Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences , Nagasaki University , 1-7-1 Sakamoto-machi , Nagasaki 852-8588 , Japan.
Department of Analytical Chemistry for Pharmaceutics, Graduate School of Biomedical Sciences , Nagasaki University , 1-14 Bunkyo-machi , Nagasaki 852-8521 , Japan.
Mol Pharm. 2018 Oct 1;15(10):4481-4490. doi: 10.1021/acs.molpharmaceut.8b00476. Epub 2018 Sep 4.
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) ) as a spacer of HFQ lipids and to substitute a conventional PEG spacer. We demonstrated the advantage of using (SG) spacers for peptide ligand presentation on the liposomal surface in vitro; however, the use of (SG) 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) -lipid) to target integrin αβ and prepared RGD-(SG) /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)/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)/PEGylated liposomes compared with that of conventional RGD-PEG/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 αβ-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.
高功能和高质量（HFQ）脂质具有离散的分子量和良好的水分散性，可以通过固相肽合成来生产。因此，HFQ 脂质是制备配体接枝聚乙二醇化脂质体的有前途的材料。最近，我们报道了丝氨酸-甘氨酸重复肽（(SG)）作为 HFQ 脂质的间隔物，并替代了传统的 PEG 间隔物。我们证明了在体外使用(SG)间隔物在脂质体表面展示肽配体的优势；然而，(SG)间隔物在体内的配体接枝聚乙二醇化脂质体中的应用尚未得到验证。本研究旨在验证 HFQ 脂质接枝聚乙二醇化脂质体的体内靶向能力。我们合成了含有 GRGDS（RGD-(SG)-lipid）的脂质来靶向整合素αβ，并制备了 RGD-(SG)/PEGylated liposomes。随后，评估了它们在鼠结肠癌细胞（Colon-26 细胞）中的细胞摄取特性。进行了组织透明后的双色成像，以检查脂质体在肿瘤内的空间分布。RGD-(SG)/PEGylated liposomes 在体外与细胞选择性结合。组织透明后对肿瘤内分布的体内分析表明，与传统的 RGD-PEG/PEGylated liposomes 相比，RGD-(SG)/PEGylated liposomes 对肿瘤组织和肿瘤血管具有更好的靶向能力。我们成功合成了 RGD-HFQ 脂质，以制备 RGD 接枝聚乙二醇化脂质体，用于靶向表达整合素αβ的细胞。据我们所知，这是组织透明后通过双色成像报告配体接枝聚乙二醇化脂质体在肿瘤内分布的首次报道。
