Abstract
In recent years, interest in the development of improved therapies to treat cancer in a more targeted and efficient manner has grown exponentially. Doxorubicin (DOX) is one of the drugs currently used in chemotherapy for the treatment of patients with cancer. However, this compound causes severe side effects, ranging from hair loss to heart disease, due to a lack of selectivity towards cancerous cells over healthy cells. The overall aim of this project is to use a new class of probes based on carbon dots (CDs) as a non-toxic drug delivery platform for cancer therapy.CDs are typically small, quasi-spherical nanoparticles, generated from carbon starting materials, e.g., sugars. In this project, glucosamine and 4,7,10-trioxa-1,13-tridecanediamine were used to access amine-coated CDs that can be further functionalised using succinic anhydride to generate acid-coated CDs. The different surface functionalities on the CDs were harnessed to allow further conjugation to a range of biomolecules.
As a model system, I studied the loading of DOX to both amine and acid coated CDs via amide bond formation as well as non-covalent loading of the drug and evaluated how the mode of conjugation influences DOX cell internalisation and subsequent drug release. Confocal imaging revealed cell internalisation of the free DOX within the cell nucleus, whereas DOX-CD conjugates demonstrated DOX accumulation in the cell cytoplasm and slow nucleus delivery.
Moreover, the functionalization of CDs with lactose, which can act as a cell targeting moiety taking advantage of protein/carbohydrate interactions on the cell surface, was also investigated. The carbohydrate coating substantially reduced CDs capacity at retaining the drug via non-covalent interactions. To address this, bifunctional CDs (e.g., CDs decorated with linkers featuring two orthogonally protecting groups) were synthesised to incorporate a targeting agent while leaving free exposed amines can be used to load DOX.
| Date of Award | 27 Sept 2022 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | M C Galan (Supervisor) & Kevin I Booker-Milburn (Supervisor) |