聚乙二醇化增强肝癌细胞靶向脂质体介导的体外基因传递通过asialalglyprotein受体

N. K. Mkhwanazi, C. D. de Koning, W. V. van Otterlo, M. Ariatti, Moganavelli Singh
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引用次数: 3

摘要

肝细胞癌是撒哈拉以南非洲和东亚地区一个新兴的健康问题,在那里它是最普遍的。对这种疾病的基因药物治疗方式的研究代表了对当前治疗方案的一种新颖的背离,并且正在获得动力。在这里,我们报道了非聚乙二醇化和空间稳定的聚乙二醇化阳离子脂质体,这些脂质体由连接24.1 Å间隔物的d -半乳糖修饰,用于asialglycoprotein receptor (ASGP-R)靶向pCMV-luc质粒DNA的载体化。货物DNA是完全脂质体,N/P比=3:1,部分保护不受血清核酸酶的影响。此外,在这个比例下,脂质体尺寸(89-97 nm)符合体内外渗的要求。乙啶置换试验表明,报告DNA在与聚乙二醇化脂质体结合时比与非聚乙二醇化脂质体结合时处于更少的凝聚状态。聚乙二醇化脂质体对HEK293 (ASGP-R阴性)和HepG2 (ASGP-R阳性)细胞系均具有良好的耐受性,并通过ASGP-R介导向人肝癌细胞系HepG2传递DNA,其水平比非聚乙二醇化脂质体高3倍。本研究报道的聚乙二醇化asgp - r靶向脂质体具有致肝基因传递所需的特性,可以考虑进一步在体内应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PEGylation potentiates hepatoma cell targeted liposome-mediated in vitro gene delivery via the asialoglycoprotein receptor
Abstract Hepatocellular carcinoma is a burgeoning health issue in sub-Saharan Africa and East Asia where it is most prevalent. The search for gene medicine treatment modalities for this condition represents a novel departure from current treatment options and is gaining momentum. Here we report on nonPEGylated and on sterically stabilized PEGylated cationic liposomes decorated with D-galacto moieties linked to 24.1 Å spacers for asialoglycoprotein receptor (ASGP-R)-targeted vehiculation of pCMV-luc plasmid DNA. Cargo DNA is fully liposome associated at N/P ratio=3:1 and is partially protected from the effects of serum nucleases. Moreover, at this ratio, lipoplex dimensions (89–97 nm) are compatible with the requirements for extravasation in vivo. Ethidium displacement assays show that the reporter DNA is in a less condensed state when bound to PEGylated liposomes than with nonPEGylated liposomes. PEGylated lipoplexes were well tolerated by both HEK293 (ASGP-R-negative) and HepG2 (ASGP-R-positive) cell lines and delivered DNA to the human hepatoma cell line HepG2 by ASGP-R mediation at levels three-fold greater than nonPEGylated lipoplexes. PEGylated ASGP-R-targeted liposomes reported in this study possess the required characteristics for hepatotropic gene delivery and may be considered for further application in vivo.
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