Bioreductive Activated Prodrugs to Target Tumour Hypoxia

Abstract

Hypoxia is a common feature of solid tumours and is characterised by a very low oxygen content, typically less than 1%. This poor oxygen level contributes to a harsher tumour environment and is associated with poor patient prognosis. Additionally, hypoxia is also known to induce tumour progression and resistance to conventional therapies. Therefore, hypoxia represents an extremely valuable target to be exploited for certain anti-cancer therapy strategies. One way of exploiting tumour hypoxia in anti-cancer treatments is to target the hypoxia responsive pathway (HIF-1α) which plays a key role in the hypoxic tumour microenvironment. Another way of exploiting tumour hypoxia is by using hypoxia-activated prodrugs (HAPs). The HAP purpose is to deliver an active drug selectively in the hypoxic environment. In this thesis we describe the design, synthesis and biological evaluation of different novel HAPs. We propose the development of carbonic anhydrase IX inhibitor HAPs, immunotherapeutic HAPs and of a new immunotherapeutic HAP for antibody-HAP conjugation in order to improve tumour targeting.