Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
Mol Ther. 2013 Aug;21(8):1570-8. doi: 10.1038/mt.2013.124. Epub 2013 Jun 25.
In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available.
近年来，RNA 干扰（RNAi）疗法，尤其是基于脂质纳米颗粒的递药系统，已进入人体临床试验。这些早期临床试验的结果表明，脂质纳米颗粒（LNPs）及其组成的新型可离子化脂质将成为这一新兴医学领域的重要材料。在生物医学应用材料的使用中，一个持续的主题是将生物降解性作为提高生物相容性和/或促进消除的一种手段。因此，本工作的目的是通过开发新型的下一代脂质进一步推进 LNP 平台，这些脂质将当前可用的最先进脂质的优异效力与可生物降解功能结合在一起。作为这类新型可生物降解脂质的代表性实例，本工作中评估的脂质在血浆和组织中的消除速度更快，在临床前研究中耐受性大大提高，同时保持与当前可用的最先进脂质相当的体内效力。
