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Aberrant glycosylation patterns on cancer cells: Therapeutic opportunities for glycodendrimers/metallodendrimers oncology

Advanced Review

René Roy, Serge Mignani, Leila Mousavifar, Tze Chieh Shiao, Serge Moffett

Published Online: Aug 10 2020

DOI: 10.1002/wnan.1659

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Abstract Despite exciting discoveries and progresses in drug design against cancer, its cure is still rather elusive and remains one of the humanities major challenges in health care. The safety profiles of common small molecule anti‐cancer therapeutics are less than at acceptable levels and limiting deleterious side‐effects have to be urgently addressed. This is mainly caused by their incapacity to differentiate healthy cells from cancer cells; hence, the use of high dosage becomes necessary. One possible solution to improve the therapeutic windows of anti‐cancer agents undoubtedly resides in modern nanotechnology. This review presents a discussion concerning multivalent carbohydrate–protein interactions as this topic pertains to the fundamental aspects that lead glycoscientists to tackle glyconanoparticles. The second section describes the detailed properties of cancer cells and how their aberrant glycan surfaces differ from those of healthy cells. The third section briefly describes the immune systems, both innate and adaptative, because the numerous displays of cell surface protein receptors necessitate to be addressed from the multivalent angles, a strength full characteristic of nanoparticles. The next chapter presents recent advances in glyconanotechnologies, including glycodendrimers in particular, as they apply to glycobiology and carbohydrate‐based cancer vaccines. This was followed by an overview of metallodendrimers and how this rapidly evolving field may contribute to our arsenal of therapeutic tools to fight cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Altered glycosylation patterns of O‐linked glycoproteins (mucins) in healthy versus cancer cells

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Octameric TF dendrimer using a novel route for SPPS of glycopeptide dendrimer synthesis involving an interesting N‐alkylcysteine (NAC) assisted thioesterification through a powerful N‐ to S‐ acyl migration following quenching with excess mercaptopropionic acid intermediate

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Heterobifunctional cyclic glycopeptides harboring both the Tn and the TF antigens organized as clusters (left) or in alternative fashion (right) (Pifferi et al., 2017)

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Structure of the MAG‐Tn3 (H‐[S*T*T*‐QYIKANSKFIGITEL]₄‐K)₂‐K‐ßA‐OH fully synthetic anti‐Tn vaccine entering clinical phase I

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Synthesis of dimeric GM2 glycopeptide (Bay et al., 2009)

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Left: Structures of the TF‐L‐lysine dendron with a biotin ending (a) together with its corresponding dendrimeric peptide mimotope (b), the peptide sequence that mimic the TF‐Ag (c) is circled in red. Right: microarray used for the phage display identification of the peptide mimotopes, biotin‐ending TF‐tetrameric dendron was adsorbed onto ELISA plates through streptavidin capture

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Liposomal MUC1 glycopeptide TACA vaccine based on L‐Rhamnoside as selective immune cell targeting using FC‐γ receptors of APCs against naturally circulating anti‐rhamnoside antibodies

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Self‐assembling glycodendrimersomes harboring α‐C‐linked galactopyranosides mounted on a 2,2‐bis(hydroxymethyl)‐propionic acid (bis‐HMPA) scaffold and ending with palmitic acid dimers. The glycolipid hybrid was made to mimic the natural KRN 7000 immunostimulant (Trant et al., 2016)

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Left: Gold‐glyconanoparticles harboring the TF‐antigen. Right: Mannodendrons containing carbohydrate moieties and a pyrene tail were surface‐adsorbed onto the SWCNT surface via π–π interactions

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Lectins of the innate immune system. “The lectins studied comprise several multimodular membrane receptors that contain C‐type carbohydrate‐recognition domains. Soluble lectins include two C‐type lectins of the collectin family (so‐called because they contain a collagenous region), which form different multimeric structures based on similar trimeric units. Other soluble lectins studied are different members of the galectin family, intelectin‐1, and a peptidoglycan recognition protein”

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Classification of (dendritic) glyconanoparticles such as, dendrimers, dendronized polymers, liposomes, fullerenes, nanotubes, and metal nanoparticles

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Example of a glycopeptide sandwiched into an MHC class I protein wherein the carbohydrate moiety is clearly protruding out of the groove and exposed to the solvent for further exposition

