This study aimed to develop and optimize tivozanib-loaded amine-functionalized mesoporous silica nanoparticles (AF-MSNs) to enhance solubility, drug loading, and enhanced delivery for renal cell carcinoma therapy. Tivozanib was loaded into MCM-41 and MCM-41 silica carriers using solvent impregnation, and initial batches were screened for encapsulation efficiency, particle size, zeta potential, and solubility. A Box-Behnken factorial design was employed to optimize DETAS concentration, reaction time, and temperature for effective amine functionalization. Characterization was performed via FTIR, DSC, UV, and in vitro release studies. Cell viability was evaluated using MTT assay on A498 renal cell carcinoma cells. MCM-41 with a 1:2 drug-to-silica ratio showed the best performance with an encapsulation efficiency of 85.2 %, solubility of 68.4 µg/mL, and particle size of 175 nm. Optimization using Box-Behnken design identified SF14 as the best batch, exhibiting amine content of 2.52 mmol/g, zeta potential + 35.8 mV, and drug loading of 78.4 %. In vitro release showed sustained drug release of 78.42 % over 12 h. The dose-response analysis revealed IC₅₀ values of 18.4 ± 1.2 μg/mL for the optimized silica formulation, 25.2 ± 1.8 μg/mL for pure tivozanib, and 31.7 ± 2.1 μg/mL for sorafenib standard. Statistical analysis showed significant differences between all groups (one-way ANOVA, F (2,6) = 28.45, p = 0.0008). The optimized formulation demonstrated significantly lower IC₅₀ compared to pure tivozanib (p = 0.012) and sorafenib (p = 0.0003), while pure tivozanib showed significantly lower IC₅₀ than sorafenib (p = 0.024). The positive control doxorubicin showed an IC₅₀ of 2.8 ± 0.4 μg/mL, confirming assay sensitivity. Empty AF-MSNs demonstrated minimal cytotoxicity with > 85 % cell viability at the highest tested concentration (200 μg/mL), indicating that the observed cytotoxic effects were primarily due to the loaded drug rather than the carrier system. The optimized batch remained stable over 6 months under ICH conditions with no significant changes in critical parameters. The optimized AF-MSN formulation significantly improved the physicochemical properties, enhanced anticancer efficacy, and sustained release profile of tivozanib, supporting its potential to enhance clinical efficacy and reduce systemic toxicity. These findings indicate strong promise for future in vivo studies and potential clinical translation in targeted cancer therapy.
Siddheshwar et al. (Sat,) studied this question.