Sakai Kosuke, Katsumi Hidemasa, Kamano Kentaro, Yamauchi Kiyo, Hajima Ayuko, Morishita Masaki, Sakane Toshiyasu, Yamamoto Akira
Department of Biopharmaceutics, Kyoto Pharmaceutical University.
Department of Pharmaceutical Technology, Kobe Pharmaceutical University.
Biol Pharm Bull. 2019;42(2):273-279. doi: 10.1248/bpb.b18-00773.
Hydrogen sulfide (HS) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of HS prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of HS) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released HS in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and HS was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released HS intracellularly. In a biodistribution study, up to 80% of In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of HS prodrug to a specific type of liver cells was successfully achieved by bioconjugation.
硫化氢（HS）是一种内源性气体递质，已知在生物功能中发挥重要作用。为了在细胞水平上实现HS前药的肝脏及肝内靶向，我们开发了两种磺化白蛋白，其中五个硫化物基团（HS的来源）与琥珀酰化（Suc）或半乳糖基化（Gal）牛血清白蛋白（BSA）共价结合。磺化牛血清白蛋白-琥珀酰化（Sulfo-BSA-Suc）和聚乙二醇（PEG）-磺化牛血清白蛋白-半乳糖基化（PEG-Sulfo-BSA-Gal）在5 mM谷胱甘肽溶液中均能释放HS，但在血浆中则不能。Sulfo-BSA-Suc和PEG-Sulfo-BSA-Gal分别被RAW264.7细胞（小鼠巨噬细胞样细胞）和Hep G2细胞（人肝癌细胞）摄取，并释放出HS。这些结果表明，Sulfo-BSA-Suc和PEG-Sulfo-BSA-Gal在细胞内选择性释放HS。在一项生物分布研究中，静脉注射小鼠30分钟后，高达80%的铟标记的Sulfo-BSA-Suc和PEG-Sulfo-BSA-Gal迅速在肝脏中积累。此外，铟标记的Sulfo-BSA-Suc和PEG-Sulfo-BSA-Gal分别主要在肝脏非实质细胞（内皮细胞和库普弗细胞）和实质细胞（肝细胞）中积累。这些发现表明，通过生物共轭成功实现了HS前药向特定类型肝细胞的靶向递送。
