- This project can be modified to suit Honours, PhD or Clinical students.
Background: Significant pathology accompanies body iron accumulation in both primary and secondary iron loading disorders, so iron removal is a key therapeutic strategy. This is often achieved using drugs called iron chelators. Of the three chelators in clinical use, Desferrioxamine (DFO) is the most effective iron binding compound, but an onerous administration regimen limits its clinical use. Nanotechnology approaches offer an attractive alternative method for delivery DFO efficiently.
Aims: To examine the efficacy of nanoparticulate formulations of DFO (DFO-NP) in iron removal and to develop targeted nanoparticles for delivering DFO to specific organs.
Approaches: A variety of DFO-NP formulations will be developed by using a range PLGA polymers and novel DFO derivatives with improved pharmacokinetic properties. Their efficiency in removing iron will first be tested in cell lines, and the most efficient formulations will subsequently be trialled in established murine models of iron loading (parenterally loaded wild-type mice, beta-thalassaemia intermedia mice and haemochromatosis mice). To develop targeted therapies for iron removal, the most effective DFO-NPs will be decorated with ligands that specifically target cardiomyocytes and hepatocytes, cells particularly prone to iron loading. The efficacy of these agents will be tested in animal models. To provide a platform for the efficient oral delivery of DFO, NP-based chelator formulations will be prepared using ligands that target molecules on the surface of intestinal enterocytes. The efficiency of delivery will be examined in mouse models. In all of these studies, a range of experiments will be carried out to assess the safety and tolerability of the NP formulations.
These studies will lay the foundation for a new generation of iron removing therapeutics that can be applied to iron loading disorders, as well as to a range of other conditions where excess iron has been implicated in pathogenesis.
Techniques to be used include nanoparticle preparation and characterisation, cell culture, mouse studies, and a range of biochemical and molecular analysis techniques.