The bisphosphonates have emerged as powerful new weapons in the therapeutic arsenal employed to treat bone metastases and cancer osteolysis. These metabolically stable pyrophosphate mimetics incorporate in bone and interact with osteoclasts and osteoblasts through various biochemical pathways to prevent bone resorption and inhibit tumor cell adhesion and invasion of the extracellular matrix. Despite their established efficacy in oncology, a major disadvantage of bisphosphonates is that they must be administered by intravenous infusion because of their poor oral bioavailability. In this Phase I SBIR/FLAIR proposal, we aim to enhance the oral availability of existing FDA-approved bisphosphonates by developing a drug delivery strategy that targets a known intestinal carrier system with a bisphosphonate prodrug whose structure is substantially identical to the native substrate of the carrier- that is, a Trojan-Horse prodrug. We propose that one or more of these Trojan-Horse prodrugs will hijack the intestinal carrier and efficiently transport the cloaked bisphosphonate into the cell, whereupon the cloaked bisphosphonate will be released from the prodrug in the general circulation or at the site of action. An orally available bisphosphonate that obviates the necessity for intravenous administration would immediately benefit oncology patients with bone metastases currently treated with bisphosphonates, and may permit the future testing of high-dose/high-frequency oral delivery protocols.
