A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence.
Liver dysfunction is associated with a variety of liver diseases, including viral or alcoholic hepatitis, fibrosis, cirrhosis, and portal hypertension. A targeted drug delivery system would be very useful in the treatment of these diseases. We herein describe the development of a system comprised of a new peptide-lipid conjugate for the efficient delivery of molecules to LEC. The RLTRKRGLK sequence (3359-3367), which mediates the association of LDL with arterial CSPG and an LDL receptor, was utilized as a ligand for achieving this goal. The peptide modified PEG-LPs (RLTR-PEG-LPs) were efficiently taken up by primary liver endothelial cells (liver ECs) and other types of cells. In vivo biodistribution and confocal microscopy analysis showed that RLTR-PEG-LPs became widely accumulated in LECs within a short time. Distribution of RLTR-PEG-LPs was greatly reduced with a pretreatment of unlabeled RLTR-PEG-LPs, not cationic LPs, indicating that the sequence is important for LECs. The findings indicate that a reverse sequence of RLTR (KLGR) modified PEG-LPs (KLGR-PEG-LP) did the same pattern compared with RLTR-PEG-LPs, suggesting that the RKR or RXXR sequence might be essential for LECs targeting. Collectively RLTR-PEG-LPs and KLGR-PEG-LPs have the potential for delivering drugs to LECs.
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan; Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-0812, Japan.
Afsana
A
Akhter
Yasuhiro
Y
Hayashi
Yu
Y
Sakurai
Noritaka
N
Ohga
Kyoko
K
Hida
Hideyoshi
H
Harashima
D000818:Animals; D053299:Apolipoprotein B-100 / Q000737:chemistry*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D008081:Liposomes; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013154:Spleen / Q000378:metabolism
D053299:Apolipoprotein B-100; D008081:Liposomes; D008301:Maleimides; D009842:Oligopeptides; D010714:Phosphatidylethanolamines; C038089:1,2-distearoylphosphatidylethanolamine; C043592:maleimide; D011092:Polyethylene Glycols
ApoB-100 sequence; CSPG; KLGR peptide; LDL receptor; Liver endothelial cell; RLTR peptide