利用 Fc 区介导的抗体修饰合成新型适配脂质,用于插入后制备转铁蛋白受体靶向信使 RNA 脂质纳米颗粒。

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutics and Biopharmaceutics Pub Date : 2024-08-22 DOI:10.1016/j.ejpb.2024.114468
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引用次数: 0

摘要

脂质纳米颗粒(LNPs)是一种前景广阔的递送系统,能够将小干扰 RNA(siRNA)和信使 RNA(mRNA)递送到患病组织和细胞内的作用位点。然而,通过全身给药将其递送至非肝脏组织仍具有挑战性。对 LNPs 进行抗体修饰是提高其对靶组织选择性的一种可行方法。传统的抗体修饰方法是通过硫醇-马来酰亚胺连接,但由于抗体在 LNPs 表面的取向不同,会降低对疾病相关靶分子的识别效率。在这项研究中,我们开发了一种新型适配脂肽,用于通过 Fc 区域对 LNPs 进行抗体修饰。我们选择了抗转铁蛋白受体抗体 RI7-217 作为配体。通过对间隔肽的优化,我们发现一种 FcBP-EKGG 脂质具有高水分散性,可用于后插入 LNPs 的方法。我们用 FcBP-EKGG 脂质修饰 LNPs 并混合抗体,制备了 RI7-217 修饰的 LNPs。我们发现,针对表达转铁蛋白受体的 U-87 MG 细胞,RI7-217 修饰的 LNPs 以抗体特异性的方式显著增强了荧光素酶蛋白的表达。这些信息对于开发用于细胞选择性靶向的抗体修饰 LNPs 很有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Synthesis of a novel adapter lipid using Fc-region mediated antibody modification for post-insert preparation of transferrin receptor targeted messenger RNA-loaded lipid nanoparticles

Lipid nanoparticles (LNPs) are promising delivery systems with the ability to deliver small interfering RNA (siRNA) and messenger RNA (mRNA) in diseased tissues and intracellular sites of action. However, delivery to non-hepatic tissues via systemic administration remains challenging. Antibody modification of LNPs is a hopeful approach for improving their selectivity to target tissues. The conventional method of antibody modification via thiol–maleimide linkage is concerned with reduced recognition efficiency of the disease-related target molecules owing to variations in antibody orientation on the surface of the LNPs. In this study, we developed a novel adapter lipopeptide for antibody modification of LNPs via the Fc-region. Here, we selected RI7-217, an anti-transferrin receptor antibody, as the ligand. Through optimization of spacer peptides, we found a FcBP-EKGG-lipid exhibits high water-dispersibility for post-insertion method to LNPs. We prepared RI7-217-modified LNPs by modifying LNPs with FcBP-EKGG-lipids and mixing the antibodies. We found that the luciferase protein expression of RI7-217-modified LNPs was significantly enhanced in an antibody-specific manner against transferrin receptor-expressing U-87 MG cells. This information would be valuable in the development of antibody-modified LNPs for cell-selective targeting.

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来源期刊
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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