Tran Phuc, Weldemichael Tsigereda, Liu Zhichao, Li Hong-Yu
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
Pharmaceutics. 2022 Feb 1;14(2):342. doi: 10.3390/pharmaceutics14020342.
Oligonucleotides have shifted drug discovery into a new paradigm due to their ability to silence the genes and inhibit protein translation. Importantly, they can drug the un-druggable targets from the conventional small-molecule perspective. Unfortunately, poor cellular permeability and susceptibility to nuclease degradation remain as major hurdles for the development of oligonucleotide therapeutic agents. Studies of safe and effective delivery technique with lipid bioconjugates gains attention to resolve these issues. Our review article summarizes the physicochemical effect of well-studied hydrophobic moieties to enhance the cellular entry of oligonucleotides. The structural impacts of fatty acids, cholesterol, tocopherol, and squalene on cellular internalization and membrane penetration in vitro and in vivo were discussed first. The crucial assays for delivery evaluation within this section were analyzed sequentially. Next, we provided a few successful examples of lipid-conjugated oligonucleotides advanced into clinical studies for treating patients with different medical backgrounds. Finally, we pinpointed current limitations and outlooks in this research field along with opportunities to explore new modifications and efficacy studies.
由于能够使基因沉默并抑制蛋白质翻译，寡核苷酸已将药物发现带入了一个新的范式。重要的是，从传统小分子的角度来看，它们可以作用于难以成药的靶点。不幸的是，较差的细胞通透性和对核酸酶降解的敏感性仍然是寡核苷酸治疗剂开发的主要障碍。对脂质生物共轭物安全有效的递送技术的研究受到关注，以解决这些问题。我们的综述文章总结了经过充分研究的疏水部分对增强寡核苷酸细胞摄取的物理化学作用。首先讨论了脂肪酸、胆固醇、生育酚和角鲨烯在体外和体内对细胞内化和膜穿透的结构影响。依次分析了本节中用于递送评估的关键试验。接下来，我们提供了一些脂质共轭寡核苷酸进入临床研究以治疗不同医学背景患者的成功例子。最后，我们指出了该研究领域当前的局限性和前景，以及探索新修饰和疗效研究的机会。
