Metal complexes and 2D materials like graphene were combined to produce structures that can function as sensors. Using spin crossover materials, both in bulk single crystal form and in thin layer... Show moreMetal complexes and 2D materials like graphene were combined to produce structures that can function as sensors. Using spin crossover materials, both in bulk single crystal form and in thin layer form, graphene-based electronic sensors were produced and characterized that can detect spin switches in the spin crossover materials. At the same time, the light-activatable ruthenium complexes were researched for their application in sensors that can monitor reactions that were triggered by light. We found that the photoreaction of a ruthenium complex with a nucleobase could be triggered in paper-based graphene devices. Moreover, we found that this ruthenium scaffold could also be used to increase the signal strength in a nanopore-based DNA detection system. Lastly, a ruthenium complex was designed that had a sensing function built in, as a dual-function molecule with a sensing and anticancer function. Overall, combining metal complexes with graphene was found to be a successful strategy to produce hybrid structures for sensing. Show less
In this thesis, we will utilize embryonic zebrafish tumour models to understand the interaction between engrafted human cancer cells and macrophages from the host, test drug administration... Show moreIn this thesis, we will utilize embryonic zebrafish tumour models to understand the interaction between engrafted human cancer cells and macrophages from the host, test drug administration modalities and anti-cancer efficacies of newly-developed PDT and PACT compounds, and test a light-triggered liposomal system for targeted drug delivery specifically to cancer cells in vivo. In chapter 2, we investigate the role of macrophages in tumour-induced angiogenesis. We show that macrophage-dependent angiogenesis is driven by macrophage recruitment to lactic acid secreted by glycolytic B16 melanoma cells. Chemical inhibition of macrophages and glycolysis blocks the initiation of angiogenesis in these models, suggesting that macrophages attracted to glycolytic melanoma cells contribute to the tumour-induced angiogenesis process.In chapters 3 and 4, we explore novel PDT and PACT compounds, respectively, for treatment of conjunctival melanoma in zebrafish. We inject conjunctival melanoma cells into the retro-orbital site to establish an orthotopic model and into the Duct of Cuvier to generate an ectopic model. Our results prove that zebrafish provides a fast vertebrate cancer model to test the optimal administration regimen of drugs, conditions of light irradiation, host toxicity and anti-cancer efficacy of PDT and PACT drugs against conjunctival melanoma.In chapter 5, we focus on modifying liposomes to be light triggered in order to deliver drugs specifically to cancer cells. We inject MDA231 breast cancer cells into the Duct of Cuvier at 2 days post fertilization (dpf) to initiate metastasis to the CHT. We successfully demonstrate that light-triggered, cell-specific delivery of liposome-encapsulated doxorubicin reduces the xenograft cancer cell burden without enhanced cytotoxicity of the zebrafish embryos. In chapter 6, we summarize the novel anti-cancer strategies, which we have developed using zebrafish xenograft models. In the same chapter, we frame our findings in the current scientific landscape and discuss future perspectives. Show less
In photoactivated chemotherapy (PACT), a biologically active compound is caged by a light-cleavable protecting group. Light irradiation leads to the release of the active species which can then... Show moreIn photoactivated chemotherapy (PACT), a biologically active compound is caged by a light-cleavable protecting group. Light irradiation leads to the release of the active species which can then interact with the cell environment to induce cell death. In recent years, ruthenium polypyridyl complexes have proved to be promising candidates for PACT. To obtain more insight in the mode of action of these potential anticancer complexes, we explored their intracellular distribution. Post-treatment fluorophore labelling via click chemistry allowed for the visualization of the non-emissive ruthenium polypyridyl complexes in fixed cells. Show less
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
