Design and synthesis of multivalent drug delivery system with CA IX inhibitors as ligands

Mengyuan Ding; Qiwen Zhu; Wei Lu; Shulei Zhu

doi:10.1016/j.bmc.2023.117456

Design and synthesis of multivalent drug delivery system with CA IX inhibitors as ligands

Bioorg Med Chem. 2023 Oct 1:93:117456. doi: 10.1016/j.bmc.2023.117456. Epub 2023 Aug 23.

Authors

Mengyuan Ding¹, Qiwen Zhu¹, Wei Lu², Shulei Zhu³

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: slzhu@chem.ecnu.edu.cn.

PMID: 37678058
DOI: 10.1016/j.bmc.2023.117456

Abstract

A multivalent ligand delivery system holds tremendous potential in the field of tumor-targeted drug delivery. It addresses the challenges posed by the low affinity between small molecule ligand receptors and the rapid metabolism of small molecule drug conjugates (SMDCs) in vivo. Notably, existing multivalent ligand systems have demonstrated significant anti-tumor activity in various tumor models. In this study, we have developed a novel multivalent ligand delivery system for SN38, utilizing acetazolamide, a carbonic anhydrase IX (CA IX) inhibitor, as the target ligand. Our multivalent ligand delivery systems exhibited superior metabolic stability and enhanced targeting specificity compared to SMDC molecules. Furthermore, they demonstrated improved anti-proliferation activity, addressing the existing challenges associated with the low receptor affinity and rapid metabolism of SMDCs.

Keywords: CA IX; Hypoxic; Metabolic stability; Multivalent ligand; Targeting specificity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetazolamide*
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors* / pharmacology
Drug Delivery Systems
Ligands

Substances

Carbonic Anhydrase Inhibitors
Ligands
Carbonic Anhydrase IX
Acetazolamide