Abstract
Studies on treating the cancer stem cells (CSCs, around 4% of most solidtumours) have grown rapidly due to their potential role in tumour growth,
maintenance, recurrence and metastasis after initial treatment. CSCs divide more
slowly than other malignant cells. As most treatments target fast growing cells, CSCs
remain untouched, leading to tumour relapse. CSCs are thought to follow a nonstochastic
grow profile suggesting they are functionally and biologically distinct from
bulk cancer cells and need to be treated differently. Specific features of CSCs and
components within their vulnerable microenvironments have been identified and
can be potentially targeted. Although most of the therapeutic molecules reported to
date are purely organic, more recently, the ability of metal complexes to eradicate
the CSCs has gained more attention due to their unique and diverse structural and
functional features.
The research presented in this thesis aims to synthesise, breast CSC active,
endogenous metal (Mn(II) and Cu(II)) polypyridyl complexes and encapsulate the
most potent compounds into core-shell polymeric nanoparticles for tumour delivery.
The optimal nanoparticle formulations were selected to conduct extensive in vitro
studies. Smart nanoparticle structures have also been developed to potentially
deliver the metal complexes actively to breast CSCs, by attaching biomolecules such
as anti CD44-antibody that can recognise markers on the breast CSC surface.
Various biophysical and cell-based studies were carried out to decipher the
interaction of the metal(II) polypyridyl complexes with DNA and explore the potential
cellular mechanism of action for the synthesised compounds and nanoparticle
formulations. Biophysical studies included lipophilicity measurements, UV-Vis
stability assessments, and DNA binding (cleavage/ non-covalent interaction) studies.
In vitro studies employed included cytotoxicity in 2D and 3D format, cellular uptake,
intracellular reactive oxygen species (ROS) and immunoblotting assays. The
nanoparticle formulations were characterised in terms of size and surface charge
distributions as well as morphology. The stability of the nanoparticle formulations in
biologically relevant solutions and their payload-release properties were also
investigated. The cellular mechanism of action of the nanoparticle formulations was
also studied and compared with their respective payloads. In general, the payloads
and nanoparticle formulations induced similar cellular features.
| Date of Award | 1 May 2020 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Rama Suntharalingam (Supervisor) |