Abstract
Platinum(II)-based chemotherapeutics, notably cisplatin and oxaliplatin derivatives, remain central to clinical oncology yet are hampered by poor aqueous solubility, systemic toxicity, and off-target degradation by biological nucleophiles. In this study, host-guest supramolecular encapsulation strategies using native and modified cyclodextrins (β-cyclodextrin and hydroxypropyl-β-cyclodextrin, HP-β-CD) were investigated to enhance the physicochemical stability and pharmacokinetic profile of a synthetic hydrophobic platinum(II) diamine complex, [Pt(dach)(malonato)] (dach = (1R,2R)-1,2-diaminocyclohexane). Utilizing an integrated spectroscopic framework combining UV-Vis spectrophotometry, fluorescence quenching titrations, 1H NMR, and 2D ROESY spectroscopy alongside density functional theory (DFT) and molecular dynamics (MD) simulations, we established the precise thermodynamics and spatial topology of the inclusion complexes. The association constants (Ka) revealed a robust, entropy-driven 1:1 host-guest stoichiometry with HP-β-CD exhibiting superior affinity (Ka = (4.82 ± 0.21) × 103 M−1) relative to native β-CD. 2D ROESY cross-peaks between the dach protons and the interior H3/H5 cavity protons of cyclodextrin confirm deep axial inclusion of the hydrophobic core. Computational analyses corroborated non-covalent stabilization governed primarily by London dispersion forces and classical hydrogen bonding, with binding free energies of −8.42 kcal/mol for HP-β-CD. Furthermore, in vitro stability assays demonstrated that cyclodextrin encapsulation substantially retarded drug deactivation by L-glutathione. These findings offer molecular-level insights for engineering cyclodextrin-based supramolecular carriers to optimize the delivery of platinum-based metallodrugs.
