Nanoemulsion containing a synergistic combination of curcumin and quercetin for nose-to-brain delivery:In vitro and in vivo studies

Objective:To characterize a nanoemulsion containing a synergistic combination of curcumin(CUR)and quercetin(QUE)for brain targeting through the nose.Methods:The synergistic activity of the combination of two phytoconstituents,curcumin and quercetin(CUR-QUE)was determined at a 2:1 ratio.Nanoemulsions containing the synergistic combination were prepared using high-pressure homogenization technique.Nanoemulsion formulation was characterized for globule size,drug content,thermodynamic stability,zeta potential measurement,and drug release.Histological studies were performed using isolated nasal mucosa of sheep.Moreover,in vivo studies using allograft model were performed.Results:CUR-QUE in a 2:1 ratio combination showed the lowest combination index values 0.99(combination index<1)for treatment of human glioblastoma U373-MG cell.The combination inhibited the growth of human glioblastoma U373 MG cells.The significant drug targeting efficiency percentage(178.25±2.86 for CUR and 170.54±6.11 for QUE)and nose to brain drug direct transport percentage(44.05±0.93 for CUR and 38.25±0.83 for QUE)of optimized nanoemulsion(F9)indicated effective central nervous system targeting via the intranasal route.In vivo anticancer study using allograft model of nude mice demonstrated potential anticancer activity of the synergistic combination of CUR-QUE as compared to doxorubicin.Conclusions:This study demonstrates that synergistic combination of CUR-QUE was optimal for treatment of human glioblastoma.Moreover,significant site-specific delivery to the brain was achieved by administering nanoemulsion through the nose.The study also reveals that intranasal delivery of nanoemulsion containing synergistic combination of CUR and QUE could be a promising strategy for brain tumor treatment.