Synthesis and evaluation of novel fluorescent probes as novel therapeutic platforms

Abstract

In recent years, carbon dots (CDs) have received widespread attention as
non-toxic, fluorescent carbon-based materials with applications in the field of
therapeutics, since these nanomaterials are highly biocompatible, and easy to
prepare and functionalised. In this study, glucosamine was used as the starting
material to synthesize, in a one-step hydrothermal method, amine-coated CDs, which
were subsequently functionalized with succinic anhydride to obtain acid-coated CDs. These CDs can be functionalized in many ways via amide coupling, making the
nanomaterial a multifunctional platform for therapeutic purposes. In this thesis, two
applications of functionalised CDs were pursued, the first part of the work was
devoted to exploring the use of CDs for drug delivery applications, while the latter
related to developing a platform for gene delivery. Galactose/galactosamine as terminal sugars found on the surface of
mammalian cells are known glycans that interact with carbohydrate binding proteins
present in for example cancer cells. Thus, multivalent glycan-probes can be used to
target cancer cells for drug delivery application, however their affinity and selectivity to
specific cancer cells still needs to be further improved. In order to improve their
carbohydrate/protein binding affinity, D-galactal was used to synthesize
2-deoxygalactoside (which lacks a substituent at C2) featuring an amino-containing
linker, which was subsequently conjugated to acid-coated CDs, to evaluate the effect
of the substituent at C2 on the glycoside on the intracellular uptake in cancer HeLa
cells. Furthermore, CDs functionalized by this sugar and loaded with Dox were also
prepared to explore the drug delivery potential of this system. Cationic polymers are commonly used as gene trapping agents, which can
efficiently catch DNA/RNA, but their high cytotoxicity still limits their development and
application. CDs have excellent biocompatibility and biodegradability, and can greatly
reduce the toxicity of polymers to cells. Therefore, I synthesized CDs which were
surface passivated with cationic polymer. The materials were used for the
electrostatic loading of DNA that could be used as a platform for gene delivery. The
impact of the nature of the polymer shells of different lengths or structures on gene
delivery efficiency was explored

Date of Award	19 Mar 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	M C Galan (Supervisor)