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新型细胞穿透两性离子肽脂质衍生物修饰的纳米材料增强细胞内递送的研究。

Investigation of enhanced intracellular delivery of nanomaterials modified with novel cell-penetrating zwitterionic peptide-lipid derivatives.

机构信息

Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Department of Chemistry of Functional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

出版信息

Drug Deliv. 2023 Dec;30(1):2191891. doi: 10.1080/10717544.2023.2191891.

DOI:10.1080/10717544.2023.2191891
PMID:36964673
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10044157/
Abstract

Functionalized drug delivery systems have been investigated to improve the targetability and intracellular translocation of therapeutic drugs. We developed high functionality and quality lipids that met unique requirements, focusing on the quality of functional lipids for the preparation of targeted nanoparticles using microfluidic devices. While searching for a lipid with high solubility and dispersibility in solvents, which is one of the requirements, we noted that KK-(EK)-lipid imparts nonspecific cellular association to polyethylene glycol (PEG)-modified (PEGylated) liposomes, such as cell-penetrating peptides (CPPs). We investigated whether KK-(EK)-lipid, which has a near-neutral charge, is a novel CPP-modified lipid that enhances the intracellular translocation of nanoparticles. However, the cellular association mechanism of KK-(EK)-lipid is unknown. Therefore, we synthesized (EK)-lipid derivatives based on the sequence of KK-(EK)-lipid and determined the sequence sites involved in cellular association. In addition, KK-(EK)-lipid was applied to extracellular vesicles (EVs) and mRNA encapsulated lipid nanoparticles (mRNA-LNPs). KK-(EK)-lipid-modified EVs and mRNA-LNPs showed higher cellular association and in vitro protein expression, respectively, compared to unmodified ones. We elucidated KK-(EK)-lipid to have potential for applicability in the intracellular delivery of liposomes, EVs, and mRNA-LNPs.

摘要

功能化药物递送系统已被研究用于提高治疗药物的靶向性和细胞内转位。我们开发了具有高功能和高质量的脂质，这些脂质满足独特的要求，专注于使用微流控设备制备靶向纳米颗粒的功能性脂质的质量。在寻找一种在溶剂中具有高溶解性和分散性的脂质（这是要求之一）时，我们注意到 KK-(EK)-脂质赋予聚乙二醇（PEG）修饰（PEGylated）脂质体非特异性细胞结合，例如细胞穿透肽（CPP）。我们研究了带近中性电荷的 KK-(EK)-脂质是否是一种新型 CPP 修饰脂质，能够增强纳米颗粒的细胞内转位。然而，KK-(EK)-脂质的细胞结合机制尚不清楚。因此，我们根据 KK-(EK)-脂质的序列合成了(EK)-脂质衍生物，并确定了参与细胞结合的序列位点。此外，KK-(EK)-脂质被应用于细胞外囊泡（EVs）和封装 mRNA 的脂质纳米颗粒（mRNA-LNPs）。与未修饰的相比，KK-(EK)-脂质修饰的 EVs 和 mRNA-LNPs 分别显示出更高的细胞结合和体外蛋白表达。我们阐明了 KK-(EK)-脂质在脂质体、EVs 和 mRNA-LNPs 的细胞内递送上具有潜在的应用前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/acb78dec59d2/IDRD_A_2191891_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/eed2b9783301/IDRD_A_2191891_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/4568df6e066d/IDRD_A_2191891_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/15cc054cf5a0/IDRD_A_2191891_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/ab1d5ff65dde/IDRD_A_2191891_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/a3b88c1f4d0f/IDRD_A_2191891_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/3813b5500167/IDRD_A_2191891_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/acb78dec59d2/IDRD_A_2191891_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/eed2b9783301/IDRD_A_2191891_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/4568df6e066d/IDRD_A_2191891_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/15cc054cf5a0/IDRD_A_2191891_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/ab1d5ff65dde/IDRD_A_2191891_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/a3b88c1f4d0f/IDRD_A_2191891_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/3813b5500167/IDRD_A_2191891_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a5f/10044157/acb78dec59d2/IDRD_A_2191891_F0007_B.jpg

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