IN-VITRO INHIBITION OF MEMBRANE-MEDIATED CALCIFICATION BY NOVEL PHOSPHONATES

The effects of a series of novel phosphonates on the kinetics of miner al development in an ionophore-primed 7:2:1 phosphatidylcholine (PC): dicetylphosphate (DCP): cholesterol (Chol) liposomal model system are reported. When present at 2.5 mu mol/liter or 25 mu mol/liter concentr ations in the solution surrounding the liposomes, the investigated pho sphonates did not significantly delay the initial formation of hydroxy apatite-like calcium phosphate salts (HAP) within the liposomes or the penetration of HAP crystals through the enclosing membranes. However, the phosphonates variably retarded the subsequent growth and prolifer ation of the HAP crystals once they became directly exposed to the pho sphonate-containing solution. The effectiveness of phosphonates in inh ibiting extraliposomal precipitation strongly depended on their struct ure. The inhibitory action on active surface growth sites of released intraliposomal crystals was found to be the most effective if the phos phonate molecule contained two phosphonic groups Linked to the same C atom. At a phosphonate concentration of 25 mu mol/liter, the following general order of effectiveness was established: geminal bisphosphonat e greater than or equal to geminal tetrakisphosphonate > bisacylphosph onates > monoacylphosphonate > bisalkylphosphonate. Within the bisacyl phosphonate family, the highest inhibitory action was observed when fo ur or five -CH2- groups separated the ketophosphonic groups.