Zirconium Metal-Organic Framework-Based Composite Drug Delivery System for Precise Drug Release and Synergistic Modulation of the Tumor Microenvironment in Liver Cancer Therapy.

Abstract

Zirconium-based metal-organic framework (MOF-808) materials were selected as drug delivery carriers, with 5-fluorouracil (5-Flu) as the model drug. MOF-808@5-Flu drug-loaded carriers were designed and prepared at different ratios. The drug release behavior of the MOF-808@5-Flu nanocomposite was investigated under different pH conditions (7.4/6.5/5.0). The results showed that when the mass ratio of MOF-808 to 5-Flu was 1:0.25, the material released 55.56% of the drug within 50 hours at pH 5.0, compared with 47.85% and 48.00% at pH 7.4 and 6.5, respectively. The drug release behavior was well fitted by the Higuchi model the Higuchi model. Cell and animal experiments demonstrated that MOF-808@5-Flu exhibited good biocompatibility and significantly inhibited the growth of Hepa1-6 cells, indicating its potential as a targeted nanocarrier to enhance therapeutic efficacy. Studies indicate that MOF-808@5-Flu induces cancer cell death through the apoptotic pathway. The catalytic activity of Zr⁴⁺ acted synergistically with the pharmacological effects of 5-Flu, generated a large amount of reactive oxygen species (ROS), significantly reducing tumor cell viability. Theoretical calculations indicated that MOF-808@5-Flu exhibits synergistic effects through multiple interactions, including π-π stacking, electrostatic attraction, and hydrophobic interactions. This results further highlights the advantages of MOF-808@5-Flu as a drug delivery platform. In summary, MOF-808@5-Flu shows great potential as a targeted nanocarrier for anticancer drug delivery. STATEMENT OF SIGNIFICANCE: Developed MOF-808@5-Flu nanocarriers with strong potential for targeted anticancer drug delivery. Achieved pH-responsive 5-Flu release, with the highest release rate of 55.56% at pH 5.0 within 50 h. Confirmed that the drug release profile follows the Higuchi model. Demonstrated good biocompatibility and effective inhibition of Hepa1-6 tumor cell growth. Revealed a "carrier-drug" synergistic mechanism driven by Zr⁴⁺ catalysis and multiple intermolecular interactions.