Targeting galectin-4 with glycoconjugates of varying architectures: a multivalency étude with accent on anti-tumor effect and protection against apoptosis

Abstract

Galectin-4 (Gal-4) is a protumorigenic protein that strongly participates especially in gastrointestinal cancer and is increasingly recognized as a therapeutic target in gastrointestinal malignancies, where its dysregulated expression contributes to tumor progression and immune modulation. Its abundance and the extent of its involvement in these pathologies are comparable with its much better-studied counterparts, galectin-1 and -3. However, to date, no systematic effort has been made to design efficient defined Gal-4 inhibitors with a potential therapeutic effect. In this work, we present a library of biocompatible multivalent Gal-4 inhibitors with diverse architectures to investigate how different modes of multivalent presentation of a common ligand, lactose, influence the binding affinity to Gal-4. The most efficient scaffold was then loaded with a high-affinity tetrasaccharide ligand of Gal-4, derived from lacto-N-tetraose, to further enhance Gal-4 binding. The resulting glycopolymer exhibited outstanding performance in inhibiting Gal-4-induced apoptosis of T lymphocytes, and, in addition, it efficiently scavenged Gal-4 from the surface of cancer cells. Both of these processes are relevant for tumor immune evasion. Given the high biocompatibility, and low toxicity of the POx carrier, this glycopolymer has a strong potential as a candidate for further development of glycotherapeutics against Gal-4-associated diseases such as gastrointestinal cancer.