A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence

• Published in: International journal of pharmaceutics 2013-11, Vol.456 (1), p.195-201
• Main Authors: Akhter, Afsana, Hayashi, Yasuhiro, Sakurai, Yu, Ohga, Noritaka, Hida, Kyoko, Harashima, Hideyoshi
• Format: Article
• Language: English
• Subjects: alcoholic hepatitis; Animals; ApoB-100 sequence; Apolipoprotein B-100 - chemistry; Cell Line, Tumor; CSPG; drugs; endothelial cells; Endothelial Cells - metabolism; Female; fibrosis; KLGR peptide; LDL receptor; Liposomes; liver; Liver - cytology; Liver - metabolism; Liver endothelial cell; low density lipoprotein; Lung - metabolism; Male; Maleimides - chemistry; Mice; Mice, Inbred ICR; microscopy; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; portal hypertension; RLTR peptide; Spleen - metabolism
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2013.07.068

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.