The development of efficient galectin-3 (Gal-3) inhibitors draws attention in the field of anti-cancer therapy, especially due to the prominent role of extra- and intracellular Gal-3 in vital processes of cancerogenesis, such as immunosuppression, stimulation of tumor cells proliferation, survival, invasion, apoptotic resistance, and metastasis formation and progression. Here, by combining poly-LacNAc (Galβ4GlcNAc)-derived oligosaccharides with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, we synthesized multivalent glycopolymer inhibitors with a high potential to target extracellular and intracellular Gal-3. The inhibitory capabilities of the best conjugate in the studied series were in the nanomolar range proving the excellent Gal-3 inhibitory potential. Moreover, thorough investigation of the inhibitory effect in the biological conditions showed that the glycopolymers strongly inhibited Gal-3-induced apoptosis of T lymphocytes and suppressed migration and spreading of colorectal, breast, melanoma, and prostate cancer cells. In sum, the strong inhibitory activity toward Gal-3, combined with favorable pharmacokinetics of HPMA copolymers ensuring enhanced tumor accumulation via the enhanced permeability and retention effect, nominate the glycopolymers containing LacdiNAc-LacNAc (GalNAcβ4GlcNAcβ3Galβ4GlcNAc) tetrasaccharide as promising tools for preclinical in anti-cancer therapy evaluation.

Department of Health Care Disciplines and Population Protection Faculty of Biomedical Engineering Czech Technical University Prague Sítná Sq 3105 CZ 27201 Kladno Czech Republic

Institute of Biotechnology and Helmholtz Institute for Biomedical Engineering RWTH Aachen Pauwelstr 20 D 52079 Aachen Germany

Institute of Macromolecular Chemistry of the Czech Academy of Sciences Heyrovského nám 2 CZ 16206 Prague 6 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 14220 Prague 4 Czech Republic

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