Back to Search
Start Over
Exploring Receptor Binding Affinities and Hepatic Cell Association of N -Acetyl-d-Galactosamine-Modified β-Cyclodextrin-Based Polyrotaxanes for Liver-Targeted Therapies.
- Source :
-
Biomacromolecules [Biomacromolecules] 2023 May 08; Vol. 24 (5), pp. 2327-2341. Date of Electronic Publication: 2023 Apr 10. - Publication Year :
- 2023
-
Abstract
- 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 ( K <subscript>D</subscript> ) values between recombinant ASGR and GalNAc-PRXs decreased with an increase in the number of modified GalNAc units. Additionally, the K <subscript>D</subscript> 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.
Details
- Language :
- English
- ISSN :
- 1526-4602
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biomacromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 37036902
- Full Text :
- https://doi.org/10.1021/acs.biomac.3c00194