Antibody functionalized nanoliposomes to slow the progression of ovarian cancer
Date
2021
Authors
Hoosen, Yasar
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Abstract
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
Description
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