Difficult to Cure: Treating Hypoxic Tumours with Targeted Drug Delivery using New Hypoxia-Responsive Nanocomposites

Hypoxia is one of the hallmarks of cancer. Cancer cells have a unique ability to adapt and survive in a hypoxic environment, which bestows protective mechanisms against conventional chemo- and radiotherapy. Strategies for the efficient therapeutic targeting of hypoxic tumours are therefore of significant clinical interest. Despite significant efforts, hypoxia-based pro-drugs have yet to reach the clinic. More recently, interest in hypoxia- triggered release of encapsulated cytotoxics has grown. Both approaches typically rely on over-expression of redox enzymes in hypoxic tumours to reduce organic groups such as nitro or azo functions. Selectivity can be poor, however, since flavoproteins outside hypoxic regions can also cause reduction. By contrast, N-oxide functional groups are reduced by hemeprotein-mediated, oxygen-inhibited processes, giving greater hypoxia selectivity. This strategy has been used in pro-drugs (e.g. A4QN, an N-oxide pro-drug of anti-tumour agent A4Q) and in hypoxia imaging, but not yet as a strategy for nanocarrier cleavage, and subsequent drug release. In this project, we will develop new, modular nanocarriers based on biodegradable poly(amino acids) which will exploit enamine N- oxides as a novel hypoxia-sensitive cleavage trigger to prompt cytotoxic release. The modular nanocarrier synthesis will also address the issue of tumour targeting by functionalisation with tumour-specific targeting agents (Affimers) developed by the secondary supervisor and industry partner (Avacta Life Sciences Ltd).