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

Advanced Review

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

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

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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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References

Abdel‐Motal,, U. M., Berg,, L., Rosén,, A., Bengtsson,, M., Thorpe,, C. J., Kihlberg,, J., … Jondal,, M. (1996). Immunization with glycosylated K^b‐binding peptides generates carbohydrate‐specific, understricted cytotoxic T cells. European Journal of Immunology, 26, 544–551.
Adak,, A.K., Li,, B.‐Y., &. C.‐C. Lin,. (2015). Advances in multifunctional glycosylated nanomaterials: Preparation and applications in glycoscience. Carbohydrate Research, 405, 2–12.
Ahamad,, T., Mapolie,, S. F., & Alshehri,, S. M. (2012). Synthesis and characterization of polyamide metallodendrimers and their anti‐bacterial and anti‐tumor activities. Medicinal Chemistry Research, 21, 2023–2031.
Appelhans,, D., Klajnert‐Maculewicz,, B., Janaszewska,, A., Lazniewskab,, J., & Voit,, B. (2015). Dendritic glycopolymers based on dendritic polyamine scaffolds: View on their synthetic approaches, characteristics and potential for biomedical applications. Chemical Society Reviews, 44, 3968–3996.
Astronomo,, R. D., & Burton,, D. R. (2010). Carbohydrate vaccines: Developing sweet solutions to sticky situations? Nature Reviews Drug Discovery, 9, 308–324.
Baartzes,, N., Stringer,, T., Seldon,, R., Warner,, D. F., de Kock,, C., Smith,, P. J., & Smith,, G. S. (2016). Synthesis, characterization and antimicrobial evaluation of mono and polynuclear ferrocenyl‐derived amino and imino complexes. Journal of Organometallic Chemistry, 809, 79–85.
Baartzes,, N., Szabo,, C., Cenariu,, M., Imre‐Lucaci,, F., Dorneanu,, S. A., Fischer‐Fodor,, E., & Smith,, G. S. (2018). In vitro antitumour activity of two ferrocenyl metallodendrimers in a colon cancer cell line. International Chemical Communication, 98, 75–79.
Baek,, M.‐G., Rittenhouse‐Olson,, K., & Roy,, R. (2001). Synthesis and antibody binding properties of glycodendrimers bearing the tumor related T‐antigen. Chemical Communications, 32, 257–258.
Baek,, M.‐G., & Roy,, R. (2000). Design and synthesis of water‐soluble glycopolymers bearing breast tumor marker and enhanced lipophilicity for solid‐phase assays. Biomacromolecules, 1, 768–770.
Baek,, M.‐G., & Roy,, R. (2001a). Relative lectin binding properties of T‐antigen‐containing glycopolymers: Copolymerization of N‐acryloylated T‐antigen monomer vs. graft conjugation of aminated T‐antigen ligands onto poly(N‐acryloxysuccinimide). Macromolecular Bioscience, 1, 305–311.
Baek,, M.‐G., & Roy,, R. (2001b). Simultaneous binding of mouse monoclonal antibody and streptavidin to hetero‐bifunctional dendritic L‐lysine core bearing T‐antigen tumor marker and biotin. Bioorganic %26 Medicinal Chemistry, 9, 3005–3011.
Baek,, M.‐G., & Roy,, R. (2002a). Glycodendrimers: Novel glycotope isosteres unmasking sugar coding. Case study with T‐antigen markers from breast cancer MUC1 glycoprotein. Reviews in Molecular Biotechnology, 90, 291–309.
Baek,, M.‐G., & Roy,, R. (2002b). Synthesis and protein binding properties of T‐antigen containing glycoPAMAM dendrimers. Bioorganic %26 Medicinal Chemistry, 10, 11–17.
Ballut,, S., Naud‐Martin,, D., Loock,, B., & Maillard,, P. (2011). A strategy for the targeting of photosensitizers. Synthesis, characterization, and photobiological property of porphyrins bearing glycodendrimeric moieties. Journal of Organic Chemistry, 76, 2010–2028.
Bandaru,, N. M., & Hans Voelcker,, N. (2012). Glycoconjugate‐functionalized carbon nanotubes in biomedicine. Journal of Materials Chemistry, 22, 8748–8758.
Banday,, A. H., Jeelani,, S., & Hruby,, V. J. (2014). Cancer vaccine adjuvants‐recent clinical progress and future perspectives. Immunopharmacology and Immunotoxicology, 37, 1–11.
