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Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death

[Image: see text] Zinc(II)-bis(dipicolylamine) (Zn-BDPA) coordination complexes selectively target the surfaces of dead and dying mammalian cells, and they have promise as molecular probes for imaging cell death. A necessary step toward eventual clinical imaging applications is the development of ne...

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Autores principales: Plaunt, Adam J., Harmatys, Kara M., Wolter, William R., Suckow, Mark A., Smith, Bradley D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993938/
https://www.ncbi.nlm.nih.gov/pubmed/24575875
http://dx.doi.org/10.1021/bc500003x
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author Plaunt, Adam J.
Harmatys, Kara M.
Wolter, William R.
Suckow, Mark A.
Smith, Bradley D.
author_facet Plaunt, Adam J.
Harmatys, Kara M.
Wolter, William R.
Suckow, Mark A.
Smith, Bradley D.
author_sort Plaunt, Adam J.
collection PubMed
description [Image: see text] Zinc(II)-bis(dipicolylamine) (Zn-BDPA) coordination complexes selectively target the surfaces of dead and dying mammalian cells, and they have promise as molecular probes for imaging cell death. A necessary step toward eventual clinical imaging applications is the development of next-generation Zn-BDPA complexes with enhanced affinity for the cell death membrane biomarker, phosphatidylserine (PS). This study employed an iterative cycle of library synthesis and screening, using a novel rapid equilibrium dialysis assay, to discover a modified Zn-BDPA structure with high and selective affinity for vesicles containing PS. The lead structure was converted into a deep-red fluorescent probe and its targeting and imaging performance was compared with an unmodified control Zn-BDPA probe. The evaluation process included a series of FRET-based vesicle titration studies, cell microscopy experiments, and rat tumor biodistribution measurements. In all cases, the modified probe exhibited comparatively higher affinity and selectivity for the target membranes of dead and dying cells. The results show that this next-generation deep-red fluorescent Zn-BDPA probe is well suited for preclinical molecular imaging of cell death in cell cultures and animal models. Furthermore, it should be possible to substitute the deep-red fluorophore with alternative reporter groups that enable clinically useful, deep-tissue imaging modalities, such as MRI and nuclear imaging.
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spelling pubmed-39939382015-02-27 Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death Plaunt, Adam J. Harmatys, Kara M. Wolter, William R. Suckow, Mark A. Smith, Bradley D. Bioconjug Chem [Image: see text] Zinc(II)-bis(dipicolylamine) (Zn-BDPA) coordination complexes selectively target the surfaces of dead and dying mammalian cells, and they have promise as molecular probes for imaging cell death. A necessary step toward eventual clinical imaging applications is the development of next-generation Zn-BDPA complexes with enhanced affinity for the cell death membrane biomarker, phosphatidylserine (PS). This study employed an iterative cycle of library synthesis and screening, using a novel rapid equilibrium dialysis assay, to discover a modified Zn-BDPA structure with high and selective affinity for vesicles containing PS. The lead structure was converted into a deep-red fluorescent probe and its targeting and imaging performance was compared with an unmodified control Zn-BDPA probe. The evaluation process included a series of FRET-based vesicle titration studies, cell microscopy experiments, and rat tumor biodistribution measurements. In all cases, the modified probe exhibited comparatively higher affinity and selectivity for the target membranes of dead and dying cells. The results show that this next-generation deep-red fluorescent Zn-BDPA probe is well suited for preclinical molecular imaging of cell death in cell cultures and animal models. Furthermore, it should be possible to substitute the deep-red fluorophore with alternative reporter groups that enable clinically useful, deep-tissue imaging modalities, such as MRI and nuclear imaging. American Chemical Society 2014-02-27 2014-04-16 /pmc/articles/PMC3993938/ /pubmed/24575875 http://dx.doi.org/10.1021/bc500003x Text en Copyright © 2014 American Chemical Society
spellingShingle Plaunt, Adam J.
Harmatys, Kara M.
Wolter, William R.
Suckow, Mark A.
Smith, Bradley D.
Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title_full Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title_fullStr Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title_full_unstemmed Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title_short Library Synthesis, Screening, and Discovery of Modified Zinc(II)-Bis(dipicolylamine) Probe for Enhanced Molecular Imaging of Cell Death
title_sort library synthesis, screening, and discovery of modified zinc(ii)-bis(dipicolylamine) probe for enhanced molecular imaging of cell death
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993938/
https://www.ncbi.nlm.nih.gov/pubmed/24575875
http://dx.doi.org/10.1021/bc500003x
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