The network covers the broad discipline of metals in medicine including the synthesis and characterisation of new drugs involving metal complexes, the development of new and selective metal chelators for the treatment of diseases that involve metal-imbalances or heavy metal poisoning, and the indentification of metalloproteins as drug targets. It brings together researchers in chemistry, radiochemistry, biochemistry, cell biology, pharmacology, toxicology, and clinical studies, with pharmaceutical companies and investors. While the areas of investigation are broad, the methodologies and techniques used for the characterisation of the roles of the metal ions link them and often drugs have activities in more than one area of interest. Specific areas of interest to the Network are given below.
1. Metal-Based Drugs
The mostly widely used drugs in chemotherapy (Pt drugs) are metal-based drugs and there are a large number of other metals that exhibit powerful anti-cancer effects. There are over 20 projects currently underway in the Network that have yielded promising results and many are the subject of patents. Diverse approaches to chemotherapy involving such complexes include: selective cytotoxins for chemotherapy; hypoxia-selective chemotherapy; photodynamic therapy; chelate therapy; sensitisers for radiotherapy; and boron neutron activation therapy. Promising research involves a range of complexes with different metal ions including those of cobalt, copper, gold, iron, molybdenum, niobium, platinum, ruthenium, tin and titanium.
2. Anti-inflammatory Drugs
The drug market for inflammatory diseases is well over $10B worldwide and the cost of treatment and lost productivity due to these diseases is a many times greater. All anti-inflammatory drugs (including the new COX-II inhibitors) can have serious side effects and the costs of treating these side-effects are even greater than the costs of the drugs themselves and lead to over 10,000 deaths pa worldwide. Extensive research is being conducted within the Network into Cu and Zn anti-inflammatory drugs that have less side-effects with similar or higher efficacy than the parent organic drugs commonly in use. Some such drugs are in the advanced stages of development and are expected to go to clinical trials soon, while others need further development through the collaborative environment that the Network will develop.
The safety, efficacy and mode of action of Cr and V anti-diabetic drugs are being investigated. The Network has members that are leading the way in the understanding of the metabolism of Cr dietary supplements, which constitute a billion dollar per annum industry, but pose a potential cancer risk to the many people that take such supplements. There is also active research in vanadium anti-diabetics, particularly in understanding their metabolism. These drugs hold considerable promise for both treating diabetes and its side-effects. Research is also being performed on the effects of insulin on Cu metabolism, which may be linked to the fact that insulin does not treat the degenerative side-effects of diabetes.
Many metal complexes have powerful anti-microbial activities and are already in common day-to-day use in medicine in areas such as silver bandages for treatment of burns, Zn antiseptic creams, bismuth drugs for the treatment of ulcers, and metal clusters as anti-HIV drugs. The potential for further development of metal-based drugs and treatments as anti-microbial agents is enormous and also of great importance with the evolution of drug-resistant bacteria and threats from a range of viral diseases. This Network contains specialists in the development of such drugs, with anti-bacterial, anti-fungal and anti-viral activities, as well as specialists in the molecular biology of microbes, including targeting metal metabolic pathways and metalloenzymes in microbes for the development of new agents.
Drugs that target metal imbalance or metalloproteins
5. Metal Deficiency Diseases
Metal deficiency diseases have long been known, and diets deficient in Ca, Cu, Zn and Fe are known to cause serious health problems. More recently, selenium deficiency has become of increasing concern. Australian soils are ancient and deficiencies of essential nutrients in crops grown in such soils is of fundamental importance. The research that will be carried out into metal metabolism will provide new insights into the essential roles of metals in human health and the effective delivery of trace metals to treat deficiency diseases.
6. Metals in Degenerative Diseases
While many metals, such as Cu, Zn and Fe are essential for human health and protect us against many diseases, they are also implicated as being involved in many degenerative diseases, including atherosclerosis (heart disease and strokes), degenerative brain disorders, arthritis, cancers, etc. Normally, the distributions and concentrations of such metals are tightly controlled by human metabolic processes and the causes of these metal-imbalances, which may be an important factor in all degenerative diseases, are uncertain. While chelation therapy (see below) has shown promise in the treatment of many of these diseases, it is not desirable for long-term use as it also affects other essential biological functions. A much more thorough understanding of the metabolism of metals in biology is likely to lead to treatments that can be used to prevent metal-imbalances occurring and, hence, has enormous potential to lead to healthier aging of our population and greatly reduced health costs in the long term. The Network brings together experts in chelation therapy, metal metabolism and its roles in degenerative diseases, and clinicians in the area in order to develop effective chelation therapies in the medium term and better understanding and treatments of degenerative diseases in the long term.
7. Metal Toxicity and New Chelation Therapy
We have considerable expertise within the network of researchers who develop selective metal chelators and experts in the treatment of cancers, degenerative brain diseases, overload diseases (Fe, Cu), heavy metal poisoning and potentially atherosclerosis, using chelation therapy. The Network also brings together leading international researchers in chromium-, nickel, and arsenic-induced cancers and toxicity, all of which have important occupational health and environmental health implications.