Bay,, S., Fort,, S., Birikaki,, L., Ganneau,, C., Samain,, E., Coïc,, Y.‐M., … Lo‐Man,, R. (2009). Induction of a melanoma‐specific antibody response by a monovalent, but not a divalent, synthetic GM2 neoglycopeptide. ChemMedChem, 4, 582–587.
Bernardi,, A., Jiménez‐Barbero,, J., Casnati,, A., De Castro,, C., Darbre,, T., Fieschi,, F., … Imberty,, A. (2013). Multivalent glycoconjugates as anti‐pathogenic agents. Chemical Society Reviews, 42, 4709–4727.
Bhardwaj,, N. (2007). Harnessing the immune system to treat cancer. Journal of Clinical Investigation, 117, 1130–1136.
Biswas,, S., Medina,, S. H., & Barchi,, J. J., Jr. (2015). Synthesis and cell‐selective antitumor properties of amino acid conjugated tumor‐associated carbohydrate antigen‐coated gold nanoparticles. Carbohydrate Research, 405, 93–101.
Bobisse,, S., Foukas,, P. G., Coukos,, G., & Harari,, A. (2016). Neoantigen‐based cancer immunotherapy. Annals of Translational Medicine, 4, 262–271.
Bojarová,, P., Rosencrantz,, R. R., Elling,, L., & Křen,, V. (2013). Enzymatic glycosylation of multivalent scaffolds. Chemical Society Reviews, 2013(42), 4774–4797.
Brennick,, C. A., George,, M. M., Corwin,, W. L., Srivastava,, P. K., & Ebrahimi‐Nik,, H. (2017). Neoepitopes as cancer immunotherapy targets: Key challenges and opportunities. Immunotherapy, 9, 361–371.
Brinãs,, R. P., Sundgren,, A., Sahoo,, P., Morey,, S., Rittenhouse‐Olson,, K., Wilding,, G. E., … Barchi,, J. J., Jr. (2012). Design and synthesis of multifunctional gold nanoparticles bearing tumor‐associated glycopeptide antigens as potential cancer vaccines. Bioconjugate Chemistry, 23, 1513–1523.
Caminade,, A.‐M., Turrin,, C.‐O., & Majoral,, J.‐P. (2018). Phosphorus dendrimers in biology and nanomedicine [Chapter 9]. Singapore: Pan Stanford Publishing.
Campanero‐Rhodes,, M. A., Sa Palma,, A., Menéndez,, M., & Solís,, D. (2020). Microarray strategies for exploring bacterial surface glycans and their interactions with glycan‐binding proteins. Frontiers in Microbiology, 10, 2909.
Carloni,, R., del Olmo,, N. S., Ortega,, P., Fattori,, A., Gómez,, R., Ottaviani,, M. F., … de la Mata,, F. J. (2019). Exploring the interactions of ruthenium (II) Carbosilane metallodendrimers and precursors with model cell membranes through a dual spin‐label spin‐probe Tectnique using EPR. Biomolecules, 9, 540. https://doi.org/10.3390/biom9100540
Cazet,, A., Julien,, S., Bobowski,, M., Burchell,, J., & Delannoy,, P. (2010). Tumour‐associated carbohydrate antigens in breast cancer. Breast Cancer Research, 12, 2041–2013.
Cazet,, A., Julien,, S., Bobowski,, M., Krzewinski‐Recchi,, M.‐A., Harduin‐Lepers,, A., Groux‐Degroote,, S., & Delannoy,, P. (2010). Consequences of the expression of sialylated antigens in breast cancer. Carbohydrate Research, 345, 1377–1383.
Chabre,, Y. M., & Roy,, R. (2010). Design and creativity in multivalent neoglycoconjugate synthesis. Advances in Carbohydrate Chemistry and Biochemistry, 63, 165–393.
Chabre,, Y. M., & Roy,, R. (2013). Multivalent glycoconjugate syntheses and applications using aromatic scaffolds. Chemical Society Reviews, 42, 4657–4708.
Chen,, X., & Jensen,, P. E. (2008). The role of B lymphocytes as antigen‐presenting cells. Archivum Immunologiae et Therapiae Experimentalis, 56, 77–83.
