Development of porphyrin-antiangiogenic antibody immunoconjugates for photodynamic therapy

Photodynamic therapy is a novel cancer treatment, involving the combination of light, photosensitiser and molecular oxygen to produce cytotoxic species. Currently, commercially available photosensitisers, including Photofrin and Foscan, only exhibit a passive selectively towards cancerous tissue. Therapeutically, this results in a variety of unfavourable characteristics, obstructing PDT from becoming a more viable cancer treatment. Research has been directed towards improving the pharmacokinetic and biodistribution profiles of photosensitisers, which can be achieved by conjugating the photosensitiser moiety to a biomolecule which has affinity for the diseased tissue; these 3rd generation photosensitisers include photoimmunoconjugates. Three synthetic routes were developed, with the aim of producing novel bioconjugatable porphyrins, which could be subsequently conjugated to cysteine residues expressed by a suitable monoclonal antibody (SIP(L19)). Two cationic, thiol reactive photosensitisers were synthesised and successfully conjugated to SIP(L19) in a reproducible manner, affording well defined immunoconjugates, which retained both the immunoreactivity of the antibody moiety and the photoactivity of the photosensitiser. The effect of the length and hydrophilicity of the linker connecting the photosensitiser and bioconjugatable group was investigated, and it was observed that the photoactivity of the immunoconjugate was enhanced using a longer, hydrophilic chain. Synthetic routes leading to the production of bioconjugatable porphyrin dimers, and photosensitisers from symmetrical porphyrin, were developed, but failed to yield final products.EThOS - Electronic Theses Online ServiceGBUnited Kingdo