In vitro demonstration of the heavy-atom effect for photodynamic therapy

Gorman, Aoife, Killoran, John, O'Shea, Caroline, Kenna, Tony, Gallagher, William M., & O'Shea, Donal F. (2004) In vitro demonstration of the heavy-atom effect for photodynamic therapy. Journal of the American Chemical Society, 126(34), pp. 10619-10631.

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Photodynamic therapy (PDT) is an emerging treatment modality for a range of disease classes, both cancerous and noncancerous. This has brought about an active pursuit of new PDT agents that can be optimized for the unique set of photophysical characteristics that are required for a successful clinical agent. We now describe a totally new class of PDT agent, the BF2-chelated 3,5-diaryl-1H-pyrrol-2-yl-3,5-diarylpyrrol-2-ylideneamines (tetraarylazadipyrromethenes). Optimized synthetic procedures have been developed to facilitate the generation of an array of specifically substituted derivatives to demonstrate how control of key therapeutic parameters such as wavelength of maximum absorbance and singlet-oxygen generation can be achieved. Photosensitizer absorption maxima can be varied within the body's therapeutic window between 650 and 700 nm, with high extinction coefficients ranging from 75,000 to 85,000 M(-1) cm(-1). Photosensitizer singlet-oxygen generation level was modulated by the exploitation of the heavy-atom effect. An array of photosensitizers with and without bromine atom substituents gave rise to a series of compounds with varying singlet-oxygen generation profiles. X-ray structural evidence indicates that the substitution of the bromine atoms has not caused a planarity distortion of the photosensitizer. Comparative singlet-oxygen production levels of each photosensitizer versus two standards demonstrated a modulating effect on singlet-oxygen generation depending upon substituent patterns about the photosensitizer. Confocal laser scanning microscopy imaging of 18a in HeLa cervical carcinoma cells proved that the photosensitizer was exclusively localized to the cellular cytoplasm. In vitro light-induced toxicity assays in HeLa cervical carcinoma and MRC5-SV40 transformed fibroblast cancer cell lines confirmed that the heavy-atom effect is viable in a live cellular system and that it can be exploited to modulate assay efficacy. Direct comparison of the efficacy of the photosensitizers 18b and 19b, which only differ in molecular structure by the presence of two bromine atoms, illustrated an increase in efficacy of more than a 1000-fold in both cell lines. All photosensitizers have very low to nondeterminable dark toxicity in our assay system.

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403 citations in Web of Science®
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ID Code: 94057
Item Type: Journal Article
Refereed: Yes
Keywords: Aza Compounds/chemical synthesis/ chemistry/pharmacology, Boron Compounds/chemical synthesis/ chemistry/pharmacology, Crystallography, X-Ray, HeLa Cells, Humans, Molecular Structure, Photochemotherapy/ methods, Photosensitizing Agents/chemical synthesis/ chemistry/pharmacology, Pyrroles/chemical synthesis/ chemistry/pharmacology, Singlet Oxygen/chemistry, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet
DOI: 10.1021/ja047649e
ISSN: 0002-7863
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2004 American Chemical Society
Deposited On: 21 Mar 2016 02:34
Last Modified: 21 Mar 2016 02:34

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