Cheng,, Y., Zhao,, L., Li,, Y., & Xu,, T. (2011). Design of biocompatible dendrimers for cancer diagnosis and therapy: Current status and future perspectives. Chemical Society Reviews, 40, 2673–2703.
Corthay,, A., Bäcklund,, J., Broddefalk,, J., Michaëlsoon,, E., Goldschmidt,, T. J., Kihlberg,, J., & Holmdahl,, R. (1998). Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen‐induced arthritis. European Journal of Immunology, 28, 2580–2590.
Dag,, A., Omurtag Ozgen,, P. S., & Atasoy,, S. (2019). Glyconanoparticles for targeted tumor therapy of platinum anticancer drug. Biomacromolecules, 20(8), 2962–2972.
Dam,, T. K., Gerken,, T. A., & Brewer,, C. F. (2002). Thermodynamics of multivalent carbohydrate‐lectin cross‐linking interactions: Importance of entropy in the bind and jump mechanism. Biochemistry, 41, 1359–1363.
DeFranco,, A. L. (1997). The complexity of signaling pathways activated by the BCR. Current Opinion in Immunology, 9, 296–308.
Dengjel,, J., & Stevanović,, S. (2006). Naturally presented MHC ligands carrying glycans. Transfusion Medicine and Hemotherapy, 33, 38–44.
Donavan,, R., S., Datti,, A., Baek,, M.‐G., Wu,, Q., Sas,, I. J., Korczak,, B., Berger,, E. G., Roy,, R., Dennis,, J. W. (1992). A solid‐phase glycosyltransferase assay for high‐throughput screening in drug discovery research. Glycoconjugate Journal, 16, 607–615.
Dudler,, T., Altmann,, F., Carballido,, J. M., & Blaser,, K. (1995). Carbohydrate‐dependent, HLA class II‐restricted, human T cell response to the bee venom allergen phospholipase A2 in allergic patients. European Journal of Immunology, 25, 538–542.
Dunn,, G. P., Old,, L. J., & Schreiber,, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 2, 137–148.
Dzhambazov,, B., Holmdahl,, M., Yamada,, H., Lu,, S., Vestberg,, M., Holm,, B., … Holmddah,, R. (2005). The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans. European Journal of Immunology, 35, 357–366.
El Kazzouli,, S., El Brahmi,, N., Mignani,, S., Bousmina,, M., Zablocka,, M., & Majoral,, J.‐P. (2012). From metallodrugs to metallodendrimers for nanotherapy in oncology: A concise overview. Current Medicinal Chemistry, 19, 4995–5010.
Embgenbroich,, M., & Burgdorf,, S. (2018). Current concepts of antigen cross‐presentation. Frontiers in Immunology, 9, 1643–1653.
Finn,, O. J. (2003). Cancer vaccines: Between the idea and the reality. Nature Reviews. Immunology, 3, 630–641.
Finn,, O. J., & Beatty,, P. L. (2016). Cancer immunoprevention. Current Opinion in Immunology, 39, 52–58.
Finn,, O. J., & Lohmueller,, J. (2017). Current modalities in cancer immunotherapy: Immunomodulatory antibodies, CARs and vaccines. Pharmacology Therapy, 178, 31–47.
Franco,, A. (2005). CTL‐based cancer preventive/therapeutic vaccines for carcinomas: Role of tumour‐associated carbohydrate antigens. Immunology, 61, 391–397.
Gaidzik,, N., Westerlind,, U., & Kunz,, H. (2013). The development of synthetic antitumour vaccines from mucin glycopeptide antigens. Chemical Society Reviews, 42, 4421–4442.
Galan,, M. C., Dumy,, P., & Renaudet,, O. (2013). Multivalent glyco(cyclo)peptides. Chemical Society Reviews, 42, 4599–4612.
Galili,, U. (2005). The alpha‐gal epitope and the anti‐gal antibody in xenotransplantation and in cancer immunotherapy. Immunology and Cell Biology, 83, 674–686.
Ganneau,, C., Simenel,, C., Emptas,, E., Courtiol,, T., Coïc,, Y.‐M., Artaud,, C., … Bay,, S. (2017). Large‐scale synthesis and structural analysis of a synthetic glycopeptide dendrimer as an anti‐cancer vaccine candidate. Organic %26 Biomolecular Chemistry, 15, 114–123.
