Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR)

Youxi Zhang; Xinfu Zhang; Chunxi Zeng; Bin Li; Chengxiang Zhang; Wenqing Li; Xucheng Hou; Yizhou Dong

doi:10.1016/j.bmc.2019.04.019

Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR)

Bioorg Med Chem. 2019 Jun 1;27(11):2187-2191. doi: 10.1016/j.bmc.2019.04.019. Epub 2019 Apr 11.

Authors

Youxi Zhang¹, Xinfu Zhang², Chunxi Zeng³, Bin Li³, Chengxiang Zhang³, Wenqing Li³, Xucheng Hou³, Yizhou Dong⁴

Affiliations

¹ 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.
² 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.
³ Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
⁴ Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States; Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, United States; The Center for Clinical and Translational Science, The Ohio State University, Columbus, OH 43210, United States; The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States; Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, United States. Electronic address: dong.525@osu.edu.

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.

Keywords: Asialoglycoprotein receptor; Atorvastatin; Ligand conjugates; N-Acetylgalactosamine; Targeted delivery.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylgalactosamine / analogs & derivatives*
Acetylgalactosamine / metabolism
Acetylgalactosamine / pharmacology*
Animals
Asialoglycoprotein Receptor / metabolism*
Atorvastatin / chemical synthesis
Atorvastatin / metabolism
Atorvastatin / pharmacology*
Cell Line, Tumor
Hepatocytes / metabolism
Humans
Hydroxymethylglutaryl CoA Reductases / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis
Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Ligands
Receptors, LDL / metabolism
Swine

Substances

Asialoglycoprotein Receptor
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Ligands
Receptors, LDL
Atorvastatin
Hydroxymethylglutaryl CoA Reductases
Acetylgalactosamine

Grants and funding

R35 GM119679/GM/NIGMS NIH HHS/United States