Influence of cisplatin hydration state on drug delivery efficiency and anticancer activity of heparin-based nanogels

Cisplatin (Cis) is a widely used chemotherapeutic agent whose intracellular activation involves aquation of its chloride ligands. Although heparin-based nanocarriers have been investigated for platinum delivery, the influence of cisplatin hydration state on nanocarrier performance remains incompletely understood. Here, pristine Cis and aquated cisplatin species (CisOH) were directly compared within the same heparin-Pluronic F68 (Hep-F68) nanogel platform. The resulting formulations were characterized for physicochemical properties, platinum loading, release behavior, cytotoxicity, intracellular platinum accumulation, and hemolytic activity. The nanogels exhibited hydrodynamic diameters of approximately 173-196 nm with PDI values below 0.30. Compared with pristine Cis, CisOH markedly increased loading capacity from 2.85% to 25.07% and entrapment efficiency from 2.93% to 33.46%, consistent with more extensive interactions between aquated platinum species and anionic groups of heparin. Both formulations exhibited sustained, pH-dependent platinum release, with faster release under acidic conditions. Release-kinetic analysis indicated predominantly diffusion-controlled release for Hep-F68/CisOH, whereas Hep-F68/Cis showed a greater contribution from polymer relaxation. CisOH generally produced greater cytotoxic effects than Cis across five cancer cell lines, and the CisOH-containing treatments showed higher intracellular Pt accumulation. Blank Hep-F68 nanogels maintained >90% MCF-7 cell viability, while both drug-loaded formulations exhibited low hemolytic activity under the tested conditions. Collectively, these findings identify cisplatin hydration state as an important contributing formulation factor influencing platinum loading, release behavior, intracellular exposure, and biological activity in Hep-F68 nanogels.