Abstract
Treatments of central nervous system (CNS) diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA) as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC) and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated) liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA) were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes.
Highlights
Access for drugs to the central nervous system (CNS) is highly restricted due to the presence of the blood–brain barrier (BBB)
Transcytosis of cationized serum albumin through brain capillary endothelial cells (BCEC) is known to occur ex vivo and in vivo [18,19] and we showed uptake of liposomes conjugated with cationized bovine serum albumin into BCEC in vitro and ex vivo [6]
Since cationized bovine serum albumin (cBSA) has a hydrodynamic radius of 3.48 nm, this increase cannot be explained by protein addition alone [29]
Summary
Access for drugs to the central nervous system (CNS) is highly restricted due to the presence of the blood–brain barrier (BBB). The exceptional barrier function of the BBB, apart from the tight junctions, is provided by ABC export proteins in the luminal membrane of the capillary endothelial cells, e.g., P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) or the multi-drug resistance protein family (MRPs). Their composition is very flexible and can be adapted to suit their purpose. (apoE4) are of interest, which are being transported into the brain via the transferrin- and low-density lipoprotein receptors, respectively. Both receptors are highly expressed at the BBB [5,15,16]. Liposomes, coupled with the signal sequence bearing the apoE4 peptide, were shown to be taken up by brain capillary endothelial cells (BCEC) in vitro [17]. A closer look at the uptake of these cBSA-liposomes in vitro and in vivo will be presented here
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