; D019438:Ritonavir