Mesoporous Silica Nanoparticle–Based Combination of NQO1 Inhibitor and 5-Fluorouracil for Potent Antitumor Effect Against Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

AbstractHead and neck squamous cell carcinomas (HNSCC) are one of the deadliest forms of cancer, and 90% of its origin is from squamous cells. NAD(P)H:quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in squamous cell carcinoma, plays an important role in proliferation and chemoresistance. The main aims were to study the inhibitory effect of ß-lapachone (ARQ761 in clinical form) in HNSCC and to study the combinational effect of 5-FU and ß-lap in improving the therapeutic efficacy in HNSCC. Lipid bilayer–assembled mesoporous silica nanoparticles loaded with 5-FU/ß-lap were prepared and studied for its physicochemical and biological properties. ß-lap showed a concentration-dependent inhibition of NQO1 enzyme activity in Cal33 cells. Notably, significant inhibitory effect was observed at a dose of 20–50 μg/ml of ß-lap. Combination of 5-FU+ß-lap resulted in lower cell viability; most notably, 5-FU/ß-lap-loaded mesoporous silica nanoparticles (FNQ-MSN) exhibited significantly lower cell viability compared with that of any of the individual drug or physical combinations. ß-lap resulted in a decrease in the protein band of NQO1 compared with control; however, most notable decrease in the NQO1 level was observed in the FNQ-MSN-treated cell group. FNQ-MSN resulted in more than 60% of cell apoptosis (early and late apoptosis) and predominant nuclear fragmentation of cancer cells indicating the superior anticancer effect of a carrier-based combination regimen. Notable decrease in tumor volume was observed with the physical mixture of 5-FU+ß-lap; however, combined treatment of carrier-based 5-FU and ß-lap (FNQ-MSN) significantly delayed the tumor growth and prolonged the survival of tumor-bearing xenograft mice. These findings suggest the potential of NQO1 inhibitor in enhancing the chemotherapeutic potential of 5-FU in the treatment of HNSCC.