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Hepatocellular targeted α-tocopherol based pH sensitive galactosylated lipids: design, synthesis and transfection studies†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-12-06 00:00:00 , DOI: 10.1039/c7md00503b Venkanna Muripiti 1 , Brijesh Lohchania 2 , Srujan Kumar Marepally 2 , Srilakshmi V Patri 1
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-12-06 00:00:00 , DOI: 10.1039/c7md00503b Venkanna Muripiti 1 , Brijesh Lohchania 2 , Srujan Kumar Marepally 2 , Srilakshmi V Patri 1
Affiliation
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Receptor mediated gene delivery to the liver offers advantages in treating genetic disorders such as hemophilia and hereditary tyrosinemia type I (HTI). Prior findings demonstrated that tethering the D-galactose head group to cationic lipids directs genes to the liver via asialoglycoprotein receptors (ASGPRs). In our continued efforts to develop safer and efficient lipofectins, we demonstrated that cationic lipids bearing α-tocopherol, an antioxidant, as a hydrophobic domain could deliver genes efficiently with high safety profiles in multiple cell lines. Towards developing ASGPR targeted pH sensitive cationic lipids, we have designed a galactosylated cationic lipid (Toc-Gal) with α-tocopherol as the hydrophobic core covalently connected with a pH responsive triazole moiety and a non-targeting control lipid (Toc-OH) without the galactose head group. In this study, we present the design and synthesis of a pH sensitive galactosylated cationic lipid (Toc-Gal), its comparative transfection biology, cellular uptake studies, serum stability and cytotoxicity profiles in both ASGPR positive and negative liver cells, i.e. HepG2 and SK-Hep-1, respectively.
中文翻译：
基于肝细胞靶向 α-生育酚的 pH 敏感半乳糖基化脂质：设计、合成和转染研究†
受体介导的基因递送至肝脏在治疗血友病和 I 型遗传性酪氨酸血症 (HTI) 等遗传性疾病方面具有优势。先前的研究结果表明，将D-半乳糖头基与阳离子脂质连接可通过脱唾液酸糖蛋白受体 (ASGPR)将基因引导至肝脏。在我们不断努力开发更安全、高效的脂质体转染剂的过程中，我们证明了带有α-生育酚（一种抗氧化剂）作为疏水结构域的阳离子脂质可以在多种细胞系中高效地传递基因，且安全性高。为了开发 ASGPR 靶向 pH 敏感的阳离子脂质，我们设计了一种半乳糖基化阳离子脂质 (Toc-Gal)，以 α-生育酚为疏水核心，与 pH 响应性三唑部分共价连接，以及非靶向对照脂质 (Toc-OH)，不含半乳糖头基。在本研究中，我们介绍了 pH 敏感性半乳糖基化阳离子脂质 (Toc-Gal) 的设计和合成、其比较转染生物学、细胞摄取研究、ASGPR 阳性和阴性肝细胞（即HepG2 和 SK）中的血清稳定性和细胞毒性特征。分别为-Hep-1。
更新日期：2017-12-06
中文翻译：
基于肝细胞靶向 α-生育酚的 pH 敏感半乳糖基化脂质：设计、合成和转染研究†
受体介导的基因递送至肝脏在治疗血友病和 I 型遗传性酪氨酸血症 (HTI) 等遗传性疾病方面具有优势。先前的研究结果表明，将D-半乳糖头基与阳离子脂质连接可通过脱唾液酸糖蛋白受体 (ASGPR)将基因引导至肝脏。在我们不断努力开发更安全、高效的脂质体转染剂的过程中，我们证明了带有α-生育酚（一种抗氧化剂）作为疏水结构域的阳离子脂质可以在多种细胞系中高效地传递基因，且安全性高。为了开发 ASGPR 靶向 pH 敏感的阳离子脂质，我们设计了一种半乳糖基化阳离子脂质 (Toc-Gal)，以 α-生育酚为疏水核心，与 pH 响应性三唑部分共价连接，以及非靶向对照脂质 (Toc-OH)，不含半乳糖头基。在本研究中，我们介绍了 pH 敏感性半乳糖基化阳离子脂质 (Toc-Gal) 的设计和合成、其比较转染生物学、细胞摄取研究、ASGPR 阳性和阴性肝细胞（即HepG2 和 SK）中的血清稳定性和细胞毒性特征。分别为-Hep-1。
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