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BroadPharm技术讲座-What is ALC-0315?

更新时间:2023-09-08   点击次数:346次

中文介绍:

脂质纳米颗粒(LNP)在mRNA疫苗的创建和批准中发挥了重要作用。辉瑞公司的疫苗 BNT162b2 中使用的脂质之一是 ALC-0315。

ALC-0315是一种氨基脂质,其叔胺通过酯键与支链尾相连。叔胺允许脂质形成两性离子脂质。ALC-0315是一种无色油性化合物,分子量为766.3,CAS号为2036272-55-4 IUPAC名称为[(4-羟基丁基)氮杂二基]二(己烷-6,1-二基)双(2-己基癸酸酯)。

ALC-0315因其快速清除率、耐受性、免疫原性和蛋白表达而成为理想的药物载体。虽然ALC-0315可溶于有机溶剂,但悬浮在极性溶剂中时会形成膜。叔胺与mRNA形成离子键,允许mRNA有效载荷的理想封装。ALC-0315在生理pH下保持中性,并在酸性环境中带正电荷。这种在生理pH下保持中性的特性允许脂质与血细胞阴离子膜的相互作用更少。ALC-0315带正电荷的能力在细胞摄取后起着重要作用。当ALC-0315与酸性内体相互作用时,叔胺变成质子化并形成锥形离子对,驱动从双层到倒六边形相的转变。这个阶段促进内体逃逸和mRNA释放到细胞质中。一旦mRNA被释放,ALC-0315通过两个连续的酯水解反应代谢,首先产生单酯代谢物,然后产生双重脱酯代谢物。两种水解反应的产物是6-己基癸酸。剩余的脂肪族头组通过胆道和肾脏清除消除。

随着纳米颗粒药物递送技术的最新进展,科学界正处于许多新疗法的边缘。为了进一步增强药物输送能力,BroadPharm(国内客户联系靶点科技)提供了广泛的可电离脂质、阳离子脂质、PEG 脂质和磷脂选择。BroadPharm(国内客户联系靶点科技)还提供定制的脂质合成,以进一步满足您的研究需求。

英文介绍:

Lipid nanoparticles (LNP) have played an important role in the creation and approval of mRNA vaccines. One of the more notable lipids found in Pfizer’s vaccine BNT162b2 is ALC- 0315.

ALC-0315 is an amino lipid with a tertiary amine linked with a branched tail through ester bonds. The tertiary amine allows the lipid to form a zwitterionic lipid. ALC-0315 is a colorless oily compound with a molecular weight of 766.3 and a CAS number of 2036272-55-4 IUPAC name is [(4-Hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate).

ALC-0315 can be synthesized through the route as shown in Figure 1.

alc-0315 image

Figure 1. Shows the synthesis route of ALC-0315.

ALC-0315 is an ideal drug carrier due to its fast clearance rate, tolerability, immunogenicity, and protein expression. While ALC-0315 is soluble in organic solvents, it forms a membrane when suspended in polar solvents. The tertiary amine forms an ionic bond to mRNA allowing for ideal encapsulation of the mRNA payload. ALC-0315 remains neutral at physiological pH and takes on a positive charge in an acidic environment. This property to stay neutral at physiological pH allows the lipid to have fewer interactions with the anionic membranes of blood cells. ALC- 0315’s ability to take on a positive charge plays an important role after cellular uptake. When ALC-0315 interacts with the acidic endosome, the tertiary amine becomes protonated and forms cone-shaped ion pairs that drive the transition from a bilayer to an inverted hexagon phase. This phase promotes endosomal escape and the release of the mRNA into the cytosol. Once the mRNA is released, ALC-0315 is metabolized through two sequential ester hydrolysis reactions first yielding the monoester metabolite followed by the doubly de-esterified metabolite. The product of both hydrolysis reactions is 6-hexyldecanoic acid. The remaining aliphatic head group is eliminated via biliary and renal clearance.

With the recent advances in nanoparticle drug delivery technology, the scientific community is on the edge of many new therapeutics being created. To further empower drug delivery, BroadPharm offers a broad selection of ionizable lipids, cationic lipids, PEG lipids, and Phospholipids. BroadPharm also offers custom lipid syntheses to further satisfy your research need.



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