1. Detailed Biological Profiling of a Photoactivated and Apoptosis Inducing pdppz Ruthenium(II) Polypyridyl Complex in Cancer Cells.
- Author
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Cloonan SM, Elmes RB, Erby M, Bright SA, Poynton FE, Nolan DE, Quinn SJ, Gunnlaugsson T, and Williams DC
- Subjects
- Antineoplastic Agents chemistry, Cell Proliferation radiation effects, Comet Assay, DNA Cleavage drug effects, Humans, Membrane Potentials drug effects, Membrane Potentials radiation effects, Models, Molecular, Molecular Structure, Neoplasms drug therapy, Neoplasms pathology, Photosensitizing Agents chemistry, Reactive Oxygen Species metabolism, Ruthenium Compounds chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Light, Photosensitizing Agents pharmacology, Pyridines chemistry, Ruthenium Compounds pharmacology
- Abstract
Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their development. We have designed a new Ru(II) PDT candidate that efficiently enters cells by incorporation of the lipophilic aromatic pdppz ([2,3-h]dipyrido[3,2-a:2',3'-c]phenazine) ligand and exhibits photoactivity through incorporation of 1,4,5,8-tetraazaphenanthrene ancillary ligands. Its photoreactivity toward biomolecules was studied in vitro, where light activation caused DNA cleavage. Cellular internalization occurred via an energy dependent mechanism. Confocal and transmission electron microscopy revealed that the complex localizes in various organelles, including the mitochondria. The complex is nontoxic in the dark, with cellular clearance within 96 h; however, upon visible light activation it induces caspase-dependent and reactive-oxygen-species-dependent apoptosis, with low micromolar IC50 values. This investigation greatly increases our understanding of such systems in cellulo, aiding development and realization of their application in cancer therapy.
- Published
- 2015
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