Optimization of Hydrophobic Group Structures Covalently Incorporated into Gelatin Hydrogels for Efficient Adsorption...

Hydrophobically modified gelatin (HMG) hydrogels are promising proof-of-concept drug delivery carriers. However, the structural effects of incorporated hydrophobic groups remain systematically unexamined. Here, twelve linear fatty and aromatic hydrophobic groups with varying carbon numbers were incorporated into gelatin to identify optimal structures for hydrophobic drug loading. Adsorption behaviors of three drug models were quantitatively evaluated per mole of incorporated carbon atoms. Linear fatty aldehydes with 11 and 12 carbon atoms (F-CHO-C11 and C12) achieved maximum adsorption efficiency, with equilibrium adsorption capacities of 0.35×10-3 and 0.34×10-3 mol-rhodamine B/mol-carbon atoms, respectively. Thermodynamic calculations (COSMO-SAC) and quantum chemical simulations (Gaussian MP2) supported the idea that longer alkyl chains enhance affinity, yielding higher interaction energy (-11.8kcal/mol for C12 vs. -5.73kcal/mol for C4). Furthermore, F-CHO-C12 HMG hydrogel achieved a substantial dexamethasone loading capacity of approximately 2.8×10-6 mol/g-dry polymer (unmodified gelatin showed negligible loading <0.08×10-6 mol/g-dry polymer) and sustained release at 37 °C (∼95% cumulative release without initial burst). These findings establish quantitative design guidelines for hydrophobically modified polymer hydrogels.