title: Synthesis, self-assembly, and immunological activity of α-galactose-functionalized dendron-lipid amphiphiles.
abstract: Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron-lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron-lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in water through a solvent exchange process resulted in vesicles for the 0 through 2ndgeneration systems and micelles for the 3rdand 4thgeneration systems. The critical aggregation concentrations decreased with increasing dendron generation, suggesting that the effects of increasing molar mass dominated over the effects of increasing the hydrophilic weight fraction. The binding of the assemblies to Griffonia simplicifolia Lectin I (GSL 1), a protein with specificity for α-Gal was studied by quantifying the binding of fluorescently labeled assemblies to GSL 1-coated beads. It was found that binding was enhanced for amphiphiles containing higher generation dendrons. Despite their substantial structural differences with the natural ligands for the CD1d receptor, the glycodendron-lipid hybrids were capable of stimulating invariant natural killer T (iNKT) cells, a class of innate-like T cells that recognize lipid and glycolipid antigens presented by CD1d and that are implicated in a wide range of diseases and conditions including but not limited to infectious diseases, diabetes and cancer.
authors.affiliation: Department of Chemistry and Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5B7. egillie@uwo.ca.
authors.forename: John F
authors.initials: JF
authors.lastname: Trant
authors.affiliation: Department of Chemistry and Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5B7. egillie@uwo.ca.
authors.forename: Namrata
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Microbiology and Immunology, Department of Medicine, Centre for Human Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5C1.
authors.forename: Delfina M
authors.initials: DM
authors.lastname: Mazzuca
authors.affiliation: Department of Chemistry and Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5B7. egillie@uwo.ca.
authors.forename: James T
authors.initials: JT
authors.lastname: McIntosh
authors.affiliation: Department of Chemical and Biochemical Engineering, The University of Western Ontario, 1151 Richmond St., London, Canada N6A 5B9.
authors.forename: Bo
authors.initials: B
authors.lastname: Fan
authors.affiliation: Department of Microbiology and Immunology, Department of Medicine, Centre for Human Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5C1.
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
authors.affiliation: Univ. Bordeaux, Bordeaux-INP ENSCBP, CNRS, Laboratoire de Chimie des Polymères Organique (LCPO), UMR 5629, 16 avenue Pey Berland, F-33600, Pessac, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lecommandoux
authors.affiliation: Department of Chemistry and Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Canada N6A 5B7. egillie@uwo.ca and Department of Chemical and Biochemical Engineering, The University of Western Ontario, 1151 Richmond St., London, Canada N6A 5B9.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gillies
mesh_terms: D000818:Animals; D002460:Cell Line; D050091:Dendrimers; D005690:Galactose / Q000276:immunology*; D008055:Lipids / Q000276:immunology*; D051379:Mice; D015394:Molecular Structure; D055611:Natural Killer T-Cells / Q000187:drug effects*
chemical_list: D050091:Dendrimers; D008055:Lipids; D005690:Galactose