Antibody functionalized nanoliposomes to slow the progression of ovarian cancer

Hoosen, Yasar
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Ovarian Cancer (OC) is ranked amongst the top virulent gynecological malignancies, implicated with high rates of disease relapse and failed drug therapies. The integration of innate biological macromolecules in cancerous environments facilitates complex inter-and intra-cellular cascades, which induce a formidable attack against healthy tissue leading to tumour cell dissemination. For decades, cancer cells, receptors and proteins were defined as key therapeutic drug targets for conventional molecules. However, a recent revolution in research has diversified the scope of niche molecular targets, such as the ones contained in the extra-tumoral spaces i.e., the extracellular matrix (ECM). The ECM contains over expressed glycosaminoglycans (GAGs) such as the anionic chondroitin sulphate-E (CS-E) carbohydrate polymer. CS-E aggressively stimulates OC cell migration, proliferation, adhesion, and catalyzes the up-regulation of a plethora of growth factors. Inherent with this research was a world’s first hypothesis which anchored the foundations of this project. Herein, an innovative mechanistic forecast to treat OC independently of drug therapy is described. Using two chemical techniques: 1) chemical crosslinking and 2) polyelectrolyte complexations, we aimed to irreversibly modify the structural architecture of CS-E polymer backbone to impede its functional role in OC metastasis. To validate the integrity of the hypothesis, didodecyldimethyl ammonium bromide (DDAB) and 1,12 diaminododecane were assessed as suitable CS-E modifying agents, with extensive characterization performed on the CS-DDAB and CS-1,12 diaminododecane archetypes in Chapters 4 and 5. Upon validation, advanced drug delivery platforms engineered in tandem with nanotechnological techniques that feature active targeting mechanisms drastically enhanced the site specific cytotoxicity of these molecules, detailed in Chapters 6 and 7. The ability of these nano-archetypes to alter the genetic integrity expressions of OC cells was a hallmark discovery that conclusively supported the CS-E mediated arresting induced by these systems, in addition to displaying toxic potentials on 3D tumourosphere models. Lastly, a clinically mimetic, stage-4 cancer model in athymic nude mice was established, where the Anti-MUC 16 functionalized cationic nanoliposomal implant restricted the growth, prolonged the survival times, and increased tumour inhibition rates with minimal off-target effects. To this end, the validation of this hypothesis and the therapeutic benefits was concluded
A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, 2021