Alginate-coated ZIF-8 and PCN-222 metal-organic frameworks for controlled delivery of a benzanthrone derivative: Structure-function relationships, release kinetics, and antibacterial mechanisms.
TL;DR
It is demonstrated that alginate-coated ZIF-8 is a promising in vitro antibacterial nanoplatform for controlled drug delivery and inhibition of biofilm-associated bacterial growth.
Abstract
The development of multifunctional antibacterial nanoplatforms capable of overcoming poor drug stability, uncontrolled release, and biofilm-associated bacterial resistance remains a major challenge in antimicrobial activity. Herein, ZIF-8 and PCN-222 metal-organic frameworks (MOFs), with and without alginate coating, were investigated as carriers for the controlled delivery of a benzanthrone derivative (6A). Physicochemical characterization confirmed successful drug incorporation, preservation of framework crystallinity, enhanced colloidal stability, and effective alginate surface modification. PCN-222 exhibited the highest encapsulation efficiency owing to its large mesoporous channels. In contrast, because the molecular dimensions of 6A exceed the pore aperture of ZIF-8, drug loading in ZIF-8 occurred predominantly through surface adsorption rather than pore encapsulation, whereas alginate-coated ZIF-8 provided superior structural stability and diffusion-regulated release behavior. In vitro release studies demonstrated pronounced pH-responsive release under acidic conditions, while kinetic modeling indicated predominantly diffusion-controlled transport following Higuchi and Korsmeyer-Peppas mechanisms. Among all investigated formulations, 6A@ZIF-8@Alginate exhibited the strongest antibacterial activity against both Gram-positive and Gram-negative bacterial strains, with a minimum inhibitory concentration of 16 ± 0.8 μg mL-1 against Staphylococcus aureus. The formulation additionally displayed rapid bactericidal kinetics, strong antibiofilm activity, enhanced intracellular reactive oxygen species (ROS) generation, and severe bacterial membrane damage, as confirmed by CLSM, live/dead fluorescence staining, SEM, and TEM analyses. Mechanistic investigations, including bacterial surface zeta potential measurements, ICP-OES quantification of Zn2+ release, and ROS scavenger experiments, revealed that the superior antibacterial performance originated from the synergistic effects of nanoparticle-bacteria interactions, controlled release of 6A and Zn2+ ions, oxidative stress induction, and membrane destabilization. Although PCN-222 exhibited superior drug loading capacity, alginate-coated ZIF-8 provided the most favorable balance between pH-responsive release, antibacterial efficacy, and biocompatibility. Furthermore, 6A@ZIF-8@Alginate demonstrated low hemolytic activity, favorable cytocompatibility, and enhanced colloidal stability compared with pristine ZIF-8. The antibacterial, antibiofilm, hemocompatibility, and cytocompatibility properties of the developed formulations were evaluated through in vitro assays. Overall, the results demonstrate that alginate-coated ZIF-8 is a promising in vitro antibacterial nanoplatform for controlled drug delivery and inhibition of biofilm-associated bacterial growth.