Journal of Neuroimmune Pharmacology

, Volume 5, Issue 4, pp 592–601

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

  • Ari S. Nowacek
  • JoEllyn McMillan
  • Reagan Miller
  • Alec Anderson
  • Barrett Rabinow
  • Howard E. Gendelman
Original Article

DOI: 10.1007/s11481-010-9198-7

Cite this article as:
Nowacek, A.S., McMillan, J., Miller, R. et al. J Neuroimmune Pharmacol (2010) 5: 592. doi:10.1007/s11481-010-9198-7
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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.

Keywords

antiretroviral therapynanoparticlesmacrophagesdrug deliveryHIVnanomedicine

Supplementary material

11481_2010_9198_Fig6_ESM.gif (118 kb)
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)

11481_2010_9198_MOESM1_ESM.tif (18.5 mb)
High Resolution Image 1 (TIFF 18918 kb)

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ari S. Nowacek
    • 1
  • JoEllyn McMillan
    • 1
  • Reagan Miller
    • 2
  • Alec Anderson
    • 1
  • Barrett Rabinow
    • 2
  • Howard E. Gendelman
    • 1
  1. 1.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Baxter Healthcare CorporationRound LakeUSA