Phenoxide-Bridged Zinc(II)-Bis(dipicolylamine) Probes for Molecular Imaging of Cell Death

Kasey J. Clear, Kara M. Harmatys, Douglas R. Rice, William R. Wolter, Mark A. Suckow, Yuzhen Wang, Mary Rusckowski, Bradley D. Smith

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cell death is involved in many pathological conditions, and there is a need for clinical and preclinical imaging agents that can target and report cell death. One of the best known biomarkers of cell death is exposure of the anionic phospholipid phosphatidylserine (PS) on the surface of dead and dying cells. Synthetic zinc(II)-bis(dipicolylamine) (Zn2BDPA) coordination complexes are known to selectively recognize PS-rich membranes and act as cell death molecular imaging agents. However, there is a need to improve in vivo imaging performance by selectively increasing target affinity and decreasing off-target accumulation. This present study compared the cell death targeting ability of two new deep-red fluorescent probes containing phenoxide-bridged Zn2BDPA complexes. One probe was a bivalent version of the other and associated more strongly with PS-rich liposome membranes. However, the bivalent probe exhibited self-quenching on the membrane surface, so the monovalent version produced brighter micrographs of dead and dying cells in cell culture and also better fluorescence imaging contrast in two living animal models of cell death (rat implanted tumor with necrotic core and mouse thymus atrophy). An 111In-labeled radiotracer version of the monovalent probe also exhibited selective cell death targeting ability in the mouse thymus atrophy model, with relatively high amounts detected in dead and dying tissue and low off-target accumulation in nonclearance organs. The in vivo biodistribution profile is the most favorable yet reported for a Zn2BDPA complex; thus, the monovalent phenoxide-bridged Zn2BDPA scaffold is a promising candidate for further development as a cell death imaging agent in living subjects.

Original languageEnglish (US)
Pages (from-to)363-375
Number of pages13
JournalBioconjugate Chemistry
Volume27
Issue number2
DOIs
StatePublished - Feb 17 2016

Bibliographical note

Funding Information:
We are grateful for funding support from the NIH (RO1GM059078 to B.D.S. and T32GM075762 to D.R.R.) and GAANN (K.J.C. and K.M.H.) and technical support from the University of Notre Dame, the Notre Dame Integrated Imaging Facility, the Harper Cancer Research Institute Imaging and Flow Cytometry Core Facility, and the Freimann Life Sciences Center. We thank M. Smith and S. Turkyilmaz for excellent technical assistance.

Publisher Copyright:
© 2015 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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