Designing a high-performance smart drug delivery system for the synergetic co-absorption of DOX and EGCG on ZIF-8

Due to the extreme pore volume and valuable surface area, zeolitic imidazole frameworks (ZIFs) are promising vehicles that enhance the delivery of therapeutic agents to tissues. Furthermore, these nanoporous materials have high stability in the pH and temperature of the surrounding healthy cells (37 °C and pH = 7) and an exotic potential to deform in carcinogenic environment (T > 37 °C and pH ∼ 5.5), which make them perfect smart drug delivery vehicle candidates. In this work, a series of molecular dynamics (MD) and metadynamics simulations have been performed to gain molecular insight into the mechanisms involved in the process of co-loading of doxorubicin (DOX) and EpiGalloCatechin-3 Gallate (EGCG) on ZIF-8, which form a smart drug delivery system (SDDS). The obtained results revealed that DOX was adsorbed on the carrier mostly through electrostatic interactions (Ecoul = ∼−1200 kJ mol−1, Etot = −1700 kJ mol−1), and EGCG was stacked on ZIF-8 mainly via van der Waals interactions (EL-J = ∼−600 kJ mol−1, Etot = ∼−1200 kJ mol−1). It is worth mentioning that the drug–drug L-J interactions (EL-J = ∼500 kJ mol−1) were also important in the co-loading process. The insertion of DOX and EGCG as additive agents to the initial ZIF-8/EGCG and ZIF-8/DOX systems led to the enhancement of the drug–carrier pair interactions to about ∼−2300 kJ mol−1 and ∼−2000 kJ mol−1, respectively. This finding implied that the drug–drug interactions had a complementary role in the development of SDDS via ZIF-8. From the metadynamics simulation, it was found that the geometry of the drugs is a determining factor in an efficient co-loading SDDS.