Different kinds of cancers present particular types of challenges to researchers seeking improved treatments. Not all are amenable to surgery and cancerous cells at the heart of solid tumours are very hard to reach with standard anti-cancer drug delivery methods. Tumours contain relatively few, and rather disorganised, blood vessels making drug delivery inefficient. To kill the cells drugs have to diffuse long distances away from the blood vessels into a more acidic, low-oxygen environment. The chemistry of most drugs is not compatible with this sort of environment. Work done by Dr Natsuho Yamamoto, Dr Nicole Bryce and Prof. Trevor Hambley at the University of Sydney tackles this problem by turning these properties to advantage. They designed prodrugs (inactive forms of drugs made active by particular bodily processes) that can diffuse readily throughout the tumour and be taken up preferentially by cells in the acidic, low oxygen conditions in the heart of these tumours. This work was published recently in the Journal of Medicinal Chemistry.
The approach was to design a weakly acidic prodrug that would be complexed with cobalt(III) as a chaperone to form stable and inert complexes that can travel safely through the bloodstream. Once the complex reaches the reducing, low pH environment in the tumour, the cobalt(III) releases the active form of the drug. Fine-tuning the prodrug’s behaviour was achieved by associating it with a variety of negatively charged ancillary molecules.
As a model to test this system the team used a fluorescently labelled drug in the complex with cobalt. Conveniently, in this state, the fluorescence is quenched making it easy to tell if it has been released from the complex. Through the use of live-cell imaging in the AMMRF at the University of Sydney Drs Yamamoto and Bryce showed that uptake of the drug into cultured colorectal cancer cells was dependent on the precise pH of the cellular environment. Also, three-dimensional clusters of tumour cells around 700μm in diameter, called spheroids, mimic solid tumours. They enabled the researchers to demonstrate that the most negatively charged cobalt-chaperoned complexes moved most efficiently to the hypoxic centres of the spheroids. The negatively charged complexes cannot be taken up by the outer layers of cells. However, once they reach the acidic centre, the charge on the complex changes, the labelled drug is released and can now be taken up by the hypoxic cells.
This work demonstrates that it is possible to effectively deliver cytotoxic drugs to attack currently difficult-to-treat and highly malignant tumours through manipulation of the chemistry of cobalt-chaperoned complexes.
February 11, 2013