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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
呼呼啦呼啦完成签到,获得积分10
1秒前
1秒前
Jasper应助sylnd126采纳,获得10
1秒前
哈哈发布了新的文献求助20
3秒前
Anita完成签到,获得积分10
3秒前
所所应助和谐一万采纳,获得10
4秒前
高有财完成签到 ,获得积分10
4秒前
4秒前
闪闪自中完成签到,获得积分10
5秒前
7秒前
jjym完成签到,获得积分10
8秒前
图南完成签到 ,获得积分10
8秒前
酷小裤完成签到,获得积分10
8秒前
9秒前
10秒前
项初蝶发布了新的文献求助10
10秒前
独特凡松发布了新的文献求助10
10秒前
10秒前
科研通AI5应助Luminous采纳,获得10
11秒前
傅寻菱完成签到,获得积分10
12秒前
方格发布了新的文献求助10
14秒前
14秒前
量子星尘发布了新的文献求助10
14秒前
14秒前
15秒前
16秒前
风清扬发布了新的文献求助10
16秒前
会发光的碳完成签到 ,获得积分10
16秒前
17秒前
17秒前
bkagyin应助斜玉采纳,获得10
17秒前
cookie发布了新的文献求助10
18秒前
笨小孩发布了新的文献求助200
18秒前
星辰大海应助苗条遥采纳,获得10
19秒前
赘婿应助kangkang采纳,获得10
19秒前
20秒前
冥月发布了新的文献求助10
21秒前
GGBOND完成签到,获得积分10
21秒前
是莉莉娅发布了新的文献求助10
22秒前
汉堡包应助哈哈哈大赞采纳,获得10
23秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988732
求助须知:如何正确求助?哪些是违规求助? 3531027
关于积分的说明 11252281
捐赠科研通 3269732
什么是DOI,文献DOI怎么找? 1804764
邀请新用户注册赠送积分活动 881869
科研通“疑难数据库(出版商)”最低求助积分说明 809021