Tailoring Syringic Acid–Trimesic Acid Mixed-Linker MIL-100(Fe): Evaluation of Drug-Loading Capacity, Bioavailability, and Toxicity

Background/Objectives: The use of the drug delivery system is notable for the systemic improvement of low orally bioavailable compounds, such as the bioactive phenolic acid, syringic acid. Innovative techniques are employed to enhance the performance of certain drug delivery systems. In connection with our previously reported journal with the use of MIL-100(Fe) as a drug carrier for syringic acid, this study utilized a mixed-linker synthesis of syringic acid and trimesic acid and characterized the properties in comparison with the unmodified MIL-100(Fe) through a solid solution approach. Methods: Modified MIL-100(Fe) was synthesized by substituting different molar concentrations of syringic acid for trimesic acid through de novo synthesis. Simple impregnation of syringic acid was carried out at 12, 24, 36, and 48 h and at 1:1 and 1:2 molar ratios of MIL-100(Fe) to syringic acid. Characterization was performed via PXRD, FTIR, BET, SEM, and DLS. In vivo studies included acute oral toxicity testing (OECD 425) and bioavailability assessment in Sprague Dawley rats. Results: The optimized amount of syringic acid to be substituted for trimesic acid is 0.10 mmol, as confirmed by the value of the PXRD. Optimized drug loading of 66.85 ± 0.004% was achieved using a 1:2 ratio of syringic acid to MIL-100(Fe)-10% over 36 h. Structural modifications were confirmed via FTIR, specifically through shifts at 1239.2 cm⁻¹, while TGA demonstrated thermal stability up to approximately 350 °C. Morphological analysis by SEM showed octahedral particles (210.70 ± 1.23 nm), and a decrease in BET surface area post-loading verified successful encapsulation. While in vitro release was media-dependent, toxicity studies at 2000 mg/kg showed no adverse effects; notably, SGOT and SGPT levels decreased, though BUN and creatinine levels rose. Compared to pure oral syringic acid, the SYA@MIL-100(Fe)-10% formulation demonstrated a 5.09-fold increase in relative bioavailability. Furthermore, it outperformed intraperitoneal administration of the drug by 1.65-fold. Conclusions: Modification of MIL-100(Fe) by incorporating syringic acid into the framework as a substituted organic linker indicates that SYA@MIL-100(Fe)-10% is a safe and effective delivery system for syringic acid, enhancing oral bioavailability. To the best of our knowledge, this is the first study to investigate the mixed-linker synthesis of MIL-100(Fe) by utilizing syringic acid as a structural co-ligand, rather than solely as an encapsulated guest. While MIL-100(Fe) has been extensively employed as a carrier for various therapeutics, this research uniquely integrates the active agent into the framework lattice itself to modulate porosity and loading capacity, subsequently evaluating its systemic performance in an in vivo model.