Carbohydrate-based nanocarriers for targeted drug and siRNA delivery
Tan, Yu Jia
Date of Issue2016-12-23
School of Physical and Mathematical Sciences
The specific delivery of chemotherapeutics to target cancer cells is a clinical challenge that warrants research attention. Herein, the design of the delivery systems is fundamentally based on the interactions between boronic acid and carbohydrates, as well as the specific recognition of lectins for sugars. Owing to the wide range of topics integral to the thesis, an introduction to these important concepts and recent developments are first described. In the next part of the thesis, a multi-component system based on boronic acid conjugated carbohydrate-functionalised gold nanoparticles is presented. Target specific uptake is achieved through recognition of the carbohydrates and the cell surface lectins, and cleavage to release the fluorophore and pro-drug occurs under thiol-reducing conditions commonly found within cancer cells. In vitro assays demonstrated the cell-type specificity of the delivery vehicle, with significant cytotoxicity observed only in the target cells. A notable feature of the delivery system is the potential to target different cells depending on the cell surface lectins expressed and corresponding carbohydrates conjugated onto the nanoparticles. The synthesis of a boronic acid-functionalised chitosan polymer as a siRNA delivery vehicle is explored in the third part of the thesis. The boronic acid is hypothesized to act as a targeting ligand through interactions with cell surface sialic acids, while the polymer protects the siRNA against nuclease degradation. Release of the siRNA is designed to be stimuli-responsive, in which the polymer sheds the ligand under acidic condition to expose the thiol-linked siRNA that can be cleaved from the polymer under GSH-rich conditions. The formation of the stable siRNA-polymer complex has been demonstrated via gel retardation assay and optimised.