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

[Display omitted] •We have developed a novel multivalent ligand delivery system for SN38, with 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.•Our multivalent ligand delivery systems demonstrated improved anti-proliferation activity, addressing the existing problems associated with the low receptor affinity and rapid metabolism of SMDCs. 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.