TTFA-Platin Conjugate: Deciphering the Therapeutic Roles of Combo-Prodrug through Evaluating Stability–Activity Relationship

This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. <i>In vitro</i> studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. <i>In vivo</i> studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.