Glycopolymers for efficient inhibition of galectin-3: in vitro proof of efficacy using suppression of T lymphocyte apoptosis and tumor cell migration

0531504 - ÚMCH 2021 RIV US eng J - Journal Article
Filipová, Marcela - Bojarová, Pavla - Tavares, Marina Rodrigues - Bumba, Ladislav - Elling, L. - Chytil, Petr - Gunár, Kristýna - Křen, Vladimír - Etrych, Tomáš - Janoušková, Olga
Glycopolymers for efficient inhibition of galectin-3: in vitro proof of efficacy using suppression of T lymphocyte apoptosis and tumor cell migration.
Biomacromolecules. Roč. 21, č. 8 (2020), s. 3122-3133. ISSN 1525-7797. E-ISSN 1526-4602
R&D Projects: GA MŠMT(CZ) LQ1604; GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA17-13283S; GA ČR(CZ) GA19-01417S; GA MŠMT(CZ) LTAUSA18083; GA MŠMT(CZ) LTC17005; GA MŠMT(CZ) LTC19038; GA MŠMT(CZ) LM2018133
Institutional support: RVO:61389013 ; RVO:61388971
Keywords : apoptosis * cancer cell migration * carbohydrate
OECD category: Polymer science; Polymer science (MBU-M)
Impact factor: 6.988, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.biomac.0c00515

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.
Permanent Link: http://hdl.handle.net/11104/0310682