Award details

Mitochondrial- and lysosomal-targeted iron chelators for the monitoring and adjustment of cellular labile iron pools

Reference	BB/J008060/1
Principal Investigator / Supervisor	Professor Robert Hider
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Pharmaceutical Sciences
Funding type	Research
Value (£)	211,660
Status	Completed
Type	Research Grant
Start date	01/04/2012
End date	31/03/2015
Duration	36 months

Abstract

Recent cellular studies have indicated that mitochondrial and lysosomal redox active and chelatable labile iron (LI) plays a key role in conferring cellular sensitivity to oxidative damage and the resulting pathologies and cell death. The design of organelle-targeted iron sensors for sensitive evaluations of LI distribution in lysosomal and mitochondrial subcellular compartments appears therefore to be an essential prerequisite for development of highly targeted iron chelators as preventive agents for iron-related oxidative injuries. Recently we have developed a promising HPO-based fluorescent iron III sensor (HPO-20) that exclusively monitors LIP in the lysosomal compartment. However based on current literature, there is no such exclusive equivalent compound for monitoring LI in mitochondrial compartment. This proposal responds primarily to the urgent need to develop highly specific mitochondria-targeted fluorescent iron chelators to be used both as biological probes to evaluate intra-mitochondrial LI and as mitochondria-specific iron chelators to selectively remove potentially harmful LI from mitochondria. To achieve high specificity, we plan to modify a series of fluorescent iron chelators by linking them to specific mitochondrial-homing peptides that can effect targeted delivery directed to mitochondria. The specificity, mode of action and protective properties of these mitochondrial iron sensors/chelators will be evaluated in a series of specific cell lines exposed or not to oxidising agents. The subcellular LI distribution in mitochondria, lysosomes and cytosol and subcellular LI trafficking under normal and oxidative stress conditions will also be evaluated in these cell lines. With no adequate organelle-specific iron sensors/chelators available, our compounds are expected to be of significant value to both biological and pre-clinical research as powerful biological probes and as highly specific preventive agents against iron-related oxidative injuries.

Summary

Iron in the body is necessary for a series of vital functions. The chemical nature of iron makes it highly reactive, and this reactivity can be both useful and potentially harmful. Iron plays its most obvious positive role in the oxygen-carrying protein, haemoglobin, in the blood. However, iron can do damage through stimulating the formation of reactive oxygen species (ROS). These in turn generate 'oxidative stress' and modify cellular components such as proteins, fats and DNA, bringing about abnormal cell function, including possible death. Cells have evolved protective anti-oxidant mechanisms to counter these effects; however excess iron can overcome these mechanisms. In order to induce this damaging effect, iron has to be present in cells in a 'free' form, i.e. not tightly bound by other molecules. Levels of 'free' iron are generally kept very low by the presence of proteins, particularly ferritin, that bind the iron and prevent it from stimulating ROS formation. However recent studies have shown that despite these iron trapping proteins, there is a significant amount of free iron in distinct cell compartments (e.g. mitochondrial and lysosomal organelles) of healthy cells that render them susceptible to oxidative damage and cell death especially in presence of ROS or upon exposure to environmental oxidising agents such as sunlight that generate ROS. Because of the harmful role of free iron, iron trapping drugs (i.e. 'iron chelators') have been proposed as a means to remove excess iron from these subcellular compartments that is detrimental in oxidative stress conditions. Unfortunately the effectiveness of current iron chelators to counteract these effects is much reduced because they have either low permeability and therefore are unable to access their intracellular targets or are highly permeable and therefore upon administration non-specifically diffuse in all cell compartments and cause systemic iron starvation and toxicity. Much effort has gone into the development of novel subcellular organelle-specific iron-chelator drug design strategies to alleviate these problems, but with little success. There is therefore a clear need to develop smart iron chelators that could be specifically delivered to subcellular compartments, where they could register and remove potentially harmful excess iron. We have recently developed a promising iron chelator called HPO-20 that exclusively monitors the free iron content in lysosomal organelles. The high selectivity of HPO-20 for lysosomes represents a considerable step forward toward sensitive evaluation of free iron distribution in subcellular compartments under normal and oxidative stress conditions. However based on current literature, there is no such exclusive equivalent compound for monitoring free iron in mitochondrial compartment. In the present project, we propose to design a series of novel protective mitochondria-specific iron chelators that upon administration directly reach the targeted subcellular compartment. These novel compounds are unique in that they provide the possibility to register and remove potentially harmful residual iron in the organelle. So they have the potential to be used either as biological diagnostics tools or as protective agents. For example our compounds have potential to prevent iron-related oxidative injuries caused by harmful environmental agents notably skin damage caused by sunlight. So in the long term they have potential to be used as photoprotective ingredients in sunscreen formulations and to decrease dramatically the sun-related skin cancer. The possibility of monitoring lysosomal and mitochondrial free iron content with our compounds will also help the identification of pathologies related to subcellular iron-misdistribution. Therefore our compounds will have a major long term impact on public health through availability of combined diagnostic and preventive regimes.