Biomineralisation processes are essential for human health in the formation of bones and teeth and in the storage of iron in ferritin. Malfunctions of these processes are responsible for serious birth deformaties and other diseases. Hence, the genetic control of such processes needs to be better understood. In addition biomineralisation processes have essential roles in the lifecycle of serious diseases such as malaria, where the parasite causes the biomineralisation of heme groups that would otherwise be toxic to the invading parasite. There is growing evidence that most anti-malarials target this biomineralisation, hence a better understanding of the process will lead to better treatments for malaria.
9. Metal Metabolism
Metals are essential to all forms of life, but metal metabolism is different in different organisms and in diseased and non-diseased tissues in the same organs. Therefore, an understanding of the metabolic pathways of metals in pathogens and humans (and particularly their differences), is fundamental research that has enormous potential for improved health through the development of drugs that selectively target metal metabolic pathways in pathogens or diseased tissues. While there has been many recent developments in this area, our state of knowledge of metal metabolism still lags considerably behind that of organic metabolic pathways and, hence, has enormous potential for drug development as new discoveries are made. The Network brings together people with expertise in metal metabolism in human, pathogen and disease processes with the ability to tackle these fundamental questions using an interdisciplinary approach.
10. Metalloproteins as Targets
From the development of the genomics and proteomics for human and pathogenic organisms will arise a range of new metalloproteins that are potential targets for the treatment of disease. The proposed network has many researchers who use specialist techniques in the characterisation of metals in such proteins. This expertise is well placed (in combination with our expertise in drug design) to produce new drugs that target metalloproteins.
11. New drug delivery systems
Metal-based drugs often have specific requirements for effective delivery systems, due to their higher chemical reactivities than most organic drugs. The fact that many drugs can undergo substitution and/or redox processes in formulations (or before they reach their targets) means that special care needs to be taken in developing appropriate formulations, and characterisation of the stabilities of metal drugs in these formulations and drug delivery systems. The proposed Network has specialists in formulations chemistry for metal-based drugs and the characterisation of such drugs in formulations. It also has members who are experts at developing new drug delivery systems.
Researchers in Australian universities, industries, ANSTO and the Western Australia PET Cyclotron Service have a strong tradition in excellence in research in radiopharmaceuticals that has been a major contributor to the health of Australians as well as being a significant export and import replacement industry. Current research within the network ranges from improving technetium generators (technetium radiopharmaceuticals are the most widely used in medicine), to developing new drugs for diagnostic purposes and treatment of cancer and other diseases. There is also extensive research in improving the generation of new potentially useful radioisotopes for medical applications. With the Replacement Nuclear Reactor coming on stream in the near future, Australia’s international standing in radiopharmaceuticals is likely to be enhanced further. Radioisotopes are also of importance in biodistribution and clearance studies on radiolabelled analogs of non-radioactive drugs and the network brings together considerable expertise in this area.
13. MRI Agents
The use of metal complexes for targeting specific organs, diseases, and biological functions in MRI is a rapidly developing area and one in which members of the Network have considerable expertise and international collaborations. This expertise ranges from the development of new agents to research centres that specialise in MRI applications in the clinic, which have been at the forefront of international developments.
14. Fluorescence Imaging Agents
Zinc proteins are important targets for treatment of a variety of diseases and the network is involved in the development of a variety of drugs containing Zn. For these reasons it is important to be able image Zn in cells and tissues and Australia has played a prominent role in developing such agents.
15. Magnetic Imaging
Australia leads the world in the non-invasive determination of iron concentrations in internal organs using magnetic imaging. This technology has applications in the diagnosis of a range of diseases including common genetic iron overload diseases, such as Thalassaemia and Haemochromatosis. In particular, Inner Vision Biometrics Pty Ltd is seeking to continue development of and commercialise the award winning Ferriscan technology developed by researchers within the Network.
Characterisation of Metals in Proteins and Biological Tissues
16. Cutting-Edge Techniques
Fundamental to the breakthroughs in metals in medicine is the ability to the characterise metals in complexes, metalloproteins and tissues. The Network has internationally recognised expertise in the use of protein crystallography, NMR Spectroscopy, EPR spectroscopy, MCD spectroscopy, XAFS, SRIXE, protein electrochemistry, magnetism and many other techniques in characterising the roles of metals in medicine. It will continue to move the boundaries forward in these fundamental areas in order to underpin the medical outcomes of the Network. This will be enhanced considerably by the construction of the Australian Synchrotron, as most of the beamlines will be used by members of the Network.
Toxicology, Pre-Clinical and Clinical Research
17. Metal Toxicology and Carcinogenicity
The Network has centres that deal specifically with toxicology in terms of metal-based drugs and heavy metal poisoning. These Centres perform cutting-edge research on understanding the mechanisms of toxicity and genotoxicity, as well as potential treatments. They can perform an extensive array of biological testing.
18. Clinical and Pre-Clinical Research
The Network brings together fundamental researchers with clinicians who have extensive experience in the clinical use of metal-based drugs, radiopharmaceuticals and imaging agents, researchers involved in pre-clinical testing and members of the pharmaceutical industry. This will enable major questions to be addressed that are impediments for moving new drugs into the clinic, the development of new areas of research, and the generation of generic guidelines for minimising the cost and time of getting drugs into clinical trials in the Australian and International contexts.