medicinal inorganic chemistry
The projects listed here are all associated with biologically active metal complexes. The emphasis is on anti-cancer drugs and our aim is to develop drugs that have a high selectivity for tumours based on their chemistry and biochemistry and an ability to penetrate into solid tumours. High selectivity will overcome many of the toxic side effects of existing drugs and allow higher doses to be used. Better penetration will enable the destruction of cells that presently escape and contribute to resistance.
SRIXE tomographic slice of a spheroid showing the platinum distribution. Alderden
et al., J. Amer. Chem. Soc., 2007, 129, 13400-1. Photo courtesy of Professor Trevor
Hambley, School of Chemistry, The University of Sydney.
Anti-cancer drug penetration into solid tumours
For anticancer drugs to destroy a tumour they must reach all of the cells that make up the tumour. However, drug penetration into solid tumours is frequently inadequate because they have a deficient and faulty network of veins and arteries and this is believed to be a major cause of the failure of chemotherapy. In this project and those described below we are investigating how the properties of anticancer compounds can be modified to improve delivery of the compound to all cells in sufficient amounts to kill the entire tumour. Metal complexes offer unique opportunities to modify the properties of anticancer agents and to achieve selective activation in a tumour environment.
Hypoxia selective agents
Almost all drugs used in the treatment of cancer cause serious side effects because they lack selectivity for tumours. However, our understanding of the differences between tumour chemistry and biochemistry and that of normal tissues means that it is possible to envisage drugs that act selectively on tumours. Thus, the goal of our work is to develop new agents that selectively target solid tumours by taking advantage of these differences between the tumour and healthy tissues. The aims of this project are to develop new metal-based hypoxia-selective agents with the desired level of targeting. In order to do this, we are using complexes with fluorescent tags to monitor uptake, distribution and reactivity in tumours.
Platinum(IV) based anti-cancer drugs
Pt(IV) complexes are probably reduced in the body to Pt(II) and then act in the same way as cisplatin but the more slowly reduced Pt(IV) complexes are expected to be less toxic. The aim of the present project is to investigate various aspects of the chemistry of Pt(IV) anti-cancer compounds and their behaviour in solid tumours and models for such tumours. The work could involve preparative, electrochemical, kinetic, crystallographic, computer aided modelling, XANES, SRIXE and DNA or protein binding studies.
Glucose as a tumour delivery agent (with Dr Michela Simone)
The unusually large amounts of glucose taken up by cancer cells is the basis of the highly successful PET imaging agent, fluorodeoxyglucose (FDG). Based on this success, there have been attempts to use glucose and other sugars to selectively deliver metal complexes to tumours, but to date these have met with limited success. For example, a technetium labelled glucose would be have great potential as a SPECT imaging agent and glucose could be used to increase the targeting of other metal based anticancer agents, including platinum complexes. Projects in this area would involve both organic and inorganic synthesis and a range of biological and imaging studies to investigate cancer cell selectivity.
Pt (L3)XANES peak heights from different regions in spheroids treated with a platinum(IV) compound can be used to deduce sites of platinum reduction and ligand exchange.
For further information, please contact:
School of Chemistry
University of Sydney NSW 2006
Phone: +61 2 9351 2830