Glinskii,, O. V., Sud,, S., Mossine,, V. V., Mawhinney,, T. P., Anthony,, D. C., Glinsky,, G. V., … Glinsky,, V. V. (2012). Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin‐3 inhibitor lactulose‐L‐leucine. Neoplasia, 14, 65–73.
Glinsky,, G. V., Mossine,, V. V., Price,, J. E., Bielenberg,, D., Glinsky,, V. V., Ananthaswamy,, H. N., & Feather,, M. S. (1996). Inhibition of colony formation in agarose of metastatic human breast carcinoma and melanoma cells by synthetic glycoamine analogs. Clinical %26 Experimental Metastasis, 14, 253–267.
Glithero,, A., Tormo,, J., Haurum,, J. S., Arsequell,, G., Valencia,, G., Edwards,, J., … Elliott,, T. (1999). Crystal structures of two H‐2Db/glycopeptide complexes suggest a molecular basis for CTL cross‐reactivity. Immunity, 10, 63–74.
Golbaghi,, G., & Castonguay,, A. (2020). Rationally designed ruthenium complexes for breast cancer therapy. Molecules, 25, 265.
Govender,, P., Edafe,, F., Makhubela,, B. C. E., Dyson,, P. J., Therrien,, B., & Smith,, G. S. (2014). Neutral and cationic osmium(II)‐arene metallodendrimers: Synthesis, characterization and anticancer activity. Inorganica Chimica Acta, 409, 112–120.
Govender,, P., Riedel,, T., Dyson,, P. J., & Smith,, G. S. (2015). Higher generation cationic N,N‐ruthenium(II)‐ethylene‐glycol‐derived metallodendrimers: Synthesis, characterization and cytotoxicity. The Journal of Organic Chemistry, 799–800, 38–44.
Govender,, P., Sudding,, L. C., Clavel,, C. M., Dyson,, P. J., Therrien,, B., & Smith,, G. S. (2013). The influence of RAPTA moieties on the antiproliferative activity of peripheral‐functionalised poly(salicylaldiminato) metallodendrimers. Dalton Transactions, 42, 1267–1277.
Govender,, P., Therrien,, B., & Smith,, G. S. (2012). Bio‐metallodendrimers—Emerging strategies in metal‐based drug design. European Journal of Inorganic Chemistry, 17, 2853–2862.
Grabchev,, I., Qianb,, X., Bojinov,, V., Xiao,, Y., & Zhang,, W. (2002). Synthesis and photophysical properties of 1,8‐naphthalimide‐labelled PAMAM as PET sensors of protons and of transition metal ions. Polymer, 43, 5731–5736.
Grabchev,, I., Vasileva‐Tonkova,, E., Staneva,, D., Bosch,, P., Kukeva,, R., & Stoyanova,, R. (2018). Impact of cu(II) and Zn(II) ions on the functional properties of new PAMAM metallodendrimers. New Journal of Chemistry, 42, 7853–7862.
Hadrup,, A., Donia,, M., & Straten,, P. T. (2013). Effector CD4 and CD8 T cells and their role in the tumor microenvironment. Cancer Microenvironment, 6, 123–133.
Hakomori,, S. (2002). Glycosylation defining cancer malignancy: New wine in an old bottle. Proceedings of the National Academy of Sciences of the United States of America, 99, 10231–10233.
Heimburg,, J., Yan,, J., Morey,, S., Glinskii,, O. V., Huxley,, V. H., Wild,, L., … Rittenhouse‐Olson,, K. (2006). Inhibition of spontaneous breast cancer metastasis by anti‐Thomsen‐Friedenreich antigen monoclonal antibody JAA‐F11. Neoplasia, 8, 939–948.
Heimburg‐Molinaro,, J., Almogren,, A., Morey,, S., Glinskii,, O. V., Roy,, R., Wilding,, G. E., … Rittenhouse‐Olson,, K. (2009). Development, characterization, and immunotherapeutic use of peptide mimics of the Thomsen‐Friedenreich carbohydrate antigen. Neoplasia, 11, 780–792.
Hockla,, P. F., Wolosiukb,, A., Pérez‐Sáeza,, J. M., Bordonib,, A. V., Crocia,, D. O., Toum‐Terronesb,, Y., … Rabinovich,, G. A. (2016). Glyco‐nano‐oncology: Novel therapeutic opportunities by combining small and sweet. Pharmacological Research, 109, 45–54.
