title: Library synthesis, screening, and discovery of modified Zinc(II)-Bis(dipicolylamine) probe for enhanced molecular imaging of cell death.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall and ‡Department of Biological Science, Galvin Life Sciences, University of Notre Dame , Notre Dame, 46556 Indiana, United States.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Plaunt
authors.forename: Kara M
authors.initials: KM
authors.lastname: Harmatys
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D016466:CHO Cells; D016923:Cell Death; D045744:Cell Line, Tumor; D003412:Cricetulus; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010848:Picolinic Acids / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D015335:Molecular Probes; D009942:Organometallic Compounds; D010848:Picolinic Acids; C529174:bis-dipicolylamine-Zinc(II)