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

缺氧是癌症的特征之一。癌细胞具有在缺氧环境中适应和存活的独特能力，这赋予了对抗常规化疗和放疗的保护机制。因此，低氧肿瘤的有效治疗靶向策略具有重要的临床意义。尽管做出了巨大的努力，但基于缺氧的前药尚未进入临床。最近，对缺氧触发的包封的细胞毒素的释放的兴趣已经增长。这两种方法通常都依赖于缺氧肿瘤中氧化还原酶的过度表达，以减少有机基团，如硝基或偶氮官能团。然而，选择性可能很差，因为缺氧区域外的黄素蛋白也会导致减少。相比之下，N-氧化物官能团被血红素蛋白介导的氧抑制过程还原，从而产生更大的缺氧选择性。该策略已用于前药（例如A4 QN，抗肿瘤剂A4 Q的N-氧化物前药）和缺氧成像，但尚未作为纳米载体切割和随后药物释放的策略。在该项目中，我们将开发基于可生物降解聚（氨基酸）的新型模块化纳米载体，其将利用烯胺N-氧化物作为新型缺氧敏感性切割触发剂来促进细胞毒性释放。模块化纳米载体合成还将通过二级主管和行业合作伙伴（Avacta Life Sciences Ltd）开发的肿瘤特异性靶向剂（Affimers）的功能化来解决肿瘤靶向问题。

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).