Impact Summary

The present project will deliver a series of novel compounds capable of registering and removing excess free iron from subcellular organelles, which is detrimental in oxidative injuries and pathologies. Therefore the outputs of this project will have potential for a wide range of applications. In the short term these compounds may be used as research tools to advance knowledge in a wide range of iron-related biological and pre-clinical disciplines. This would provide strategies towards diagnosis, prognosis and treatment of disorders of excess iron and misdistribution. So in the long term these compounds will have potential for clinical use as diagnostics/ prognostics markers or medicaments for therapy. Potential stakeholders - Academia/Research organisations and clinical services; Public sector organisations notably Department of Health and NHS; Pharmaceutical/Biotech companies; General Public. These stakeholders may benefit in the following ways: Health Benefits - Currently there is no satisfactory drugs for prevention of iron-catalysed oxidative injuries and pathologies notably cancer, psoriasis, rheumatoid arthritis, Parkinson's disease and Friedreich's ataxia. Most of the currently applied therapeutic modalities for these diseases are associated with severe side effects and discomfort for the patients. Our proposed compounds are unique in that they provide a means of non-damaging targeted delivery of the drug to diseased cells. Furthermore they are designed to act both as biological probes to register the iron of the diseased cells and as medicaments to remove the potentially harmful excess iron. Our compounds are therefore likely to have a major long term impact on public heath through availability of combined diagnostic/prognostic and therapeutic regimes involving high selectivity, reduced side effects and corresponding improved patient compliance and quality of life for a wide range of disorders. Furthermore our compounds have potential to prevent iron-related oxidative injuries notably skin damage caused by sunlight. So in the long term they have potential to be used as photoprotective ingredients in sunscreen formulations. Given the high incidence of sun-related skin cancer in UK and the fact that its mortality rate is increasing globally, our compounds as sun-protective agents could also have a high long term impact on general public health and well-being. The more accurate diagnostics/prognostics tests with highly specific and targeted treatment for such a wide range of iron-related disorders will allow more rapid patient profiling and quicker administration of specific treatments that will benefit the general public for improved treatments and better patient outcomes. This is likely to benefit Department of Health (DOH), NHS and clinicians for improved healthcare delivery. The early diagnosis and treatment of diseases may even in the long run influence the public sector organisations (DOH, NHS) through reduction of healthcare delivery. Commercial and Economic benefits - The compounds developed in the proposed project will be of significant benefit to pharmaceutical sector, providing new potential candidate drugs for pre-clinical development and new ingredients for skin photoprotection. Diagnostics companies will benefit from being able to develop and commercialise iron-related disease test kits as biological research probes and clinical diagnostics/prognostics tools. This will maximise scientific advancement and wealth creation in a UK (i.e. value added to UK economy) and international (inward investment) context. Furthermore the availability of such diagnostic/prognostic kits could help clinicians with early diagnosis of the disease and as such to decrease considerably the costs related to advanced disease treatment modalities. This will in turn have an economical impact on DOH, NHS and private medical providers through cost reductions in delivery of healthcare services.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Ageing, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/J005223/1 Mitochondrial- and lysosomal-targeted iron chelators for the monitoring and adjustment of cellular labile iron pools

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