The development of anticancer agents with increased selectivity toward tumour cells is a key area of cancer research. Approaches which use a non-selective, biologically-active compound tethered to a molecule capable of selectively binding to tumour-associated markers have been shown to be sucessful in improving tumour:organ ratios within a few hours of intravenous drug administration [1]. This study has focussed on combining peptidic ligands which target receptors that are over-expressed on tumour cells with boron-containing entities to afford novel conjugates for potential use in Boron Neutron Capture Therapy (BNCT).
BNCT is currently undergoing Phase I/II clinical trials for the treatment of cancer, such as glioblastoma multiforme and malignant melanoma. In this therapy, 10B-containing agents that are located within tumour cells undergo rapid fission in the presence of thermal neutrons to produce high linear energy transfer 7Li3+ and alpha particles [2]. To maximise cell destruction, the 10B-containing agent should have a high boron content and the compound should exhibit some selectivity towards the tumour [2]. The latter requirement may be addressed by using tumour-targeting cyclic RGD peptides. Cyclic RGD peptides are known to bind to receptors that are over-expressed on tumour cells [3], and hence have the potential to be used to deliver a boron-containing unit selectively to tumour cells. We have synthesised a series of compounds consisting of the tumour-targeting cyclic RGD peptide, a boron-containing group and a linker (Figure 1). Each of these three components can be varied to investigate the relationship between structure and receptor binding, as well as to modify aqueous solubility and boron content.
Figure 1. General structure of boronated RGD peptides.
1. Carnemolla, B.; Borsi, L.; Balza, E.; Castellani, P.; Meazza, R.; Berndt, A.; Ferrini, S.; Kosmehl, H.; Neri, D.; Zardi, L., Blood 2002, 99, 1659-1665.
2. Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F-G.; Barth, R. F.; Codogni, I. M.; Wilson, J. G. Chem. Rev. 1998, 98, 1515-1562.
3. Haubner, R.; Gratias, R.; Diefenbach, B.; Goodman, S. L.; Jonczyk, A.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 7461-7472.
|
