Synthesis of polymeric phosphonates for selective delivery of radionuclides to osteosarcoma

Discussed in detail is the synthesis and primary structure characterization of two polymers aimed at advancing the treatment of pediatric osteosarcoma. These polymers are designed to systemically deliver radiometals specifically to osteosarcomas using the passive targeting mechanism of enhanced permeability and retention (the EPR effect). The approach begins with the synthesis of a polymer capable of binding radiometals, for which prior data show improved site-specific targeting of solid tumors. Building on this success, a second polymer has been designed for improving the efficacy of currently available radionuclide therapies by incorporating the FDA-approved small-molecule ligand Quadramet directly onto the polymer structure. Time-activity curves of the phosphonate-functionalized polymers show rapid clearance from the central compartment and nontargeted organs, with up to 65% of injected activity being excreted within 3 hours. Both polymer ligands demonstrate good osteosarcoma targeting capability with little to no uptake in organs associated with the dose-limiting bone marrow. Additionally, biodistribution studies in nonosseous tumor models demonstrate the tumor targeting mechanism of the polymer ligands, which appears to be influenced by the high affinity of the phosphonate functionality for the positively charged hydroxyapatite mineral found in bone tumors.