Lanthanide containing compounds for therapeutic care in bone resorption disorders

Lanthanide ions, Ln(III), are known functional mimics of Ca(II) ions and have been shown to affect the bone remodeling cycle. Exploiting this disruption to the bone remodeling cycle has potential for the treatment of bone density disorders, such as osteoporosis. In an effort to find new orally active agents for these disorders, a series of Ln(III) containing complexes incorporating small, non-toxic, bidentate pyrone and pyridinone ligands have been synthesized and characterized (LnL(3), Ln = La, Eu, Gd, Tb, Yb, L = 3-oxy-2-methyl-4-pyrone (ma(-)), 3-oxy-2-ethyl-4-pyrone (ema(-)), 3-oxy-1,2-dimethyl-4-pyridinone (dpp(-)) and 3-oxy-2-methyl-4(1H)-pyridinone (mpp(-))). Preliminary biological analysis included cytotoxicity, cell uptake and bidirectional transport studies in Caco-2 cells and in vitro hydroxyapatite (HA) binding studies. The proportion of intact compounds bound to HA was calculated based on determination of Ln(III) concentration by ICP-MS and by UV-vis spectrophotometric assay of the proligand in solution. The LnL(3) species were found to have IC(50) values at least 6 times greater than that of cisplatin, >or= 98% HA-binding capacity, and permeability coefficients in the moderate range. La(dpp)(3) was ascertained to be the lead compound for the treatment of bone density disorders with the highest percentage cell uptake of 9.07 +/- 2.33% and the highest preliminary P(app) value of 3.54 +/- 2.86 x 10(-6) cm s(-1) compared to the other LnL(3) complexes tested.