Cholesterol-mediated cationic solid lipid nanoparticles (CSLNs) were formulated with esterquat 1 (EQ 1) and stearylamine as positively charged external layers on hydrophobic internal cores of cacao butter. These CSLNs were employed to deliver saquinavir (SQV) to the brain. The permeability of SQV across the blood-brain barrier (BBB) using SQV-loaded CSLNs (SQV-CSLNs) was estimated with an in vitro model of a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes. The results revealed that the average diameter of SQV-CSLNs diminished when the weight percentage of cholesterol and EQ 1 increased. The morphological images indicated a uniform size of SQV-CSLNs with compact lipid structure. In addition, an increasing weight percentage of cholesterol and EQ 1 enhanced the zeta potential of SQV-CSLNs. The fluorescent staining demonstrated that HBMECs could internalize SQV-CSLNs. An increase in the weight percentage of cholesterol and EQ 1 also promoted the uptake of SQV-CSLNs by HBMECs. Moreover, a high content of cholesterol and EQ 1 in SQV-CSLNs increased the BBB permeability of SQV. The cholesterol-mediated SQV-CSLNs can be an efficacious drug delivery system for brain-targeting delivery of antiviral agents. (c) 2013 American Institute of Chemical Engineers Biotechnol. Prog., 30:198-206, 2014