化学
体内
生物物理学
生物化学
脂质体
脂质双层
纳米圆盘
赫普斯
脂质A
信使核糖核酸
生物
膜
免疫学
基因
生物技术
脂多糖
作者
Rebecca L. Goldman,Namratha Turuvekere Vittala Murthy,Trent Northen,Anuranjani Balakrishnan,Sudha Chivukula,Hillary Danz,Timothy Tibbitts,Anusha Dias,Jorel Vargas,Dustin L. Cooper,Hardip Gopani,Angela Beaulieu,Kirill Kalnin,Timothy Plitnik,Saswata Karmakar,Ramesh Dasari,Ryan F. Landis,Shrirang Karve,Frank DeRosa
出处
期刊:Biomaterials
[Elsevier]
日期:2023-10-01
卷期号:301: 122243-122243
被引量:4
标识
DOI:10.1016/j.biomaterials.2023.122243
摘要
Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious diseases including COVID-19 and influenza. The ionizable lipid incorporated within the LNP is known to be one of the main driving factors for potency and tolerability. Herein, we describe a novel family of ionizable lipids synthesized with a piperazine core derived from the HEPES Good buffer. These ionizable lipids have unique asymmetric tails and two dissimilar degradable moieties incorporated within the structure. Lipids tails of varying lengths, degrees of unsaturation, branching, and the inclusion of additional ester moieties were evaluated for protein expression. We observed several key lipid structure activity relationships that correlated with improved protein production in vivo, including lipid tails of 12 carbons on the ester side and the effect of carbon spacing on the disulfide arm of the lipids. Differences in LNP physical characteristics were observed for lipids containing an extra ester moiety. The LNP structure and lipid bilayer packing, visualized through Cryo-TEM, affected the amount of protein produced in vivo. In non-human primates, the Good HEPES LNPs formulated with an mRNA encoding an influenza hemagglutinin (HA) antigen successfully generated functional HA inhibition (HAI) antibody titers comparable to the industry standards MC3 and SM-102 LNPs, demonstrating their promise as a potential vaccine.
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