DFT study on interaction of anticancer drugs with Pd₂L₄ metallo-organic cage carrier

Cancer is a life-threatening disease that originates from uncontrolled abnormal cell growth, spreading through metastasis. Conventional chemotherapy employs drugs that lack selectivity, thus causing severe toxicity to healthy tissues. To overcome these limitations, advanced drug delivery systems are crucial for enhancing therapeutic efficacy while minimizing side effects. In this study, a supramolecular metallo-organic Pd₂L₄ cage is explored as a potential carrier to effectively bind with chemotherapeutic drugs, nitrosourea and fluorouracil. The results revealed that nitrosourea is adsorbed onto the metallo-organic cage, whereas fluorouracil is encapsulated within the central cavity. Interaction energy analysis indicates a stronger interaction of fluorouracil with Pd₂L₄ (i.e., -36.34 kcal/mol) compared to nitrosourea (i.e., -28.43 kcal/mol). Thermodynamic assessments confirm favorable drug-cage interactions. Electronic structure analysis demonstrates a significant increase in the energy gap upon complexation, from 3.88 eV in the bare cage to 6.67 eV and 6.81 eV for nitrosourea@Pd₂L₄ and fluorouracil@Pd₂L₄, respectively. In contrast, UV-Vis spectroscopy shows a substantial red shift of the dominant absorption bands from 326 nm for the bare cage to 363 nm and 418 nm upon drug binding, arising from newly formed host-guest charge-transfer-assisted excited states. Frontier molecular orbital (FMO) analysis suggests palladium-induced d-d transition. Non-covalent interaction (NCI) and quantum theory of atoms in molecules (QTAIM) analyses confirm stabilization via van der Waals forces, with stronger interactions observed in fluorouracil@Pd₂L₄. These findings provide computational evidence for the encapsulation capability of the Pd₂L₄ cage toward anticancer drugs, particularly fluorouracil, and offer a theoretical foundation for the rational design of metallo-organic cage-based interaction platforms, subject to future experimental validation.