通过去唾液酸糖蛋白受体（ASGPR）靶向递送阿托伐他汀。
Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR).
机构信息
Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States; Department of Pharmacy, The Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan Eastern Road, Shenyang 110032, China.
Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States; State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
出版信息
Bioorg Med Chem. 2019 Jun 1;27(11):2187-2191. doi: 10.1016/j.bmc.2019.04.019. Epub 2019 Apr 11.
Abstract
Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N-acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface.
摘要
靶向药物递送平台可以增加特定细胞群体中药物的浓度，减少不良反应，从而提高药物的治疗效果。在此，我们通过将靶向配体半乳糖胺（N-乙酰半乳糖胺）连接到阿托伐他汀（AT）上，设计了两种缀合物。与母体药物相比，这两种缀合物，称为 G2-AT 和 G2-K-AT，显示出增加的肝细胞摄取。此外，两种缀合物都能够释放阿托伐他汀，因此显著抑制β-羟-β-甲基戊二酸单酰辅酶 A（HMG-CoA）还原酶，并增加细胞表面的 LDL 受体。
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J Drug Target. 2018 Jun-Jul;26(5-6):466-473. doi: 10.1080/1061186X.2018.1433678. Epub 2018 Feb 8.
2
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Bioconjug Chem. 2017 Aug 16;28(8):2109-2113. doi: 10.1021/acs.bioconjchem.7b00295. Epub 2017 Aug 7.
3
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J Control Release. 2017 Sep 10;261:93-104. doi: 10.1016/j.jconrel.2017.06.023. Epub 2017 Jun 27.
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Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics.N-乙酰半乳糖胺修饰的核酸疗法的临床前和临床进展
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