Reductive activation of azido compounds for imaging and therapy

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This project will involve the activation of organic azide compounds (containing the N3 group, which can be reduced to the amine NH2 group) within cells to produce compounds which are useful for cancer imaging, diagnosis or treatment. Azides have been chosen due to their high stability and resistance to reaction under cell conditions by hydrolysis or oxidation.Two methods of targeted activation for the production of cancer-relevant molecules will be explored: 1) the use of high energy X-rays which can penetrate into tissues (radiotherapy) and 2) the use of hypoxic conditions found within cancerous tumours. Hypoxia (a marker of many cancers) is defined as low oxygen concentration (typically <2%), compared to normoxia (21% oxygen, atmospheric oxygen pressure, used for preclinical testing) or physoxia (tissue normoxia, which varies depending on the tissue). Activation under hypoxic conditions is an effective way to target cancerous tissues over normal tissues, as low oxygen concentrations are common in tumours, particularly solid tumours. X-rays are commonly used in cancer treatment currently (for radiotherapy) due to their ability to penetrate into the body and are also a targeted method. These two activation methods will be explored independently and in combination to determine their mechanisms of action, whether different products are produced following activation, and how much activation is caused by each pathway.The conditions described above will be used to activate prodrugs, defined as molecules which can be converted to active drugs within the body. These prodrugs will either be organic or metal-containing, such platinum or lanthanide complexes. The organic prodrugs will have structures which include the azide group connected to drugs which are currently approved for cancer treatment, or connected to systems which fluoresce (for use in cancer imaging). Platinum complexes are extensively used in chemotherapy (due to their ability to react with DNA to cause cell death) - in this project, platinum-based azide prodrugs will be activated to give complexes previously reported to have anticancer properties. Lanthanide complexes (containing elements from lanthanum to lutetium) are known to be luminescent and can be used in cancer imaging for diagnostic purposes.Overall, this project aims to synthesis novel organic, platinum- or lanthanide-containing complexes containing azide groups which can be activated by X-rays or under hypoxic conditions to release active drugs or provide diagnostic information on cancer. This project falls within the EPSRC research areas of chemical biology, clinical technology and medical imaging.