Abstract

Background/objectives: Colorectal cancer (CRC) remains a cause of cancer-related mortality worldwide, with therapeutic progress hindered by poor tumor selectivity and acquired drug resistance. This study investigated the anticancer efficacy of simvastatin, administered as a free drug or encapsulated within mesoporous SBA-16 nanoparticles (NPs), against HT-29 colorectal cancer cells in two-dimensional monolayer and three-dimensional spheroid culture models. Methods: SBA-16 NPs achieved drug-loading efficiency of 73.83% and accelerated cumulative release of 91.93% within 30 min, compared to 35.24% for the free drug. Cell viability and proliferation were assessed via MTT and clonogenic assays, while interleukin-6 (IL-6) levels were measured by ELISA to evaluate anti-inflammatory activity. Results: Simvastatin-loaded SBA-16 NPs reduced the IC50 from 27.86 µg/mL to 4.43 µg/mL, representing a 6.29-fold enhancement in cytotoxic potency (p < 0.001), and significantly inhibited colony formation and suppressed IL-6 secretion, indicating modulation of inflammatory pathways implicated in tumor progression. In the 3D spheroid model, the nanoparticle formulation induced dose-dependent inhibition superior to the free drug. Conclusions: These findings demonstrate that SBA-16 nanocarriers substantially amplify simvastatin’s anticancer efficacy through improved drug solubilisation and rapid release kinetics under sink conditions, with possible—but not directly proven—enhanced cellular interaction/internalisation and modulation of tumor-associated inflammatory signaling. Direct uptake, penetration, mechanistic cell-death, normal-cell selectivity, and in vivo studies are warranted to confirm clinical applicability.

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