Abstract

Liver is the main organ for metabolism but is also subject to various pathologies, from viral, genetic, cancer or metabolic origin. There is thus a crucial need to develop efficient liver-targeted drug delivery strategies. Asialoglycoprotein receptor (ASGPR) is a C-type lectin expressed in the hepatocyte plasma membrane that efficiently endocytoses glycoproteins exposing galactose (Gal) or N-acetylgalactosamine (GalNAc). Its targeting has been successfully used to drive the uptake of small molecules decorated with three or four GalNAc, thanks to an optimisation of their spatial arrangement. Herein, we assessed the biological properties of highly stable nanostructured lipid carriers (NLC) made of FDA-approved ingredients and formulated with increasing amounts of GalNAc. Cellular studies showed that a high density of GalNAc was required to favour hepatocyte internalisation via the ASGPR pathway. Interaction studies using surface plasmon resonance and the macrophage galactose-lectin as GalNAc-recognising lectin confirmed the need of high GalNAc density for specific recognition of these NLC. This work is the first step for the development of efficient nanocarriers for prolonged liver delivery of active compounds.

摘要

肝脏是新陈代谢的主要器官，但也受到各种病理的影响，从病毒、遗传、癌症或代谢起源。因此，迫切需要开发有效的肝脏靶向药物递送策略。去唾液酸糖蛋白受体 (ASGPR) 是一种在肝细胞质膜中表达的 C 型凝集素，可有效内吞暴露半乳糖 (Gal) 或 N-乙酰半乳糖胺 (GalNAc) 的糖蛋白。由于空间排列的优化，其靶向已成功用于驱动装饰有三个或四个 GalNAc 的小分子的摄取。在此，我们评估了由 FDA 批准的成分制成并用越来越多的 GalNAc 配制的高度稳定的纳米结构脂质载体 (NLC) 的生物学特性。细胞研究表明，需要高密度的 GalNAc 才能通过 ASGPR 途径促进肝细胞内化。使用表面等离子体共振和巨噬细胞半乳糖-凝集素作为 GalNAc 识别凝集素的相互作用研究证实需要高 GalNAc 密度来特异性识别这些 NLC。这项工作是开发有效纳米载体以延长肝脏递送活性化合物的第一步。