A method for inserting redox active lanthanide complexes into cells for hypoxia analysis

Hypoxia is a term used to describe any situation where oxygen is limited, for example explorers experience hypoxia at the top of Everest. Within human cancers, regions of hypoxia also occur i.e. parts of the cancer/tumour have low levels of oxygen. The presence of hypoxia in cancers is important because, the more hypoxic a cancer is the harder it is to treat/cure. Patients with hypoxic cancers do worse than those without them irrespective of how the doctor choses to treat the patient (radio/chemotherapy, surgery etc.). Unfortunately, we do not have methods that can be used in routine clinical practise to work out which patients have hypoxic tumours and which do not. The goal of my project, is to adapt structures of macrocyclic lanthanide complexes to contain structural components that can allow them to enter a cell with a very high uptake, maximising the amount of a dose making it into a cell and remaining inside a cell, addressing the low cellular uptake issue. While the complex is localised in a cell the luminescent lanthanide agent must become activated in a hypoxic environment. Then the amount of luminescence can be used for quantifying tumour hypoxia. One of the major challenges of this project is that the probes need to enter the hypoxic cells to inform on the levels of hypoxia. Most MRI probes do not enter cells, remaining in blood, extracellular fluids. Therefore distinguishing tumour hypoxia and its quantification is challenging. Lanthanide luminescence methods employ lanthanide complexes that contain lipophilic groups or sugar
like branches that can be readily accepted into a cell. In this project we intend to explore methods of improving cellular uptake of mono and di lanthanide complexes for imaging hypoxia so ideally most (all) of the administered dose is accepted into a cell. It has been explored that amino acid chains are capable of drug delivery and in this context of our research we intend to explore attaching a pH activated amino acid chains to a lanthanide ion complex and investigate their efficacy for cellular uptake. We intend to employ novel complexes containing linkages, based naturally occurring amino acids, that can be cleaved on cellular
entry allowing the lanthanide ion imaging probe to be delivered and remain in a cellular environment as part of the 1st year plan.. To the best of our knowledge, these amino acid based linkages are novel and have not been reported before. If successful this project can provide a novel class of lanthanide based hypoxia imaging agents, which can potentially improve cancer patient prognosis in cancer diagnosis and treatment.
This project falls within the EPSRC Medical Imaging Research area, for research into medical imaging and diagnostics.