Hołota,, M., Magiera,, J., Michlewska,, S., Kubczak,, M., Sanz del Olmo,, N., García‐Gallego,, S., … Bryszewska,, M. (2019). In vitro anticancer properties of copper metallodendrimers. Biomolecules, 9, 155. https://doi.org/10.3390/biom9040155
Hossain,, M. K., Vartak,, A., Sucheck,, S. J., & Wall,, K. A. (2019). Liposomal fc domain conjugated to a cancer vaccine enhances both humoral and cellular immunity. ACS Omega, 4, 5204–5208.
Houghton,, A. N., & Guevara‐Patiño,, J. A. (2004). Immune recognition of self in immunity against cancer. Journal of Clinical Investigation, 114, 468–471.
Joffre,, O. P., Segura,, E., Savina,, A., & Amigorena,, S. (2012). Cross‐presentation by dendritic cells. Nature Reviews Immunology, 12, 557–569.
Ju,, T., Otto,, V. I., & Cummings,, R. D. (2011). The Tn antigen‐structural simplicity and biological complexity. Angewandte Chemie, International Edition, 50, 1770–1791.
Juarez‐Perez,, E. J., Vinas,, C., Teixidor,, F., Santillan,, R., Farfan,, N., Abreu,, A., … Nunez,, R. (2010). Polyanionic aryl ether metallodendrimers based on cobaltabisdicarbollide derivatives. Photoluminescent properties. Macromolecules, 43, 150–159.
Karmakar,, P., Lee,, K., Sarkar,, S., Wall,, K. A., & Sucheck,, S. J. (2016). Synthesis of a liposomal MUC1 glycopeptide‐based immunotherapeutic and evaluation of the effect of L‐rhamnose targeting on cellular immune responses. Bioconjugate Chemistry, 27, 110–120.
Khanye,, S. D., Gut,, J., Rosenthal,, P. J., Chibale,, K., & Smith,, G. S. (2011). Ferrocenylthiosemicarbazones conjugated to a poly(propyleneimine) dendrimer scaffold: Synthesis and in vitro antimalarial activity. Journal of Organometallic Chemistry, 696, 3296–3300.
Kiessling,, L. L., Gestwicki,, J. E., & Strong,, L. E. (2006). Synthetic multivalent ligands as probes of signal transduction. Angewandte Chemie, International Edition, 45, 2348–2368.
Kiessling,, L. L., & Grim,, G. C. (2013). Glycopolymer probes of signal transduction. Chemical Society Reviews, 42, 4476–4491.
Koganty,, R. R., Yalamati,, D., & Jiang,, Z.‐H. (2008). Glycopeptide‐based cancer vaccines: The role of synthesis and structural definition. ACS Symposium Series, 989, 311–334.
Li,, X., Rao,, X., Cai,, L., Liu,, X., Wang,, H., Wu,, W., … Yi,, W. (2016). Targeting tumor cells by natural anti‐carbohydrate antibodies using rhamnose‐functionalized liposomes. ACS Chemical Biology, 11, 1205–1209.
Liakatos,, A., & Kunz,, H. (2007). Synthetic glycopeptides for the development of cancer vaccines. Current Opinion in Molecular Therapy, 9, 35–44.
Liu,, B., Lu,, X., Ruan,, H., Cui,, J., & Li,, H. (2016). Synthesis and applications of glyconanoparticles. Current Organic Chemistry, 20, 1502–1511.
Liu,, K., Xu,, Z., & Yin,, M. (2015). Perylenediimide‐cored dendrimers and their bioimagingand gene delivery applications. Progress in Polymer Science, 46, 25–54.
Mahanta,, C. S., Bhavsar,, R., Dash,, B. P., & Satapathy,, R. (2018). Cobaltabisdicarbollide based metallodendrimers with cyclotriphosphazene core. The Journal of Organic Chemistry, 865, 183–188.
Malaker,, S. A., Ferracane,, M., Depontieu,, F. R., Zarling,, A., Shabanowitz,, J., Bai,, D. L., … Hunt,, D. F. (2017). Identification and characterization of complex glycosylated peptides presented by the MHC class II processing pathway in melanoma. Journal of Proteome Research, 16, 228–237.
Maroto‐Díaz,, M., Elie,, B. T., Gómez‐Sal,, P., Pérez‐Serrano,, J., Gómez,, R., Contel,, M., & de la Mata,, F. J. (2016). Synthesis and anticancer activity of carbosilane metallodendrimers based on arene ruthenium(II) complexes. Dalton Transactions, 45, 7049–7066.
