TY - JOUR
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 N.
AU - McMillan, Jo Ellyn M.
AU - Bronich, Tatiana K.
AU - Edagwa, Benson J.
AU - Boska, Michael D.
AU - Gendelman, Howard E.
N1 - Funding Information:
The authors would like to thank Tom Bargar and Nicholas Conoan of the Electron Microscopy Core Facility at the UNMC for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative and the University of Nebraska Foundation, and institutionally by the Office of the Vice Chancellor for Research. We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center for providing assistance with (confocal or super resolution) microscopy. Support given to the UNMC Advanced Microscopy Core Facility was provided through the Nebraska Research Initiative, the Fred and Pamela Buffett Cancer Center Support Grant (P30CA036727), and an Institutional Development Award from NIGMS (P30GM106397). The LSM710 Zeiss Confocal Microscope used in this research was supported by the NIH grant S10RR027301. The authors thank the Nebraska Center for Materials and Nanoscience and Redox Biology at the University of Nebraska-Lincoln for ICP-MS, XRD, SQUID and AFM analyses. The authors appreciate the excellent technical assistance made by Melissa Mellon, Lirong Xu, and Celina M. Prince in support of the MRI tests. This work was supported, in part, by NIH Grants AG043540, DA028555, NS036126, NS034239, MH064570, NS043985, MH062261, AG043540, AI113883 and DOD Grant 421-20-09A, the Carol Swarts Emerging Neuroscience Fund and the Nebraska Research Initiative.
Publisher Copyright:
© Ivyspring International Publisher.
PY - 2018
Y1 - 2018
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.
AB - 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.
KW - Antiretroviral drugs
KW - Confocal microscopy
KW - Dolutegravir
KW - Magnetic resonance imaging
KW - Monocyte-derived macrophages
KW - Multimodal imaging
KW - Rats and nanomedicines
KW - Rhesus macaques
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U2 - 10.7150/thno.22764
DO - 10.7150/thno.22764
M3 - Article
C2 - 29290806
AN - SCOPUS:85035101295
SN - 1838-7640
VL - 8
SP - 256
EP - 276
JO - Theranostics
JF - Theranostics
IS - 1
ER -