Sadler, Peter

Farley, Sarah J.

2010-09-30T12:46:33Z

2010-09-30T12:46:33Z

2010

A major challenge of platinum anticancer therapy lies in overcoming the severe side-effects associated with treatment. Photoactivatable PtIV azido complexes, which are stable in the dark and reduced to cytotoxic PtII species upon irradiation, have recently emerged as a potential site-specific treatment. This thesis is concerned with the investigation of PtII and PtIV azido complexes as potential cytotoxic and photochemotherapeutic agents. PtII azido complexes such as [Pt(en)(N3)2] were shown to bind to both 5'-guanosine monophosphate (5'-GMP) and glutathione, at a much reduced rate compared with their PtII chlorido analogues. Interestingly, and unexpectedly, these PtII azido complexes showed moderate cytotoxicity towards the A2780 cancer cell line (IC50 21–47 μM). Binding to 5'-GMP was observed to occur more rapidly upon irradiation with UVA light, although the extent of binding was low and the complexes did not demonstrate phototoxicity towards HaCaT keratinocytes. The pendant hydroxyl group of a PtII azido complex was functionalised with a fluorescent probe; conjugation to one axial hydroxyl ligand of a PtIV azido complex was also achieved. The latter conjugate showed a rapid increase in fluorescence intensity upon irradiation, resulting from loss of the axial ligands upon photoreduction. The functionalisation of quantum dots with PtII complexes was also investigated. Water soluble CdSe-ZnS quantum dots were synthesised and derivatised with an amine ligand to which platinum was bound. Conjugation of apo-transferrin to quantum dots was also achieved, with subsequent platinum binding yielding a conjugate with improved aqueous solubility and fluorescence properties. However, the conjugate was inactive towards the A2780 cancer cell line, likely due to surface modifications preventing cellular internalisation. PtII chlorido and azido conjugates with a porphyrin were synthesised and found to show differing behaviour upon irradiation with visible light; evidence of hydrogen peroxide generation from the chlorido complex was much reduced in the case of the azido complex; it is suggested this may result from quenching of reactive oxygen species by the azide anion released upon irradiation. PtII chlorido and azido complexes of highly coloured azo ligands were synthesised in an attempt to shift the wavelength of activation into the visible region. TD-DFT calculations allowed frontier orbital analysis and assignment of the transitions in the absorption spectra. Irradiation of the PtII azido complexes with UVA or broadband visible light led to their decomposition; one water-soluble complex was found to show moderate cytotoxicity and phototoxicity; in addition, its intense blue colour allowed for visual monitoring of this complex inside cells.

http://hdl.handle.net/1842/3769

en

The University of Edinburgh

platinum

anticancer

photoactivation

Platinum complexes as potential photochemotherapeutic agents

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy