Controlled activation of platinum(IV) prodrugs to active cytotoxics for photochemotherapy


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Kim Robinson2, Julie Woods2, Nicky Farrer1, Ana Pizarro1, Fiona Mackay3, Viv Munk3, Peter Sadler1
1Department of Chemistry, University of Warwick, Coverntry, United Kingdom,2Photobiology Unit, Department of Dermatology, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom,3School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom

Background

Cisplatin is a well-established, successful anticancer drug, which targets nuclear DNA. However, some malignancies are resistant to cisplatin treatment and some others develop resistance following treatment. Additionally, the drug presents severe dose-limiting side-effects. A way to increase tumour selectivity is to administer a prodrug that is activated locally.

We have designed a new series of platinum(IV) compounds that exploit the prodrug concept: inactive precursors that can be activated to produce a reactive cytotoxic species. The activation mechanism of our drugs is a certain wavelength of light which is applied specifically where required.

Method

These prodrugs were investigated for toxicity and reactivity with DNA in the presence/absence of light using human tumour cell lines. This concept has been extended to in vivo studies in mice. Irradiation was performed using appropriately filtered UV, visible and monochromatic sources.

Results

The platinum(IV) prodrugs undergo photoreduction to cytotoxic reactive platinum(II) species when irradiated. They rapidly kill tumour cells in culture (including cisplatin-resistant derivatives) and can be more effective than cisplatin when tested under similar conditions. The trans geometry affords more effective agents than the cis configuration. Photochemistry, nuclear morphology studies and measurement of caspase activity by a luminescent activation assay and western blotting of caspase target proteins reveal important differences between the mechanism of action of these complexes and cisplatin.

Conclusion

The photoactivatable complexes described here act as prodrugs, with no or limited toxicity in the dark and high cytotoxicity when irradiated. The mechanism of cytotoxic action could involve other species in addition to platinum derivatives. Exploiting the potency of these drugs together with the spatial control over their activity could be beneficial for several indications including bladder and oesophageal cancer which are not suitable for conventional light-activated chemotherapy.