Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo...

We synthesized a series of polyoxometalate-bisphosphonate complexes containing Mo^VIO₆ octahedra, zoledronate, or an N-alkyl (n-C₆ or n-C₈) zoledronate analogue, and in two cases, Mn as a heterometal. Mo₆L₂ (L = Zol, ZolC₆, ZolC₈) and Mo₄L₂Mn (L = Zol, ZolC₈) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and ³¹P NMR. We found promising activity against human nonsmall cell lung cancer (NCI-H460) cells with IC₅₀ values for growth inhibition of ∼5 μM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC₅₀ decreased with increasing bisphosphonate chain length: C₀ ≈ 6.1×, C₆ ≈ 3.4×, and C₈ ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo₄Zol₂Mn(III), against SK-ES-1 sarcoma cells in a mouse xenograft system finding a ∼5× decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 μg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers.