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Title: Encapsulation of cancer stem cell potent metal complexes into polymeric nanoparticle for delivery
Author: Eskandari, Arvin
ISNI:       0000 0004 9351 5811
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Studies on treating the cancer stem cells (CSCs, around 4% of most solid tumours) 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.
Supervisor: Suntharalingam, Rama Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available