Towards Fluorescent Tools for Clinical Applications

Abstract

As our understanding of molecular biology broadens, we gain a deeper understanding of the molecular signatures and microenvironments associated with disease. In conjunction, better understanding of activatable fluorophores and the chemical transformations that occur within biological systems has enabled the development of numerous molecular probes and sensors. It is now possible to selectively sense chemical species associated with disease and use biochemical transformations to create activatable therapeutics.

Through rational design, it is possible to build tailored molecular tools with finely tuned properties. However, rational design is built upon understanding the relationship between chemical structure, physical properties and biological behaviour, and currently our understanding of these interactions is incomplete. Thus, the goal of this thesis is to explore these relationships a basis for the rational design of molecular tools.

Chapter 2 explores the development of activatable fluorescent hypoxia sensors for imaging hypoxia in 2D cell models and 3D tumour models.

Chapter 3 explores the design of novel hypoxia targeted theranostics that are capable of simultaneous imaging and treatment of hypoxic tumour models.

Chapter 4 focuses on building fast, facile and sensitive assays for detecting proteolytic activity in arthritic joints. Assay results correlated well with clinical disease markers, suggesting that our assay can also be used to indicate disease state.

Overall, there is great potential for rationally designed fluorescent sensors to be applied in the clinic, and this thesis explores novel ways to apply fluorescence to build sensors for biomolecules, chemical analytes and drug activation.