Enhanced Affinity Bifunctional Bisphosphonates for Targeted Delivery of Therapeutic Agents to Bone

Skeletal diseases have a major impact on the worldwide population and economy. Although several therapeutic agents and treatments are available for addressing bone diseases, they are not being fully utilized because of their uptake in nontargeted sites and related side effects. Active targeting with controlled delivery is an ideal approach for treatment of such diseases. Because bisphosphonates are known to have high affinity to bone and are being widely used in treatment of osteoporosis, they are well-suited for drug targeting to bone. In this study, a targeted delivery of therapeutic agent to resorption sites and wound healing sites of bone was explored. Toward this goal, bifunctional hydrazine-bisphosphonates (HBPs), with spacers of various lengths, were synthesized and studied for their enhanced affinity to bone. Crystal growth inhibition studies showed that these HBPs have high affinity to hydroxyapatite, and HBPs with shorter spacers bind more strongly than alendronate to hydroxyapatite. The HBPs did not affect proliferation of MC3T3-E1 preosteoblasts, did not induce apoptosis, and were not cytotoxic at the concentration range tested (10–6–10–4 M). Furthermore, drugs can be linked to the HBPs through a hydrazone linkage that is cleavable at the low pH of bone resorption and wound healing sites, leading to release of the drug. This was demonstrated using hydroxyapatite as a model material of bone and 4-nitrobenzaldehyde as a model drug. This study suggests that these HBPs could be used for targeted delivery of therapeutic agents to bone.