TY - JOUR
T1 - Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities
AU - Ottemann, Brendan M.
AU - Helmink, Austin J.
AU - Zhang, Wenting
AU - Mukadam, Insiya
AU - Woldstad, Christopher
AU - Hilaire, James R.
AU - Liu, Yutong
AU - McMillan, Jo Ellyn M.
AU - Edagwa, Benson J.
AU - Mosley, R. Lee
AU - Garrison, Jered C.
AU - Kevadiya, Bhavesh 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 (EMCF) at the University of Nebraska Medical Center (UNMC) for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative (NRI) 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 UNMC for providing assistance with (confocal or super resolution) microscopy. Support given to the Advanced Microscopy Core Facility was provided through the NRI , the Fred and Pamela Buffett Cancer Center Support Grant ( P30CA036727 ), and an Institutional Development Award (IDeA) from NIGMS ( P30GM106397 ). The LSM710 Zeiss Confocal Microscope used in this research was supported by National Institutes of Health awards R01 AG043540 , R56 AI38613 , PO1DA028555 , P30 MH062261 , MH115850 , R01 NS034239 , R01 NS036128 and T32 NS1055594 . We also would like to thank Drs. Alexander Lushnikov and Alexey Krasnoslobodtsev for technical assistance with AFM imaging experiments at the Nanoimaging Core Facility of the UNMC. The authors thank the Nebraska Center for Materials and Nanoscience and Redox Biology at the University of Nebraska-Lincoln for ICP-MS, XPS and XRD analyses. The authors are thankful to Samantha D. Wall and Victoria B. Smith for their help in Flow Cytometry analysis of samples. The UNMC Flow Cytometry Research Facility is administrated through the Office of the Vice Chancellor for Research and supported by state funds from the Nebraska Research Initiative (NRI) and The Fred and Pamela Buffett Cancer Center's National Cancer Institute Cancer Support Grant. Major instrumentation has been provided by the Office of the Vice Chancellor for Research, The University of Nebraska Foundation, the Nebraska Banker's Fund, and by the NIH-NCRR Shared Instrument Program. The authors are very grateful to the National Isotope Development Center, Oak Ridge National Laboratory, Oak Ridge, TN, USA, for providing radioisotopes. The authors appreciate the excellent technical assistance made by Melissa Mellon, Lirong Xu and Yaman Lu in support of the MRI and SPECT/CT tests. We would like to thank Dr. Jane Meza, UNMC, College of Public Health, Department of Biostatistics for initial statistical analyses of the data. Bhagy Laxmi Dyavar Shetty assisted UPLC-MS/MS analysis from tissue and plasma, Dr.Prasanta Dash and Sruthi Sravananm assisted in tissue sectioning and slide preparations for histopathological analyses. Wang Weimin and Dhruvkumar Soni assisted in animal handling, IV Injections, and plasma collection. The authors would also like to thank Dr. Aditya Bade for helpful discussions.
Funding Information:
The authors would like to thank Tom Bargar and Nicholas Conoan of the Electron Microscopy Core Facility (EMCF) at the University of Nebraska Medical Center (UNMC) for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative (NRI) 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 UNMC for providing assistance with (confocal or super resolution) microscopy. Support given to the Advanced Microscopy Core Facility was provided through the NRI, the Fred and Pamela Buffett Cancer Center Support Grant (P30CA036727), and an Institutional Development Award (IDeA) from NIGMS (P30GM106397). The LSM710 Zeiss Confocal Microscope used in this research was supported by National Institutes of Health awards R01 AG043540, R56 AI38613, PO1DA028555, P30 MH062261, MH115850, R01 NS034239, R01 NS036128 and T32 NS1055594. We also would like to thank Drs. Alexander Lushnikov and Alexey Krasnoslobodtsev for technical assistance with AFM imaging experiments at the Nanoimaging Core Facility of the UNMC. The authors thank the Nebraska Center for Materials and Nanoscience and Redox Biology at the University of Nebraska-Lincoln for ICP-MS, XPS and XRD analyses. The authors are thankful to Samantha D. Wall and Victoria B. Smith for their help in Flow Cytometry analysis of samples. The UNMC Flow Cytometry Research Facility is administrated through the Office of the Vice Chancellor for Research and supported by state funds from the Nebraska Research Initiative (NRI) and The Fred and Pamela Buffett Cancer Center's National Cancer Institute Cancer Support Grant. Major instrumentation has been provided by the Office of the Vice Chancellor for Research, The University of Nebraska Foundation, the Nebraska Banker's Fund, and by the NIH-NCRR Shared Instrument Program. The authors are very grateful to the National Isotope Development Center, Oak Ridge National Laboratory, Oak Ridge, TN, USA, for providing radioisotopes. The authors appreciate the excellent technical assistance made by Melissa Mellon, Lirong Xu and Yaman Lu in support of the MRI and SPECT/CT tests. We would like to thank Dr. Jane Meza, UNMC, College of Public Health, Department of Biostatistics for initial statistical analyses of the data. Bhagy Laxmi Dyavar Shetty assisted UPLC-MS/MS analysis from tissue and plasma, Dr.Prasanta Dash and Sruthi Sravananm assisted in tissue sectioning and slide preparations for histopathological analyses. Wang Weimin and Dhruvkumar Soni assisted in animal handling, IV Injections, and plasma collection. The authors would also like to thank Dr. Aditya Bade for helpful discussions.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/12
Y1 - 2018/12
N2 - Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically 111Indium (111In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (111InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. 111InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.
AB - Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically 111Indium (111In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (111InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. 111InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.
KW - Antiretroviral therapy
KW - Biodistribution
KW - Magnetic resonance imaging
KW - Single photon emission computed tomography
KW - Transformative nanotechnology
UR - http://www.scopus.com/inward/record.url?scp=85054615234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054615234&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2018.09.018
DO - 10.1016/j.biomaterials.2018.09.018
M3 - Article
C2 - 30245386
AN - SCOPUS:85054615234
VL - 185
SP - 174
EP - 193
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
ER -