Exploring Receptor Binding Affinities and Hepatic Cell Association of N-Acetyl-d-Galactosamine-Modified β-Cyclodextrin-Based Polyrotaxanes for Liver-Targeted Therapies

去唾液酸糖蛋白受体 生物化学 内吞作用 化学 细胞内 内体 重组DNA 受体 生物 肝细胞 体外 基因
作者
Moe Ohashi,Atsushi Tamura,Nobuhiko Yui
出处
期刊:Biomacromolecules [American Chemical Society]
卷期号:24 (5): 2327-2341 被引量:4
标识
DOI:10.1021/acs.biomac.3c00194
摘要

Acid-degradable polyrotaxanes (PRXs) containing threading β-cyclodextrins (β-CDs) are promising candidates for therapeutic applications of β-CDs in metabolic diseases with cholesterol overload or imbalance. To improve cellular uptake specificity and efficiency of PRXs in hepatocytes, N-acetyl-d-galactosamine (GalNAc)-modified PRXs were developed to facilitate asialoglycoprotein receptor (ASGR)-mediated endocytosis. Binding affinity studies revealed that the dissociation constant (KD) values between recombinant ASGR and GalNAc-PRXs decreased with an increase in the number of modified GalNAc units. Additionally, the KD values for GalNAc-PRXs were smaller than those for GalNAc-modified β-CD and amylose, suggesting that the PRX backbone structure improves the binding affinity with ASGR. However, the intracellular uptake levels of GalNAc-PRXs in HepG2 cells increased with a decrease in the number of modified GalNAc units, which was opposite to the trend observed in the binding affinity study. We found that GalNAc-PRXs had a large number of GalNAc units localized in recycling endosomes, resulting in the low intracellular uptake. The cholesterol-reducing abilities of GalNAc-PRXs were assessed using cholesterol-overloaded HepG2 cells. GalNAc-PRXs with a small number of GalNAc units were demonstrated to show superior cholesterol-reducing effects compared to previously designed acid-degradable PRX and clinically tested β-CD derivatives. Thus, we conclude that GalNAc modification is a promising molecular design for the therapeutic application of β-CD-threaded PRXs in various metabolic diseases with cholesterol overload or imbalance in the liver.
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