Selective Delivery of Estradiol to Bone by Aspartic Acid Oligopeptide and Its Effects on Ovariectomized Mice

We have developed a novel osteotropic prodrug of estradiol (E2) conjugated with l-Asp-hexapeptide (E2·3D6), which has very low affinity for estrogen receptors, and in this study, we examined its pharmacokinetic behavior and pharmacological potential. After a single iv injection of E2·3D6 to mice, the half-time for elimination from plasma was about 100 min; however, E2 was selectively delivered to the bone and eliminated very slowly, declining to the endogenous level at about 7 days. After a single iv injection of E2, the half-time in plasma was about 70 min, whereas E2 was highly distributed to the uterus, and the bone concentration of E2 was only slightly increased at 6 h. When E2 (0.37 μmol/kg, sc, every third day) or E2·3D6 (0.11 to 1.1 μmol/kg, sc, every seventh day) was administered to OVX mice for 4 weeks, E2 increased the bone mineral density (BMD) together with weights of liver and uterus, whereas E2·3D6 increased only the BMD, in a dose-dependent manner. E2·3D6 enhanced the expression of messenger RNAs of bone matrix proteins (osteopontin, bone sialoprotein, type I collagen α) of OVX mice at 4 h after administration, but E2 did very slightly. These results indicate that the E2 prodrug was delivered to the bone, where it gradually released E2, thereby ameliorating bone loss. This acidic oligopeptide appears to be a good candidate for selective drug delivery to bone.