Photodynamic therapy is a promising clinical alternative for the treatment of cancer, which works via the action of a photosensitiser in combination with light and molecular oxygen. Selective application of both the photosensitiser and light to tumour tissue results in a �dual selectivity�, limiting cytotoxic effects to the target tissue only, and producing few negative side effects.Use of targeting groups such as antibody fragments is a highly effective method of improving the selective localisation of the photosensitiser, with the most common methodology conjugating porphyrin photosensitisers to the numerous lysine residues present on the antibody fragment. While this strategy has previously been utilised to produce conjugates capable of complete tumour eradication, it gives only limited control over stoichiometry and regioselectivity, and can lead to problems with batch to batch reproducibility.An alternative is a site-selective conjugation strategy, bridging the single interchain disulfide bond present on antibody Fab fragments with a dibromomaleimide functionality, allowing selective conjugation without loss of structural integrity. In this work, this disulfide modification was combined with the click reaction to deliver a bioconjugation methodology which is mild, facile and highly selective. This methodology allows for attachment of a single porphyrin in a regiospecific and stoichiometric way, while increased binding ratios can be obtained through facile attachment of porphyrin-dendron units without loss of the stoichiometric and structural control made possible by disulfide bridge conjugation.To this end, synthesis of a range of hydrophilic porphyrins and porphyrin-dendron conjugates has been carried out, with all porphyrins exhibiting retention of spectroscopic and photophysical characteristics after conjugation. Utilising a novel conjugation strategy, attachment of water-soluble porphyrins to antibody fragments was successfully carried out, producing two examples of HER2-targeted photosensitiser conjugates. Biological investigation has been conducted, and has demonstrated the effectiveness of these structures as powerful and selective therapeutic agents.

Targeting the anticancer warhead: Synthesis and biological evaluation of porphyrin-dendron conjugates for photodynamic therapy

248th National Meeting (2014)

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