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

Authors

Jonathan Herskovitz, University of Nebraska Medical Center
Mahmudul Hasan, University of Nebraska Medical Center
Jatin Machhi, University of Nebraska-LincolnFollow
Insiya Mukadam, University of Nebraska Medical Center
Brendan M. Ottemann, University of Kansas Medical Center
James R. Hilaire, University of Nebraska Medical Center
Christopher Woldstad, Weill Cornell Medicine
JoEllyn McMillan, University of Nebraska-Medical Center
Yutong Liu, University of Nebraska Medical Center
Javier Seravalli, University of Nebraska-LincolnFollow
Anandakumar Sarella, University of Nebraska-LincolnFollow
Howard E. Gendelman, University of Nebraska Medical Center
Bhavesh D. Kevadiya, University of Nebraska Medical Center

Document Type

Article

Date of this Version

4-27-2021

Citation

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

Comments

OPEN ACCESS

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.