Synthesis, nanoparticle encapsulation, and magnetic resonance studies of metal-based anticancer complexes

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Thesis type
(Thesis) Ph.D.
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Since the discovery of cisplatin, metal complexes continue to gain interest as anticancer agents. Though a breadth of research has been conducted in this field, many pitfalls and questions remain, such as off-target activity and how exactly metal complexes exhibit their activity. In the search for novel complexes that address these issues, ruthenium and copper have become leading choices. Though a vast array of complexes employing these metals have been reported, their clinical development has often been hindered by low activity and a lack in understanding of their mechanism of action. The work in this thesis looks to address these issues in two ways: (i) by developing novel complexes and methods to breath new life into well-studied metal compounds and (ii) employ magnetic resonance spectroscopies to examine their behaviour in relevant biological environments. Chapter 2 discusses the synthesis of a novel Ru(II)-arene complex appended with a selective estrogen receptor modifier to target breast cancer. These novel complexes were subjected to several different cell assays, including the National Cancer Institute NCI-60 screen, which showed increased activity over the inactive parent ruthenium scaffolds. Chapter 3 presents 19F magnetic resonance imaging methods to develop the theranostic applications of a CF3-appended Keppler-type Ru(III) complex. It is shown that these methods can be used to spatially resolve redox and speciation events in tumour tissues, which is important to understanding their mechanism of action. Chapter 4 presents a robust method to encapsulate these CF3 appended Ru(III) anticancer complexes in polymer nanoparticles to increase their aqueous stability. Cell studies revealed an over 10-fold increase in anticancer activity over the free complexes. Chapter 5 presents and in-depth magnetic resonance study of the aqueous solution behaviour of the copper anticancer complex CasIII-ia. EPR and NMR studies were used to characterize Cu species following dissolution in complex solutions containing HSA, and in the presence of whole cells. Finally, Chapter 6 presents a novel Ru(II)-Ru(III) complex combing the unique biological activities of an organometallic Ru(II) RAPTA-type scaffold and a Ru(III) Keppler-type coordination complex. Cytotoxicity studies of the new dinuclear complex show increased activity relative to mononuclear parent compounds.
193 pages.
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Thesis advisor: Walsby, Charles
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