Nanotheranostics 2021; 5(4):417-430. doi:10.7150/ntno.59568

Research Paper

Europium sulfide nanoprobes predict antiretroviral drug delivery into HIV-1 cell and tissue reservoirs

Jonathan Herskovitz1, Mahmudul Hasan2,3, Jatin Machhi2, Insiya Mukadam3, Brendan M. Ottemann4, James R. Hilaire2, Christopher Woldstad5, JoEllyn McMillan2, Yutong Liu6, Javier Seravalli7, Anandakumar Sarella8, Howard E. Gendelman2,3, Bhavesh D. Kevadiya2✉

1. Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 USA.
3. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198 USA.
4. Department of Otorhinolaryngology, University of Kansas Medical Center, Kansas City, KS 66213 USA.
5. Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY 10065 USA.
6. Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198 USA.
7. Department of Biochemistry, University of Nebraska Lincoln, Lincoln, NE 68588 USA.
8. Nebraska Center for Materials and Nanoscience, University of Nebraska Lincoln, Lincoln, NE 68588 USA.

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Citation:
Herskovitz J, Hasan M, Machhi J, Mukadam I, Ottemann BM, Hilaire JR, Woldstad C, McMillan J, Liu Y, Seravalli J, Sarella A, Gendelman HE, Kevadiya BD. Europium sulfide nanoprobes predict antiretroviral drug delivery into HIV-1 cell and tissue reservoirs. Nanotheranostics 2021; 5(4):417-430. doi:10.7150/ntno.59568. Available from https://www.ntno.org/v05p0417.htm

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Abstract

Background: Delivery of long-acting nanoformulated antiretroviral drugs (ARVs) to human immunodeficiency virus type one cell and tissue reservoirs underlies next generation antiretroviral therapeutics. Nanotheranostics, comprised of trackable nanoparticle adjuncts, can facilitate ARV delivery through real-time drug tracking made possible through bioimaging platforms.

Methods: To model HIV-1 therapeutic delivery, europium sulfide (EuS) nanoprobes were developed, characterized and then deployed to cells, tissues, and rodents. Tests were performed with nanoformulated rilpivirine (NRPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to suppress or prevent HIV-1 infection. First, CD4+ T cells and monocyte-derived macrophages were EuS-treated with and without endocytic blockers to identify nanoprobe uptake into cells. Second, Balb/c mice were co-dosed with NRPV and EuS or lutetium177-doped EuS (177LuEuS) theranostic nanoparticles to assess NRPV biodistribution via mass spectrometry. Third, single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) bioimaging were used to determine nanotheranostic and NRPV anatomic redistribution over time.

Results: EuS nanoprobes and NRPV entered cells through dynamin-dependent pathways. SPECT-CT and MRI identified biodistribution patterns within the reticuloendothelial system for EuS that was coordinate with NRPV trafficking.

Conclusions: EuS nanoprobes parallel the uptake and biodistribution of NRPV. These data support their use in modeling NRPV delivery to improve treatment strategies.

Keywords: HIV-1, antiretroviral, nanotheranostics, europium, molecular imaging, SPECT-CT