cKK-E12 is an ionizable lipid that can be used to form lipid nanoparticles (LNP) for efficient delivery of siRNA and mRNA[1]. LNP formed with cKK-E12 exhibit high surface binding affinity for endogenous apolipoprotein E (ApoE), demonstrating strong tropism for hepatocytes[2]. cKK-E12 is commonly applied in targeted gene delivery and therapy, vaccine development, molecular imaging, and related fields[3,4].
In vitro, treatment of RAW 264.7 macrophages with cKK-E12 LNP (400ng/mL) for 6h significantly upregulates the expression of pro-inflammatory cytokines IL-6, TNF-α, IL-1α, IFN-β, and the chemokine MCP-1. Furthermore, treatment with cKK-E12 LNP (400ng/mL) for 24h markedly increases the proportions of apoptotic, necrotic, and pyroptotic cells[5].
In vivo, administration of Cy5-labeled mRNA-loaded cKK-E12 LNP (0.75mg/kg) via tail vein injection in C57BL/6 mice results in predominant accumulation in the liver (>60%) within 1h, followed by the spleen, lungs, and kidneys[6]. Intravenous injection of trastuzumab mRNA-loaded cKK-E12 LNP (0.5, 1, and 2mg/kg) in C57BL/6 mice leads to a dose-dependent increase in serum trastuzumab levels after 24h, reaching approximately 40µg/mL at the 2mg/kg dose[7].
References:
[1] ZENG Y, ESCALONA-RAYO O, KNOL R, et al. Lipid nanoparticle-based mRNA candidates elicit potent T cell responses[J]. Biomaterials Science, 2023, 11(3): 964-974.
[2] DONG Y, LOVE K T, DORKIN J R, et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates[J]. Proceedings of the National Academy of Sciences, 2014, 111(11): 3955-3960.
[3] FENTON O S, KAUFFMAN K J, MCCLELLAN R L, et al. Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery[J]. Advanced Materials (Deerfield Beach, Fla.), 2016, 28(15): 2939.
[4] GORDON A, LI B, WITTEN J, et al. Inhalable dry powders for lung mRNA delivery[J]. Advanced Healthcare Materials, 2024, 13(29): 2400509.
[5] OMO-LAMAI S, WANG Y, PATEL M N, et al. Lipid nanoparticle-associated inflammation is triggered by sensing of endosomal damage: engineering endosomal escape without side effects[J]. bioRxiv, 2024: 2024.04.16.589801.
[6] MELAMED J R, HAJJ K A, CHAUDHARY N, et al. Lipid nanoparticle chemistry determines how nucleoside base modifications alter mRNA delivery[J]. Journal of Controlled Release, 2022, 341: 206-214.
[7] RYBAKOVA Y, KOWALSKI P S, HUANG Y, et al. mRNA delivery for therapeutic anti-HER2 antibody expression in vivo[J]. Molecular Therapy, 2019, 27(8): 1415-1423.
cKK-E12是一种可用于形成脂质纳米颗粒（LNP）以高效传递siRNA和mRNA的可电离脂质[1]。cKK-E12形成的LNP表面可高效结合内源性载脂蛋白E（ApoE），对肝实质细胞具有极强的亲和力[2]。cKK-E12通常用于靶向基因的递送与治疗、疫苗研发及分子成像等领域[3,4]。
在体外，cKK-E12 LNP（400ng/mL）处理RAW 264.7巨噬细胞6h，显著上调了促炎细胞因子IL-6、TNF-α、IL-1α、IFN-β和趋化因子MCP-1的表达。cKK-E12 LNP（400ng/mL）处理RAW 264.7巨噬细胞24h，可显著增加凋亡、坏死和焦亡细胞的比例[5]。
在体内，Cy5标记mRNA的cKK-E12 LNP（0.75mg/kg）通过尾静脉注射处理C57BL/6小鼠，1h后cKK-E12 LNP主要积累于肝脏（＞60%），其次为脾、肺和肾[6]。载有曲妥珠单抗mRNA的cKK-E12 LNP（0.5, 1, 2mg/kg）通过静脉注射处理C57BL/6小鼠，24h后血清中曲妥珠单抗呈剂量依赖性增加，2mg/kg剂量下血清浓度达约40μg/mL[7]。