Key biochemical processes in living organisms, among others, receptor-antibody interactions, functions of enzymes, biomembranes, and transport systems, are mediated by selective carbohydrate-protein interactions enabling mutual recognition at the molecular level. When carbohydrate ligands are presented on a multivalent carrier, the resulting binding affinity may not be a mere sum of the single carbohydrate unit interactions, but it can be significantly amplified as a result of the so-called multivalent effect.
The biomedical use of multivalent carriers based on carbosilane glycodendrimers was investigated by Dr. Strašák’s research group in collaboration with Centro de Química da Madeira, Universidade da Madeira (Portugal), Faculty of Science at University of J. E. Purkynje in Ústí nad Labem and the Institute of Organic Chemistry and Biochemistry of the CAS in Prague, and the results were recently published in Biomacromolecules. The study presents a robust synthetic method for the preparation of carbosilane dendritic structures enabling multivalent presentation of sugar ligands and other biochemically relevant compounds. Regardless of series or generation, the dendrimers peripherally decorated with glucose and galactose derivatives exhibited outstanding biocompatibility with all tested cell lines indicating their potential as nanocarriers in drug delivery. These findings led to the preparation of stable glycodendrimer complexes with doxorubicin (glyco-DDM/DOX), a highly toxic substance with potent anticancer activity. In vitro cytotoxicity assay of the glyco-DDM/DOX complexes revealed generation and concentration-dependent effects across the tested cell lines, but most importantly, their general selectivity toward cancer cell lines. Moreover, glyco-DDM/DOX complexes were much less internalized in noncancerous cells compared to cancer cell lines. Higher IC50 values of the majority of the complexes compared to pure doxorubicin showed that the peripheral saccharide units substantially decreased the cytotoxicity of the glyco-DDM/DOX complexes. Thus, for the benefit of cancer therapy, a higher dose of doxorubicin can be introduced using the glyco-DDM nanocarriers, whereas slower drug release stabilizes the concentration of the therapeutic agent in cancer cells. In addition, the doxorubicin release was up to 2−3 times faster in acidic environments than under physiological conditions, indicating preferential drug release in the vicinity of tumor tissues.
- Müllerová, M.; Maciel, D.; Nunes, N.; Wrobel, D.; Stofik, M.; Červenková Šťastná, L.; Krupková, A.; Cuřínová, P.; Nováková, K.; Božík, M.; Malý, M.; Malý, J.; Rodrigues, J.; Strašák, T.: Carbosilane Glycodendrimers for Anticancer Drug Delivery: Synthetic Route, Characterization, and Biological Effect of Glycodendrimer–Doxorubicin Complexes. Biomacromolecules 2022, 23(1), 276-290. DOI: https://doi.org/10.1021/acs.biomac.1c01264