Santos Rita S, Dakwar George R, Xiong Ranhua, Forier Katrien, Remaut Katrien, Stremersch Stephan, Guimarães Nuno, Fontenete Sílvia, Wengel Jesper, Leite Marina, Figueiredo Céu, De Smedt Stefaan C, Braeckmans Kevin, Azevedo Nuno F
LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, Porto, Portugal.
Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Mol Ther Nucleic Acids. 2015 Dec 8;4(12):e269. doi: 10.1038/mtna.2015.46.
Helicobacter pylori infects more than 50% of the worldwide population. It is mostly found deep in the gastric mucus lining of the stomach, being a major cause of peptic ulcers and gastric adenocarcinoma. To face the increasing resistance of H. pylori to antibiotics, antimicrobial nucleic acid mimics are a promising alternative. In particular, locked nucleic acids (LNA)/2'-OMethyl RNA (2'OMe) have shown to specifically target H. pylori, as evidenced by in situ hybridization. The success of in vivo hybridization depends on the ability of these nucleic acids to penetrate the major physical barriers-the highly viscoelastic gastric mucus and the bacterial cell envelope. We found that LNA/2'OMe is capable of diffusing rapidly through native, undiluted, gastric mucus isolated from porcine stomachs, without degradation. Moreover, although LNA/2'OMe hybridization was still successful without permeabilization and fixation of the bacteria, which is normally part of in vitro studies, the ability of LNA/2'OMe to efficiently hybridize with H. pylori was hampered by the presence of mucus. Future research should focus on developing nanocarriers that shield LNA/2'OMe from components in the gastric mucus, while remaining capable of diffusing through the mucus and delivering these nucleic acid mimics directly into the bacteria.
幽门螺杆菌感染了全球超过50%的人口。它大多存在于胃的胃黏液深层，是消化性溃疡和胃腺癌的主要病因。为应对幽门螺杆菌对抗生素日益增加的耐药性，抗菌核酸类似物是一种有前景的替代方案。特别是，锁核酸（LNA）/2'-O-甲基核糖核酸（2'OMe）已显示出能特异性靶向幽门螺杆菌，原位杂交证明了这一点。体内杂交的成功取决于这些核酸穿透主要物理屏障——高黏弹性胃黏液和细菌细胞壁的能力。我们发现LNA/2'OMe能够快速扩散穿过从猪胃分离的天然、未稀释的胃黏液，且不会降解。此外，尽管在不进行细菌通透化和固定（这通常是体外研究的一部分）的情况下，LNA/2'OMe杂交仍能成功，但黏液的存在阻碍了LNA/2'OMe与幽门螺杆菌有效杂交。未来的研究应专注于开发纳米载体，该载体能保护LNA/2'OMe免受胃黏液中成分的影响，同时仍能扩散穿过黏液并将这些核酸类似物直接递送至细菌内。