Marradi,, M., Chiodo,, F., Garcia,, I., & Penades,, S. (2013). Glyconanoparticles as multifunctional and multimodal carbohydrate systems. Chemical Society Reviews, 42, 4728–4745.
Martínez,, I., Ortiz Mellet,, C., & García Fernández,, J. M. (2013). Cyclodextrin‐based multivalent glycodisplays: Covalent and supramolecular conjugates to assess carbohydrate–protein interactions. Chemical Society Reviews, 42, 4746–4773.
Martínez‐Riaño,, A., Bovolenta,, E. R., Mendoza,, P., Oeste,, C. L., Martín‐Bermejo,, M. J., Bovolenta,, P., … Alarcón,, B. (2018). Antigen phagocytosis by B cells is required for a potent humoral response. EMBO Reports, 19, e46016.
Melero,, I., Gaudernack,, G., Gerritsen,, W., Huber,, C., Parmiani,, G., Thatcher,, N., … Mellstedt,, H. (2014). Therapeutic vaccines for cancer: An overview of clinical trials. Nature Reviews. Clinical Oncology, 11, 509–524.
Michlewska,, S., Ionov,, M., Shcharbin,, D., Maroto‐Díaz,, M., Ramirez,, R. G., de la Mata,, F. J., & Bryszewska,, M. (2017). Ruthenium metallodendrimers with anticancer potential in an acute promyelocytic leukemia cell line (HL60). European Polymer Journal, 87, 39–47.
Nierengarten,, I., & Nierengarten,, J.‐F. (2014). Fullerene sugar balls: A new class of biologically active fullerene derivatives. Chemistry Asian Journal, 9, 1436–1444.
Ostroumov,, D., Fekete‐Drimusz,, N., Saborowski,, M., Kühnel,, F., & Woller,, N. (2018). CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cellular and Molecular Life Sciences, 75, 689–713.
Ozawa,, C., Katayama,, H., Hojo,, H., Nakahara,, Y., & Nakahara,, Y. (2008). Efficient sequential segment coupling using N‐alkylcysteine assisted thioesterification for glycopeptide dendrimer synthesis. Organic Letters, 10, 3531–3533.
Palcic,, M. M., Li,, H., Zanini,, D., Bhella,, R. S., & Roy,, R. (1998). Chemoenzymatic synthesis of dendritic sialyl Lewis x. Carbohydrate Research, 305, 433–442.
Pashov,, A., Monzavi‐Karbassi,, B., Raghava,, G. P. S., & Kieber‐Emmons,, T. (2010). Bridging innate and adaptive antitumor immunity targeting glycans. Journal of Biomedicine and Biotechnology, 2010, 354068. https://doi.org/10.1155/2010/354068
Pashov,, A. D., Monzavi‐Karbassi,, B., & Kieber‐Emmons,, T. (2011). Glycan mediated immune responses to tumor cells. Human Vaccines, 7, 156–165.
Percec,, V., Leowanawat,, P., Sun,, H.‐J., Kulikov,, O., Nusbaum,, C. D., Tran,, T. M., … Heiney,, P. A. (2013). Modular synthesis of amphiphilic Janus glycodendrimers and their self‐assembly into glycodendrimersomes and other complex architectures with bioactivity to biomedically relevant lectins. Journal of the American Chemical Society, 135, 9055–9077.
Peri,, F. (2013). Clustered carbohydrates in synthetic vaccines. Chemical Society Reviews, 42, 4543–4556.
Pifferi,, C., Thomas,, B., Goyard,, D., Berthet,, N., & Renaudet,, O. (2017). Heterovalent glycodendrimers as epitope carriers for antitumor synthetic vaccines. Chemistry A European Journal, 23, 16283–16296.
Qiao,, Y., Wan,, J., Zhou,, L., Ma,, W., Yang,, Y., Luo,, W., … Wang,, H. (2019). Stimuli‐responsive nanotherapeutics for precision drug delivery and cancer therapy. WIREs Nanomedicine and Nanobiotechnology, 11, e1527.
Renaudet,, O., & Roy,, R. (2013). Multivalent scaffolds in glycoscience: An overview. Chemical Society Reviews, 42, 4515–4517.
