Evidence for drug release from a metalla-cage delivery vector following cellular internalisation.

One of the main challenges in cancer chemotherapy is to develop drugs that selectively target cancer cells in order to reduce general toxicity and consequently side effects. One such targeting method involves using large carrier compounds that release a drug once inside a cancer cell, since large compounds selectively accumulate in cancer tissue due to the “enhanced permeability and retention effect”. Recently, we have shown that the encapsulation of a hydrophobic metallo-drug guest in a water-soluble hexacationic arene ruthenium cage delivery vector produces a synergistic effect, due to the modest cytotoxicity of the cage itself, and the cytotoxicity of the encapsulated guest compound. We have now encapsulated in the cavity of [Ru6(p-iPrC6H4Me)6 ACHTUNGTRENNUNG(tpt)2ACHTUNGTRENNUNG(C6H2O4)3] 6+ (1) (tpt=2,4,6-tris(pyridin-4-yl)-1,3,5-triazine), an intrinsically fluorescent pyrenyl compound (pyrene-R= 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene), thus giving rise to the hexanuclear metalla-prism [pyrene-R 1] , in which the pyrenyl derivative occupies the cavity of 1. The fluorescence of pyrene-R is quenched inside the metalla-prism cavity. A study of this new system has provided direct evidence that once inside the cell, the hexaruthenium cage releases the fluorescent guest, thus confirming our initial hypothesis that cage 1 can act as a Trojan horse for cancer cells. In addition, experiments into the uptake mechanism indicate that an assisted diffusion pathway is in operation. The encapsulation of guest molecules in coordinationally driven self-assembled cage compounds has been extensively studied. The encapsulation process depends on the complementary of the guest s size, shape, and chemical surface with respect to that of the host cavity. Potential applications of these systems have been found in chemistry (recognition and selective transformations), biology (translocation of drugs across membranes, sensors, biomimetics), and material science (construction of macroscopic architectures for storage and devices at the molecular level). Additionally, ruthenium complexes have considerable potential in a number of biomedical applications such as diagnostics and therapeutics and a wide range of ruthenium compounds have been evaluated as putative anticancer agents. Two ruthenium compounds have even completed phase I clinical trials. The biological properties of ruthenium complexes have been extensively studied, with a focus on how such compounds interact with DNA, and they are known to enter the cells through various pathways. Consequently, a cage built with cell permeate ruthenium complexes could be a vehicle of choice for hydrophobic molecules.