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 2 generation systems and micelles for the 3 and 4 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.

Recent Development in the Design of Neoglycoliposomes Bearing Arborescent Architectures

“…Self-assembling of arborescent neoglycodendrimersomes harboring α- C -linked galactopyranosides mounted on a 2,2-bis(hydroxymethyl)-propionic acid (bis-HMPA) scaffold ending with palmitic acid dimers has been described by the Gillies group [ 37 ] ( Scheme 7 ). The glycolipid hybrid was made to mimic the natural KRN 7000 immunostimulant ( Figure 2 ).…”

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

“…F I G U R E 9 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) F I G U R E 1 0 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 5 | GLYCODENDRIMERS: VACCINES AND DIAGNOSTICS Several glycodendrimer architectures, including NPs, harboring the TACAs have been prepared to date (Gaidzik, Westerlind, & Kunz, 2013;Liakatos & Kunz, 2007;Peri, 2013;Roy, 2004;Roy et al, 2013;Roy & Shiao, 2011;Shiao & Roy, 2012). This section will highlight the pioneering work from the main author's laboratory together with recent investigations published since then.…”

“…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)…”

Vesicles from Amphiphilic Dumbbells and Janus Dendrimers: Bioinspired Self-Assembled Structures for Biomedical Applications

“…Amphiphilic dumbbells are constituted of two flexible dendrons coupled on each side of a rigid hydrophobic core [34,35,36,37,38,39,40]. Amphiphiles with a non-dendritic hydrophobic structure (for instance, one alkyl chain (Figure 1d) or p -phenylene chains (Figure 1e)) connected to a hydrophilic dendron can be classified as dendritic amphiphiles [32,33,41,42,43,44,45,46,47].…”