Development of new peptide conjugates as biosensors and imaging tools and investigations into their interactions with prostate cancer cells

Abstract

This Thesis describes the design, synthesis and investigation of novel fluorescent imaging probes for prostate cancer cells detection. Such probes are based on the naphthalenediimides (NDIs) core which was used hereby as a synthetic scaffold to link different building blocks such as ligands for metals, peptide and fluorophore. The naphthalenediimide core is well known to form supramolecular architectures such as rotaxane and fluorogenic composite materials and these functionalities were also explored in this work. New fluorescent probes were synthesised, characterised spectroscopically and investigated by fluorescent microscopies to evaluate the uptake, localisation and targeting in living prostate cancer cell lines for their potential use as imaging agents.

Chapter 1 is the Introduction to the state-of-art and summarises the burden of non-communicable diseases and their connection with cancer and prostate cancer. Current diagnostic tests and imaging methods are briefly described for their application in prostate cancer detection. The use of biosensing, both optical and electrochemical, as an alternative method for cancer detection is pointed out as a sensitive, reliable and low-cost tool. The chemical and supramolecular characteristics of naphthalenediimides are discussed as the use of a scaffold for biological and imaging applications. The chemistry of thiosemicarbazones and their metal complexes is described with their use in cancer imaging and therapy, both under normoxic conditions and under reduced oxygen concentration (or hypoxia). Finally, the importance of receptor-targeting peptides of relevance to the therapy of prostate cancers is highlighted.

Chapter 2 presents the design, synthesis and characterisation of NDI-based thiosemicarbazone ligands and their metal complexes are presented. Such fluorescent metal complexes are investigated by confocal microscopy in living cell lines in both normoxic and hypoxic conditions.

In Chapter 3, novel psuedorotaxanes consisting of 1,5-dinaphtho[38]crown-10, as a “wheel”, and different naphthalenediimide-based “axles” with fluorescent properties are presented as a proof-of-concept bioimaging tools for prostate cancer detection.

Chapter 4 explores the design, synthesis and characterisation of naphthalenediimide derivatives which incorporate one or two units of a targeting peptide (fragment [7-13] of bombesin peptide) for gastrin-releasing peptide receptors (GRPRs). The effect of both stereochemistry and number of peptide moieties are investigated by fluorescent microscopy to evaluate their different uptake and interaction with prostate cancer cells.

Chapter 5 provides a summary of the work described throughout during this Thesis and some proposals for future work arising from the research findings described herein.

Chapter 6 is the Experimental Section and contains detailed synthetic procedure and characterisation data for the compounds investigated hereby.

Date of Award	2 Dec 2020
Original language	English
Awarding Institution	University of Bath
Supervisor	Sofia Pascu (Supervisor) & Pedro Estrela (Supervisor)