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Steps involved in the processing of antigens (TACAs) vaccine and the priming process: Multivalent glyconanoparticles harboring multiple copies of both MHC‐I restricted glycopeptides and universal T helper epitopes, for optimal immune stimulation. (1) Uptake of glyconanoparticles by professional antigen‐presenting cells (pAPCs) by endocytosis in macrophage and dendritic cells, or receptor‐mediated in B cells. (2) Degradation and/or release of glyconanoparticles in endosome or cytosol by proteolysis. Glycopeptides compete with endogenous peptides for loading onto MHC I or II in endosomes. (3) Export of glycopeptide: MHC complexes to the cell surface for display of glycopeptide to T cells in lymphoid nodes. (4) T cells from precursor populations of CD8+ or CD4+ harboring TCRs of relative affinity for glycopeptide: MHC I or II complexes, respectively, dock onto pAPCs and trigger clonal expansion of population. Co‐receptors participate in the activation of T cells. (5) T helper CD4+ cells secrete cytokines for the maturation, expansion, and Ig class switch of B cells into plasma cells secreting antibodies and memory cells, and for CD8+ to become cytotoxic (CTL). (6) Secreted antibodies in circulation opsonize cancer cell targets expressing the antigens, and kill cells by recruiting toxic NK cells and complement or neutralize glycan function. (7) Cancer cells displaying the glycopeptide: MHC I complexes are recognized by the anti‐glycan TCR of CTL and are killed by toxic granules

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Enzymatic machinery and enzymes leading to normal or aberrant glycosylation patterns

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Most common tumor‐associated carbohydrate antigens (TACAs) found on O‐linked glycoproteins of the mucin types and their biosynthetic origins

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Further Reading

Chabre,, Y. M., & Roy,, R. (2008). Recent trends in glycodendrimer syntheses and applications. Current Topics in Medicinal Chemistry, 8, 1237–1285.
Costantino,, P., Rappuoli,, R., & Berti,, F. (2011). The design of semi‐synthetic and synthetic glycoconjugate vaccines. Expert Opinion on Drug Discovery, 6, 1045–1066.
Imberty,, A., Chabre,, Y. M., & Roy,, R. (2008). Glycomimetics and glycodendrimers as high affinity microbial anti‐adhesins. Chemistry—A European Journal, 14, 7490–7499.
Li,, C., Takeo,, M., Matsuda,, M., Nagai,, H., Xizheng,, S., Hatanaka,, W., … Katayama,, Y. (2017). Facilitating the presentation of antigen peptides on dendritic cells for cancer immunotherapy using a polymer‐based synthetic receptor. Medicinal Chemistry Communications, 8, 1207–1212.
Livingston,, P. O., & Ragupathi,, G. (2006). Cancer vaccines targeting carbohydrate antigens. Human Vaccines, 2, 137–143.
Madsen,, C. B., Petersen,, C., Lavrsen,, K., Harndahl,, M., Buus,, S., Clausen,, H., … Wandall,, H. H. (2012). Cancer associated aberrant protein O‐glycosylation can modify antigen processing and immune response. PLoS One, 7, e50139.
Makkouk,, A., & Weiner,, G. J. (2015). Cancer immunotherapy and breaking immune tolerance: New approaches to an old challenge. Cancer Research, 75, 5–10.
Mayer,, A., Zhang,, Y., Perelson,, A. S., & Wingreen,, N. S. (2019). Regulation of T cell expansion by antigen presentation dynamics. Proceedings of the National Academy of Sciences of the United States of America, 116, 5914–5919.
Polonskaya,, Z., Deng,, S., Sarkar,, A., Kain,, L., Comellas‐Aragones,, M., Mckay,, C. S., … Teyton,, L. (2017). T cells control the generation of nanomolar affinity anti‐glycan antibodies. Journal of Clinical Investigation, 127, 1491–1504.
Ryan,, S. O., Turner,, M. S., Gariépy,, J., & Finn,, O. J. (2010). Tumor antigen epitopes interpreted by the immune system as self abnormal‐self differentially affect cancer vaccine responses. Cancer Research, 70, 5788–5796.
Wei,, M.‐M., Wang,, Y.‐S., & Ye,, X.‐S. (2018). Carbohydrate‐based vaccines for oncotherapy. Medicine Research Review, 38, 1003–1026.
Werdelin,, O., Meldal,, M., & Jensen,, T. (2002). Processing of glycans on glycoprotein and glycopeptide antigens in antigen‐presenting cells. Proceedings of the National Academy of Sciences of the United States of America, 99, 9611–9613.

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