The main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first... Show moreThe main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first investigated whether non-toxic ligands such as L-proline, 2-(methylthio)methylpyridine (mtmp), or 3-(methylthio)propylamine (mtpa), once coordinated to ruthenium(II) complexes, could be photosubstituted upon visible light irradiation. The lipophilicity, and in some cases the strain of the ruthenium(II) complexes, were systematically varied and the effects of such variations on the cytotoxicity of the complexes in the dark and under light irradiation were studied. In the second part, the best ligand candidates (i.e. mtmp and mtpa) were coordinated to cyclometalated ruthenium complexes of the type [Ru(bpy)(phpy)(S,N)]PF6 (bpy = 2,2’-bipyridine and phpy = 2-phenylpyridine), to shift the absorption of the complex to the red region of the spectrum. The photosubstitution properties of these cyclometallated complexes were investigated in detail. The most promising ruthenium complexes were tested in cancer cell monolayers under hypoxic conditions (1% O2) to investigate their mode of action and distinguish between PACT and PDT. Show less
The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity... Show moreThe field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. In this work we present alternative strategies such as light-activation with different transition-metals such as ruthenium and palladium that have the potential to be more selective than cisplatin type of drugs. Show less
Ruthenium complexes are promising prodrugs in photoactivated chemotherapy (PACT): to prevent systemic therapeutic side-effects, a non-toxic version of the drug is introduced in the body and is... Show moreRuthenium complexes are promising prodrugs in photoactivated chemotherapy (PACT): to prevent systemic therapeutic side-effects, a non-toxic version of the drug is introduced in the body and is only activated at the place of the tumor by means of visible light irradiation. However, most of these PACT compounds are only sensitive for UV or blue light, while this light does not permeate the body very well, in contrast to red or near-infrared light. To circumvent this problem, the principle of light-upconversion can be used to "upgrade" red light to blue light in a drug carrier such as a nanovesicle: the tumor is irradiated with red light, after which blue light is generated locally and used to activate the prodrug. Among the various methods of light-upconversion, triplet-triplet annihilation upconversion (TTA-UC) was selected as the most promising. In this thesis it is described that green-to-blue and red-to-blue upconverting nanovesicles were prepared. The red-to-blue upconverted light was successfully used to activate a ruthenium polypyridyl complex that was anchored to the same vesicle. Finally, the inherent oxygen-sensitivity of TTA-UC was greatly mitigated by the addition of water-soluble and biocompatible anti-oxidants. We expect that the results of this thesis will lead to exciting applications in PACT. Show less
