Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.
Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.
复制标题
用立体纯可电离脂质替代外消旋可电离脂质可以增加 mRNA 递送。
DOI：
10.1016/j.jconrel.2022.11.037
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dahlman,JamesE
中科院分区：
文献类型：
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作者：
DaSilvaSanchez,AlejandroJ;Zhao,Kun;Huayamares,SebastianG;Hatit,MarineZC;Lokugamage,MelissaP;Loughrey,David;Dobrowolski,Curtis;Wang,Shuaishuai;Kim,Hyejin;Paunovska,Kalina;Kuzminich,Yanina;Dahlman,JamesE
脂质纳米粒(LNPs)已经在人类体内传递了siRNA和mRNA药物，强调了改善下一代LNPs治疗窗口的潜在影响。为了增加LNP的治疗窗口，我们将小分子化学的经验应用于可电离脂质的设计。具体地说，考虑到立体化学经常影响小分子的安全性和药代动力学，我们假设LNP中脂质的立体化学将影响信使核糖核酸的传递。我们在128个新的LNPs活体中测试了这一假设，这些LNPs包括C12-200的立体视觉衍生物，C12-200是一种可电离的脂质，当配方成LNPs时，它可以在小鼠和非人类灵长类动物中传递RNA，但由于其耐受性较差，不能用于临床。我们发现新的C12-200-S LNP体内递送的mRNA量分别是其外消旋和C12-200-R对照的2.8倍和6.1倍。为了确定导致递送增加的潜在原因，我们量化了LNP的生物物理特性，并得出结论，这些特性不会随着立体化学的变化而改变。相反，我们发现在体内，立体LNPs比外消旋LNPs具有更好的耐受性。这些数据表明，通过设计包括立体可电离脂质的LNP可以改善LNP介导的mRNA传递。
Lipid nanoparticles (LNPs) have delivered siRNA and mRNA drugs in humans, underscoring the potential impact of improving the therapeutic window of next-generation LNPs. To increase the LNP therapeutic window, we applied lessons from small-molecule chemistry to ionizable lipid design. Specifically, given that stereochemistry often influences small-molecule safety and pharmacokinetics, we hypothesized that the stereochemistry of lipids within an LNP would influence mRNA delivery. We tested this hypothesisin vivousing 128 novel LNPs that included stereopure derivatives of C12‐200, an ionizable lipid that when formulated into LNPs delivers RNA in mice and non-human primates but is not used clinically due to its poor tolerability. We found that a novel C12‐200-S LNP delivered up to 2.8-fold and 6.1-fold more mRNAin vivothan its racemic and C12‐200-R controls, respectively.To identify the potential causes leading to increased delivery, we quantified LNP biophysical traits and concluded that these did not change with stereochemistry. Instead, we found that stereopure LNPs were better tolerated than racemic LNPsin vivo. These data suggest that LNP-mediated mRNA delivery can be improved by designing LNPs to include stereopure ionizable lipids.