Regions of tumours that are difficult to target with drugs are being studied to help scientists to develop more effective drugs
Researchers in Australia have devised a new way to test how well drugs penetrate the low-oxygen core of solid tumours. ’Hypoxic’ regions of tumours are notoriously difficult to target with drugs and the new work could help in the development of new compounds that can effectively reach these areas and efficiently kill the cells.
Tumours often grow faster than the blood vessels that supply them, and parts of the tumour therefore become starved of oxygen and grow slowly. This makes it difficult for drugs carried in the blood to reach these areas; furthermore many drugs rely on the rapid proliferation of cancer cells, so slowly growing ones are less susceptible.
One approach has been to develop ’prodrugs’, which become toxic to the cell only upon entering the low-oxygen environment. Some of these are based upon cobalt(III) attached to a toxic ligand. In a hypoxic environment the cobalt is reduced to cobalt(II) and the ligand is released. However, there are currently no reliable ways either to visualise the hypoxic region of a tumour or to measure penetration of the drugs.
Now, Byung Kim, Trevor Hambley and Nicole Bryce at the University of Sydney have developed a three-dimensional model of a solid tumour with a hypoxic core that allows both the hypoxic region to be highlighted and the extent of penetration of prodrugs to be measured.
The researchers cultured spherical tumours with no blood supply. Oxygen can diffuse only a short way into the spheroid, leaving the centre hypoxic. ’We introduced DNA for a fluorescent protein, Eos, which would only be expressed in hypoxic conditions,’ says Bryce. ’Using confocal microscopy we were able to see a central region of green cells surrounded by non-fluorescent cells.’
Now able to identify hypoxic cells, the team devised a way to measure the penetration of two cobalt compounds that mimic cobalt prodrugs. Each compound contained fluorescent ligands that are released upon reduction of the cobalt in low-oxygen conditions.
The team believes that the easily grown three-dimensional model of hypoxia is valid for testing a range of drugs and could form the basis of a screening system that needs no special equipment for generating hypoxia. And because the model measures both drug penetration as well as selectivity for hypoxia it can provide richer information than current assays.
Commenting on the work, Holly Barker, a member of the hypoxia and metastasis team at the Institute of Cancer Research in London, says: ’This model will provide researchers with a valuable tool to enable the development of therapeutic agents that specifically target hypoxic cancer cells. It will be exciting to see whether the new compounds discovered using this novel model will be efficacious in a clinical setting.’
Link to journal article
Visualising the hypoxia selectivity of cobalt(III) prodrugsByung J. Kim, Trevor W. Hambley and Nicole S. Bryce,?Chem. Sci., 2011, 2, 2135DOI:10.1039/c1sc00337b