Development of High-Functionality and -Quality Lipids with RGD Peptide Ligands: Application for PEGylated Liposomes and Analysis of Intratumoral Distribution in a Murine Colon Cancer Model.
High-functionality and -quality (HFQ) lipids have a discrete molecular weight and good water dispersibility and can be produced by solid-phase peptide synthesis. Therefore, HFQ lipids are a promising material for the preparation of ligand-grafted PEGylated liposomes. Recently, we have reported serine-glycine repeated peptides ((SG) n) as a spacer of HFQ lipids and to substitute a conventional PEG spacer. We demonstrated the advantage of using (SG) n spacers for peptide ligand presentation on the liposomal surface in vitro; however, the use of (SG) n spacers in ligand-grafted PEGylated liposomes in vivo has not been validated. The aim of this study was to validate the in vivo targeting ability of HFQ lipid-grafted PEGylated liposomes. We synthesized lipids containing GRGDS (RGD-(SG) n-lipid) to target integrin αvβ3 and prepared RGD-(SG) n/PEGylated liposomes. Subsequently, their cellular uptake characteristics in murine colon carcinoma (Colon-26) cells were evaluated. Two-color imaging of liposomes and tumor blood vessels following tissue clearing was performed to examine the spatial intratumoral distribution of liposomes. RGD-(SG)5/PEGylated liposomes were selectively associated with the cells in vitro. In vivo analysis of intratumoral distribution following tissue clearing revealed the superior targeting ability of RGD-(SG)5/PEGylated liposomes compared with that of conventional RGD-PEG2000/PEGylated liposomes for both tumor tissues and tumor blood vessels. We successfully synthesized RGD-HFQ lipids to prepare RGD-grafted PEGylated liposomes for the efficient targeting of integrin αvβ3-expressing cells. To the best of our knowledge, this is the first report of the intratumoral distribution of ligand-grafted PEGylated liposomes by two-color imaging following tissue clearing.
['Suga|Tadaharu|T|', 'Kato|Naoya|N|', 'Hagimori|Masayori|M|', 'Fuchigami|Yuki|Y|', 'Kuroda|Naotaka|N|', 'Kodama|Yukinobu|Y|', 'Sasaki|Hitoshi|H|', 'Kawakami|Shigeru|S|0000-0001-8765-2463']
D000818:Animals D003110:Colonic Neoplasms D007150:Immunohistochemistry D008081:Liposomes D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D009842:Oligopeptides D011092:Polyethylene Glycols
tissue clearing integrin receptor peptide-mediated targeting polyethylene glycol targeted liposomal delivery