The principal goal of this research project is to synthesise new anticancer agents for the experimental therapy known as Boron Neutron Capture Therapy (BNCT).

We aim to couple the potent DNA-binding characteristics of certain compounds with the remarkable neutron capture properties of the non-radioactive 10B nucleus.

This project involves a joint collaboration between The University of Sydney and Massachusetts Institute of Technology.

BNCT is a binary therapy currently undergoing Phase I/II clinical trials in several countries for treatments of the brain tumour glioblastoma multiforme and malignant melanoma.

The therapy utilises 10B-containing drugs and thermal neutrons of low kinetic energy (< 0.025 eV), although epithermal neutrons allow for deeper tissue penetration.

The very large, effective nuclear cross-section of the 10B nucleus (3837 barns, natural abundance = 19.8 %) makes it highly amenable to the neutron capture process. The major (94 %) reaction is shown in the equation below:

¹⁰B   +   ¹n    ®   [¹¹B^*]   ®   ⁴He²⁺   +   ⁷Li⁺   +   g  +   2.4 MeV

The primary nuclear fission products that are produced in the neutron capture reactions have a high rate of linear energy transfer and they cover a short range (ca. 10 mm, or one cell diameter). As a result, the immense amount of energy derived from the nuclear reaction is displaced in a very small volume. Therefore, the selective destruction of tumour cells is feasible with this type of therapy since nearby cells that are free of the 10B-containing drug are spared except for the minor contribution of background processes.

10B compounds that are localised near chromosomal DNA cause maximum cell damage in the presence of thermal neutrons. The proof-of-principle for the synthesis, DNA-binding, and tumour cell uptake of the archetypal Pt-B complexes 1 and 2 has already been established in our laboratory, and these complexes represent two new classes of DNA-binding agents for potential use in BNCT. This work has also led to innovative synthetic design strategies that, for example, overcome the facile decomposition of many complexes in the presence of water as a consequence of redox reactions involving the metal centre and closo-carborane.

We have recently embarked upon another project in collaboration with Dr Kate A. Jolliffe (USyd) on the evaluation of cyclic RGD peptides as potential carriers of boron to tumour sites. These peptides have the capacity to target integrin adhesion proteins such as avb3 which are over-expressed in tumour cells. The integrin proteins play a key role in tumour angiogenesis and metastasis.

Group members currently involved in these projects are: Vincent Ching, Ellen Crossley, Joseph Ioppolo, Pip MacKay and Erin Ziolkowski.