OSTEOTROPIC DRUG-DELIVERY SYSTEM (ODDS) BASED ON BISPHOSPHONIC PRODRUG .1. SYNTHESIS AND IN-VIVO CHARACTERIZATION OF OSTEOTROPIC CARBOXYFLUORESCEIN

An osteotropic drug delivery system (ODDS) based on a bisphosphonic pr odrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisph osphonic promoiety to the mineral component, hydroxyapatite, a bisphos phonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carb oxyfluorescein (CF) as a model compound and the disposition after intr avenous injection was studied in rats. The bisphosphonic prodrug of CE disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphona te (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. Th e microscopic observation showed that CF-BP was buried into the bone w ith a calcification of the bone. According to the remodeling of the bo ne, bisphosphonic prodrug buried was supposed to be released in the vi cinity of the osteoclast or resorption surface of the bone. Thus, it i s suggested that ODDS has a potential to achieve osteoclast-specific o r resorption surface-specific targeting of the drugs.