Host–Guest Interaction in Zr Metal–Organic Frameworks with a Hydrophilic Site for Drug Delivery

Metal–organic frameworks (MOFs) are promising drug carriers due to their high porosity and diverse functionalities. The interactions between MOFs and drug molecules play a crucial role in drug delivery, influencing both the loading capacity and release kinetics. In this work, we report the design and synthesis of a zirconium-based MOF (Zr-IDA), obtained by replacing the hydrophobic 2,6-naphthalenedicarboxylate (NDC) ligand in DUT-52 with a hydrophilic indole-2,5-dicarboxylate (IDA) linker. Zr-IDA exhibits a structure similar to that of DUT-52 but achieves a significantly higher loading of 5-fluorouracil (5-Fu), reaching 0.676 g/g, an increase of 100.5% compared to DUT-52 (0.337 g/g) under identical conditions. Moreover, Zr-IDA provides a much slower release profile: complete release of 5-Fu requires 6 days, whereas DUT-52 releases the same payload in only 1.5 days. To elucidate the enhanced host–guest interactions in 5-Fu@Zr-IDA, multinuclear solid-state NMR (SSNMR) experiments were conducted to probe the local structure. One-dimensional 19F, 13C, and 1H MAS SSNMR spectra confirm successful incorporation of 5-Fu within the pores of Zr-IDA. Two-dimensional 1H–1H SQ-SQ and 1H–19F HETCOR SSNMR reveal that 5-Fu molecules reside near the IDA linkers and Zr metal centers, stabilized by cooperative hydrogen bonding between the fluorine atom of 5-Fu molecules and Zr-coordinated hydroxyl groups, as well as IDA NH sites. Density functional theory calculations further support the experimental findings, identifying two major preferred 5-Fu adsorption sites within the octahedral and tetrahedral pores.