Development and evaluation of cationic surface-modified hydroxyapatite nanoparticles for enhanced membrane permeation

PURPOSE: This study aimed to develop positively charged, metronidazole-loaded hydroxyapatite (MZ-HP) nanoparticles with enhanced membrane interaction, permeation, and therapeutic efficacy through surface charge modulation using cetyltrimethylammonium bromide (CT). METHODS: Mesoporous HP nanoparticles were synthesized from eggshell-derived calcium oxide and loaded with metronidazole, followed by CT coating (1-3.5 mM/g MZ-HP) via physisorption. Drug loading and CT adsorption were confirmed by FTIR and XRD, while SEM and TEM assessed morphology and coating induced structural changes. Particle size and zeta potential were measured using dynamic light scattering to evaluate surface charge modulation. Ex vivo porcine skin permeation studies assessed drug release and permeability. Cytocompatibility was evaluated using an MTT assay on L929 fibroblasts. RESULTS: MZ-HP nanoparticles were successfully formulated with a maximum loading efficiency of 87.2% at an MZ:HP ratio of 0.83 M:1 M, showing a strong positive correlation between drug to carrier ratio and loading efficiency (r = 0.90, P = 0.039). CT coating shifted the surface charge from -28.3 ± 5.12 mV (HP) to -20.5 ± 4.1 mV (MZ-HP) and further to +21.9 ± 3.3 mV (CT-MZ-HP), confirming effective charge reversal. Permeability flux increased from 1.285 to 1.582 mg/h·cm², indicating enhanced interaction with negatively charged biological membranes. Cytotoxicity studies demonstrated improved fibroblast tolerance for CT-MZ-HP (IC₅。 = 184.9 ± 3.12 µg/mL) compared to CT, inferring its short-term dermal safety and enhanced cytocompatibility. CONCLUSION: CT coated MZ-HP nanoparticles provide an effective charge-modulated nanocarrier system with enhanced trans-barrier transport, membrane interaction, intracellular access, and cytocompatibility, supporting their potential as next-generation antimicrobial delivery platforms.