Unlike other tissues, there is abundant hydroxyapatite (HA) in bone tissues. Due to this feature, it is attractive to use HA as a target for bone selective drug delivery. Since bisphosphonates have high affinity for HA, HA affinity will be conferred on compounds, which originally do not have HA affinity, by conjugation to bisphosphonates. This approach has been proposed for bone selective drug delivery such as prostaglandin E 2 , estradiol, gemcitabine, osteoprotegerin.1-4) Our interest was to develop bone selective antitumor agents. Bone is tissue to which tumors easily metastasize, and metastatic bone tumor causes pain, pathologic fractures, compression of nerve syndrome, and hypercalcemia, all of which are factors of patient morbidity and mortality. In order to develop an effective drug for metastatic bone tumor, some conjugates of bisphosphonate and platinum(II) complexes, such as cisplatin, [5][6][7][8] which has a wide spectrum of cancer treatment, have been synthesized. 9) In most cases, bisphosphonic acids that all phosphonate groups are not substituted were used as a ligand.10) In contrast, we designed and synthesized platinum(II) complexes with dialkylated bisphosphonic acid as a ligand (Fig. 1), and evaluated its possibility as a drug for metastatic bone tumor.In vivo, dialkyl bisphosphonate platinum complexes are expected to effect bone tumor when the platinum gradually dissociates after adsorption to HA, the main component in bone. By using the dialkylated bisphosphonic acid, we expected changes of some properties of the bisphosphonate platinum complexes as compared with those of non-alkylated bisphosphonate platinum complexes as follows; non-alkylated bisphosphonate platinum complexes have high hygroscopicity. Hygroscopicity will be decreased and stability will be improved in the solid state in dialkylated bisphosphonate platinum complexes due to the hydrophobic properties of dialkylated bisphosphonic acid. Non-alkylated bisphosphonate platinum complexes show an acidic pH in an aqueous solution and pH adjustment is necessary for animal dosing, which might cause dissociation of the platinum complex. On the other hand, an aqueous solution of the dialkylated bisphosphonate platinum complexes may be near a neutral pH so pH adjustment could be omitted. ResultsWe synthesized various dialkyl bisphosphonate platinum(II) complexes.11) Among them, we intensively evaluated HA affinity, effect on the tumor cells and osteoclast of cis-diammine (P,PЈ-diethyl methylenebisphosphonato) platinum(II) (DEBP-Pt) that was synthesized efficiently and showed better properties and stability.Synthesis P,PЈ-Diethyl methylenebisphosphonic acid (DEBP) used as a ligand was synthesized through the following process. Tetraethyl methylenediphosphonate was refluxed in morpholine, and dialkylated bisphoaphonic acid morpholinium salt was obtained. Treatment of the salt with cation exchange resin in methanol gave DEBP.12) The obtained DEBP and cisplatin were reacted with silver oxide in N,N-dimethylformamide (DMF), the precipitated si...