Synthesis, self-assembly, and immunological activity of α-galactose-functionalized dendron–lipid amphiphiles

Authors

John Trant, Western University
Namrata Jain, The University of Western Ontario
D. M. Mazzuca, University of Western Ontario
J Trevor McIntosh, The University of Western Ontario
Bo Fan, Western UniversityFollow
S M Mansour Haeryfar, Western University
Sebastien Lecommandoux, Universite de BordeauxFollow
Elizabeth Gillies, Western UniversityFollow

Document Type

Article

Publication Date

Fall 9-28-2016

Journal

Nanoscale

Volume

8

First Page

17694

Last Page

17704

URL with Digital Object Identifier

https://doi.org/10.1039/c6nr05030a

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 2nd generation systems and micelles for the 3rd and 4th generation 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.