Design, Synthesis,\nand Characterization of HBP-Vectorized\nMethotrexate Prodrug Molecule 1102–39: Evaluation of In Vitro\nCytotoxicity Activity in Cell Culture Models, Preliminary In Vivo\nSafety and Efficacy Results in Rodents

A novel bone-targeted\nprodrug, 1102–39, is discussed with\nthe aim of enhancing the therapeutic effects of methotrexate (MTX)\nwithin bone tissues while minimizing systemic toxicity. Within the\n1102–39 molecule, the central linker part forms a cleavable\nester group, with MTX being also linked by a stable imine bond to\nthe specially designed hydroxybisphosphonic (HBP) vector. Synthesized\nthrough a convergent approach starting from MTX, this prodrug advantageously\nmodulates MTX’s activity by selective esterification of its\nα-carboxyl group. In vitro tests revealed a 10-fold reduction\nin cytotoxicity compared to standard MTX, in alignment with prodrug\nbehavior and correlated with gradual MTX release. In vivo in rodents,\n1102–39 displayed preliminary encouraging antitumor effects\non orthotopic osteosarcoma. Furthermore, various aspects of designing\nmolecules for selective therapy in bone tissue based on bisphosphonate\nmolecules as vectors for delivering active compounds to the bone are\ndiscussed. The 1102–39 molecule exhibits strong affinity for\nhydroxyapatite and a progressive release of MTX in aqueous environments,\nenhancing the safety and efficacy of bone-specific treatments and\nenabling sustained activity within bone and bone joints in the therapy\nof tumor and inflammation.