Lactoferrin-modified procationic liposomes as a novel drug carrier for brain delivery.

In this study, a new drug carrier for brain delivery, lactoferrin-modified procationic liposome, was developed and evaluated in vitro and in vivo. The procationic liposomes (PCLs) were neutral or negatively charged at physiological pH, and when they touched brain capillary endothelial cells with the help of a brain-targeting ligand, lactoferrin (Lf), they were changed into cationic liposomes (CL). The PCLs and lactoferrin-modified procationic liposomes (Lf-PCLs) with different CHETA/Lf ratio were prepared and characterized. The primary brain capillary endothelial cells (BCECs) were cultured to investigate the potential cytotoxicity and uptake of liposomes in vitro. An in vitro model of the blood-brain barrier (BBB), developed by the co-culture of BCECs and astrocytes (ACs), was employed to evaluate the ability and mechanisms of liposomes to cross endothelial cells. The liposome uptake by the mouse brain in vivo was detected by HPLC-fluorescence analysis. The results indicated that compared with the conventional liposomes and CLs, PCL and Lf-PCLs showed an improved performance in the uptake efficiency and cytotoxicity. Besides the uptake mediated by clathrin-dependent endocytosis of PCL, Lf-PCL crossed the BCECs through lipid raft/caveloae-mediated endocytosis. The endocytosis involved in the transport of Lf-PCL crossing BBB was mediated by both receptor- and absorption-mediated transcytosis. Compared with the conventional liposomes, PCL and Lf-PCL-8 (CHETA/Lf ratio=1:8, w/w) were observed to show much improved characteristics of the localization in the brain. This study suggested that Lf-PCL was an available brain drug delivery carrier with potential future application.