Reynolds,, M., & Pérez,, S. (2011). Thermodynamics and chemical characterization of protein–carbohydrate interactions: The multivalency issue. Comptes Rendus Chimie, 14, 74–95.
Rittenhouse‐Diakun,, K., Xia,, Z., Pickhardt,, D., Baek,, M.‐G., & Roy,, R. (1998). Development and characterization of monoclonal antibody to T‐antigen: (Galβ1‐3GalNAc‐a‐O). Hybridoma, 17, 165–173.
Rosenbaum,, P., Artaud,, C., Bay,, S., Ganneau,, C., Campone,, M., Delaloge,, S., … Leclerc,, C. (2020). The fully synthetic glycopeptide MAG‐Tn3 therapeutic vaccine induces tumor‐specific cytotoxic antibodies in breast cancer patients. Cancer Immunology, Immunotherapy, 69(5), 703–716.
Roy,, R. (1996a). Design and synthesis of glycoconjugates. In S. H. Khan, & R. A. O`Neil, (Eds.), Modern Methods in Carbohydrate Synthesis (pp. 378–402). Amsterdam: Harwood Academic.
Roy,, R. (1996b). Synthesis and some applications of chemically defined multivalent glycoconjugates. Current Opinion in Structural Biology, 6, 692–702.
Roy,, R. (2003). A decade of glycodendrimer chemistry. Trends in Glycoscience and Glycotechnology, 15, 291–310.
Roy,, R. (2004). New trends in carbohydrate‐based vaccines. Drug Discovery Today: Technologies, 1, 327–336.
Roy,, R., Baek,, M.‐G., & Rittenhouse‐Olson,, K. (2001). Synthesis ofN,N′‐bis(Acrylamido)acetic acid‐based T‐antigen Glycodendrimers and their mouse monoclonal IgG antibody binding properties. Journal of the American Chemical Society, 123, 1809–1816.
Roy,, R., & Shiao,, T. C. (2011). Organic chemistry and immunochemical strategies in the design of potent carbohydrate‐based vaccines. Chimia, 65, 24–29.
Roy,, R., Shiao,, T. C., & Rittenhouse‐Olson,, K. (2013). Glycodendrimers: Versatile tools for nanotechnology. Brazilian Journal of Pharmaceutical Sciences, 49, 85–108.
Sanginario,, A., Miccoli,, B., & Demarchi,, D. (2017). Carbon nanotubes as an effective opportunity for cancer diagnosis and treatment. Biosensors, 7, 9. https://doi.org/10.3390/bios7010009
Sansone,, F., & Casnati,, A. (2013). Multivalent glycocalixarenes for recognition of biological macromolecules: Glycocalyx mimics capable of multitasking. Chemical Society Reviews, 42, 4623–4639.
Sanz del Olmo,, N., Carloni,, R., Bajo,, A. M., Ortega,, P., Gómez,, A. F. R., Ottaviani,, M. F., … de la Mata,, F. J. (2019). Insight into the antitumor activity of carbosilane cu(II)–metallodendrimers through their interaction with biological membrane models. Nanoscale, 11, 13330–13342.
Sanz del Olmo,, N., Maroto‐Díaz,, M., Gómez,, R., Ortega,, P., Cangiotti,, M., Ottaviani,, M. F., & de la Mata,, F. J. (2017). Carbosilane metallodendrimers based on copper (II) complexes: Synthesis, EPR characterization and anticancer activity. Journal of Inorganic Biochemistry, 177, 211–218.
Sarkar,, S., Lombardo,, S.A., Herner,, D.N., Talan,, R.S., Wall,, K.A., & Sucheck, S. J (2010). Synthesis of a single‐molecule L‐rhamnose‐containing three‐component vaccine and evaluation of antigenicity in the presence of anti‐L‐rhamnose antibodies. Journal of the American Chemical Society, 132, 17236–17246.
Sarkar,, S., Salyer,, A. C. D., Wall,, K. A., & Sucheck,, S. J. (2013). Synthesis and immunological evaluation of a MUC1 glycopeptide incorporated into L‐rhamnose displaying liposomes. Bioconjugate Chemistry, 24, 363–375.
Sebestik,, J., Niederhafner,, P., & Jezek,, J. (2011). Peptide and glycopeptide dendrimers and analogous dendrimeric structures and their biomedical applications. Amino Acids, 40, 301–370.
Sharma,, P., & Allison,, J. P. (2015). The future of immune checkpoint therapy. Science, 348, 56–61.
