Theranostics 2018; 8(1):256-276. doi:10.7150/thno.22764

Research Paper

Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution

Bhavesh D. Kevadiya1*, Christopher Woldstad2*, Brendan M. Ottemann1, Prasanta Dash1, Balasrinivasa R. Sajja2, Benjamin Lamberty1, Brenda Morsey1, Ted Kocher1, Rinku Dutta1, Aditya N. Bade1, Yutong Liu2, Shannon E. Callen1, Howard S. Fox1, Siddappa N. Byrareddy1, JoEllyn M. McMillan1, Tatiana K. Bronich3, Benson J. Edagwa1, Michael D. Boska2, Howard E. Gendelman1,3✉

1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA;
2. Department of Radiology, University of Nebraska Medical Center, Omaha, NE, USA;
3. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
* The first two authors contributed equally

Abstract

RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, “multimodal imaging theranostic nanoprobes” were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models.

METHODS: Europium (Eu3+)- doped cobalt ferrite (CF) dolutegravir (DTG)- loaded (EuCF-DTG) nanoparticles were synthesized then fully characterized based on their size, shape and stability. These were then used as platforms for nanoformulated drug biodistribution.

RESULTS: Folic acid (FA) decoration of EuCF-DTG (FA-EuCF-DTG) nanoparticles facilitated macrophage targeting and sped drug entry across cell barriers. Macrophage uptake was higher for FA-EuCF-DTG than EuCF-DTG nanoparticles with relaxivities of r2 = 546 mM-1s-1 and r2 = 564 mM-1s-1 in saline, and r2 = 850 mM-1s-1 and r2 = 876 mM-1s-1 in cells, respectively. The values were ten or more times higher than what was observed for ultrasmall superparamagnetic iron oxide particles (r2 = 31.15 mM-1s-1 in saline) using identical iron concentrations. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses. After parenteral injection of FA-EuCF-DTG and EuCF-DTG into rats and rhesus macaques, drug, iron and cobalt levels, measured by LC-MS/MS, magnetic resonance imaging, and ICP-MS were coordinate.

CONCLUSION: We posit that these theranostic nanoprobes can assess LASER ART drug delivery and be used as part of a precision nanomedicine therapeutic strategy.

Keywords: Antiretroviral drugs, dolutegravir, monocyte-derived macrophages, multimodal imaging, magnetic resonance imaging, confocal microscopy, rhesus macaques, rats and nanomedicines.

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How to cite this article:
Kevadiya BD, Woldstad C, Ottemann BM, Dash P, Sajja BR, Lamberty B, Morsey B, Kocher T, Dutta R, Bade AN, Liu Y, Callen SE, Fox HS, Byrareddy SN, McMillan JM, Bronich TK, Edagwa BJ, Boska MD, Gendelman HE. Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics 2018; 8(1):256-276. doi:10.7150/thno.22764. Available from http://www.thno.org/v08p0256.htm