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Nanoformulated Antiretroviral Drug Combinations Extend Drug Release and Antiretroviral Responses in HIV-1-Infected Macrophages: Implications for NeuroAIDS Therapeutics

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Abstract

We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated individual drug release from 15 to >20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.

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Acknowledgments

The authors thank Janice A. Taylor and James R. Talaska of the Confocal Laser Scanning Microscope Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy, the Nebraska Research Initiative, and the Eppley Cancer Center for their support of the Core Facility. We also thank Ms. Robin Taylor for the critical reading of the manuscript and outstanding graphic and literary support.

Financial and competing interests disclosures

The work was supported by the National Institutes of Health grants 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P01MH64570, and P01 NS43985 (to H.E.G.) and from a research grant from Baxter Healthcare.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Ari S. Nowacek, JoEllyn McMillan, Alec Anderson & Howard E. Gendelman

  2. Baxter Healthcare Corporation, Round Lake, IL, 60073, USA

    Reagan Miller & Barrett Rabinow

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  1. Ari S. Nowacek
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  2. JoEllyn McMillan
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  4. Alec Anderson
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  6. Howard E. Gendelman
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Corresponding author

Correspondence to Howard E. Gendelman.

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Supplemental 1

3D reconstruction of nanoART laden MDM. MDM were incubated with 100 µM each of ATV-H1045 (purple) labeled with Vybrant DiO cell-labeling solution, RTV-H1025 (green) labeled with Vybrant DiD cell-labeling solution, and EFV-P1044 (red) with rhodamine B 1,2-dihexadecanoyl-sn-glycero-3-phospho-ethanolamine, triethylammonium salt. Images were acquired after 2 h of incubation with nanoART combination. Z-Stack was constructed from 25 individual fluorescent microscopy images of 1.0-μm thickness each. A 3D reconstruction of the Z-Stack was made using Zeiss LSM510 software (Carl Zeiss MicroImaging Inc., Thornwood, NY). The 3D reconstruction rotates 360° in 16 frames. All three nanoART were taken up by MDM. Overlay (white) represents colocalization of all three formulations to cytoplasmic vesicles. (GIF 117 kb; GIF 117 kb)

High Resolution Image 1 (TIFF 18918 kb)

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Nowacek, A.S., McMillan, J., Miller, R. et al. Nanoformulated Antiretroviral Drug Combinations Extend Drug Release and Antiretroviral Responses in HIV-1-Infected Macrophages: Implications for NeuroAIDS Therapeutics. J Neuroimmune Pharmacol 5, 592–601 (2010). https://doi.org/10.1007/s11481-010-9198-7

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