Mitochondria targeting metallopharmaceuticals for eradicating cancer stem cells

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Cancer relapse is thought to be linked to the existence of a subpopulation of cancer cells in solid tumours and different leukaemia called cancer stem cells (CSCs). It is now widely accepted that in order to provide a long term, therapeutic effect, cancer treatments must be able to remove the whole of the cancer population, including CSCs. Therefore, there is huge interest in developing CSC potent therapies. One CSC-specific target is mitochondria, recent studies have revealed that key mitochondrial features are different in CSCs compared to non-CSCs. The research presented in this thesis aims to prove that metal complexes could be used as mitochondriatropics to initiate cell death in CSCs. The work described here includes the design, synthesis, and characterisation of a variety of novel cyclometalated iridium(III) complexes, capable of targeting and damaging CSC mitochondria. The complexes were investigated for their photophysical properties, cytotoxicity and CSC-selectivity. The mechanism of action for the most potent complexes was also elucidated. 1,10-Phenanthroline-copper(II) dichloro complexes have been extensively investigated for their CSC potency. Here we present the synthesis and characterisation of novel phenanthroline-based mitochondria targeting ligands which were chelated to copper(II) halides. The CSC-selectivity and mitochondria targeting ability of the complexes were also investigated. Several biological studies were carried out to identify the mechanism of action of all the complexes prepared. The stability of the complexes in physiologically relevant solutions was examined in addition to a variety of biophysical and cellular experiments. The latter showed some level of mitochondrial dysfunction was achieved by most of the complexes. Finally, immunoblotting methods were used to identify proteins involved in the mechanism of action of the metal complexes, which helped determine the cell death pathway activated.
Date of Award1 May 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRama Suntharalingam (Supervisor)

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