Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution

Bhavesh D. Kevadiya, Christopher Woldstad, Brendan M. Ottemann, Prasanta Dash, Balasrinivasa R Sajja, Benjamin Lamberty, Brenda Morsey, Ted Kocher, Rinku Dutta, Aditya N. Bade, Yutong Liu, Shannon E. Callen, Howard S Fox, Siddappa Nagadenahalli Byrareddy, JoEllyn M McMillan, Tatiana K Bronich, Benson J Edagwa, Michael D. Boska, Howard Eliot Gendelman

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)256-276
Number of pages21
JournalTheranostics
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2018

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Magnetic Resonance Spectroscopy
Pharmaceutical Preparations
Folic Acid
Nanoparticles
Macrophages
Iron
Multimodal Imaging
Europium
Nanomedicine
Drug Delivery Systems
Patient Compliance
Cobalt
Theranostic Nanomedicine
dolutegravir
Macaca mulatta
Therapeutics
Animal Models
Pharmacokinetics
Fluorescence
Magnetic Resonance Imaging

Keywords

  • Antiretroviral drugs
  • Confocal microscopy
  • Dolutegravir
  • Magnetic resonance imaging
  • Monocyte-derived macrophages
  • Multimodal imaging
  • Rats and nanomedicines
  • Rhesus macaques

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution. / Kevadiya, Bhavesh D.; Woldstad, Christopher; Ottemann, Brendan M.; Dash, Prasanta; Sajja, Balasrinivasa R; Lamberty, Benjamin; Morsey, Brenda; Kocher, Ted; Dutta, Rinku; Bade, Aditya N.; Liu, Yutong; Callen, Shannon E.; Fox, Howard S; Byrareddy, Siddappa Nagadenahalli; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson J; Boska, Michael D.; Gendelman, Howard Eliot.

In: Theranostics, Vol. 8, No. 1, 01.01.2018, p. 256-276.

Research output: Contribution to journalArticle

Kevadiya, Bhavesh D. ; Woldstad, Christopher ; Ottemann, Brendan M. ; Dash, Prasanta ; Sajja, Balasrinivasa R ; Lamberty, Benjamin ; Morsey, Brenda ; Kocher, Ted ; Dutta, Rinku ; Bade, Aditya N. ; Liu, Yutong ; Callen, Shannon E. ; Fox, Howard S ; Byrareddy, Siddappa Nagadenahalli ; McMillan, JoEllyn M ; Bronich, Tatiana K ; Edagwa, Benson J ; Boska, Michael D. ; Gendelman, Howard Eliot. / Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution. In: Theranostics. 2018 ; Vol. 8, No. 1. pp. 256-276.
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T1 - Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution

AU - Kevadiya, Bhavesh D.

AU - Woldstad, Christopher

AU - Ottemann, Brendan M.

AU - Dash, Prasanta

AU - Sajja, Balasrinivasa R

AU - Lamberty, Benjamin

AU - Morsey, Brenda

AU - Kocher, Ted

AU - Dutta, Rinku

AU - Bade, Aditya N.

AU - Liu, Yutong

AU - Callen, Shannon E.

AU - Fox, Howard S

AU - Byrareddy, Siddappa Nagadenahalli

AU - McMillan, JoEllyn M

AU - Bronich, Tatiana K

AU - Edagwa, Benson J

AU - Boska, Michael D.

AU - Gendelman, Howard Eliot

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N2 - 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.

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KW - Rhesus macaques

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