Shiao,, T. C., & Roy,, R. (2012). Glycodendrimers as functional antigens and antitumorales vaccines. New Journal of Chemistry, 36, 324–339.
Solís,, D., Bovin,, N. V., Davis,, A. P., Jiménez‐Barbero,, J., Romero,, A., Roy,, R., … Gabius,, H.‐J. (2015). A guide into glycosciences: How chemistry and biochemistry cooperate to crack the sugar code. Biochimica et Biophysica Acta, 1850, 186–235.
Speir,, J. A., Abdel‐Motal,, U. M., Jondal,, M., & Wilson,, I. A. (1999). Crystal structure of an MHC class I presented glycopeptide that generates carbohydrate‐specific CTL. Immunity, 10, 51–61.
Springer,, G. F. (1984). T and Tn, general carcinoma autoantigens. Science, 224, 1198–1206.
Staneva,, D., Grabchev,, I., Bosch,, P., Vasileva‐Tonkova,, E., Kukeva,, R., & Stoyanova,, R. (2018). Synthesis, characterization and antimicrobial activity of polypropylenamine metallodendrimers modified with 1,8‐naphthalimides. Journal of Molecular Structure, 1164, 363–369.
Suzuki,, M., Kato,, C., & Kato,, A. (2015). Therapeutic antibodies: Their mechanisms of action and the pathological findings they induce in toxicity studies. Journal of Toxicologic Pathology, 28, 133–139.
Tarp,, M. A., Sorensen,, A. L., Mandel,, U., Paulsen,, H., Burchell,, J., Taylor‐Papadimitriou,, J., & Clausen,, H. (2007). Identification of a novel cancer‐specific immunodominant glycopeptide epitope in the MUC1 tandem repeat. Glycobiology, 17, 197–209.
Touaibia,, M., & Roy,, R. (2007). Application of multivalent mannosylated dendrimers in glycobiology. In J. P. Kamerling, (Ed.), Comprehensive Glycoscience (Vol. 3, pp. 821–870). Amsterdam: Elsevier.
Trant,, J. F., Jain,, N., Mazzuca,, D. M., McIntosh,, J. T., Fan,, B., Haeryfar,, S. M., … Gillies,, E. R. (2016). Synthesis, self‐assembly, and immunological activity of α‐galactose‐functionalized dendron‐lipid amphiphiles. Nanoscale, 8, 17694–17704.
Treanor,, B. (2012). B‐cell receptor: From resting state to activate. Immunology, 136, 21–27.
Tsou,, P., Katayama,, H., Ostrin,, E. J., & Hanash,, S. M. (2016). The emerging role of B cells in tumor immunity. Cancer Research, 76, 5597–5601.
Verez‐Bencomo,, V., Fernández‐Santana,, V., Hardy,, E., Toledo,, M. E., Rodríguez,, M. C., Heynngnezz,, L., … Roy,, R. (2004). A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type b. Science, 305, 522–525.
Wei,, S. C., Duffy,, C. R., & Allison,, J. P. (2018). Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery, 8, 1069–1086.
Wu,, P., Chen,, X., Hu,, N., Tam,, U. C., Blixt,, O., Zettl,, A., & Bertozzi,, C. R. (2008). Biocompatible carbon nanotubes generated by functionalization with glycodendrimers. Angewandte Chemie International Edition, 47, 5022–5025.
Xu,, Y., Gendler,, S. J., & Franco,, A. (2004). Designer glycopeptides for cytotoxic T cell‐based elimination of carcinomas. Journal of Experimental Medicine, 199, 707–716.
Yang,, J., & Reth,, M. (2016). Receptor dissociation and B‐cell activation. Current Topics in Microbiology and Immunology, 393, 27–43.
Yilmaza,, G., & Becer,, C. R. (2015). Glyconanoparticles and their interactions with lectins. Polymer Chemistry, 6, 5503–5514.
Yin,, Z., & Huang,, X. (2012). Recent development in carbohydrate based anti‐cancer vaccines. Journal of Carbohydrate Chemistry, 31, 143–186.
Zhao,, C.‐M., Wang,, K.‐R., Wang,, C., He,, X., & Li,, X.‐L. (2019). Cooling‐induced NIR emission enhancement and targeting fluorescence imaging of biperylene monoimide and glycodendrimer conjugates. ACS Macro Letters, 8, 381–386.

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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