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Library synthesis, screening, and discovery of modified Zinc(II)-Bis(dipicolylamine) probe for enhanced molecular imaging of cell death.
- Source :
-
Bioconjugate chemistry [Bioconjug Chem] 2014 Apr 16; Vol. 25 (4), pp. 724-37. Date of Electronic Publication: 2014 Mar 13. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
CHO Cells
Cell Death
Cell Line, Tumor
Cricetulus
Fluorescence Resonance Energy Transfer
Humans
Male
Molecular Probes chemistry
Molecular Probes pharmacokinetics
Molecular Structure
Organometallic Compounds chemistry
Organometallic Compounds pharmacokinetics
Picolinic Acids chemistry
Picolinic Acids pharmacokinetics
Rats
Rats, Wistar
Tissue Distribution
Breast Neoplasms pathology
Molecular Imaging methods
Molecular Probes analysis
Molecular Probes chemical synthesis
Organometallic Compounds analysis
Organometallic Compounds chemical synthesis
Picolinic Acids analysis
Picolinic Acids chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4812
- Volume :
- 25
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Bioconjugate chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24575875
- Full Text :
- https://doi.org/10.1021/bc500003x