Self-assembling PEGylated mannolipids for liposomal drug encapsulation of natural products

Abstract

The chemical synthesis of modified neoglycolipids is reported in an effort to further improve the drug delivery properties of previously described mannosylated liposomes possessing alkyl linkers in the aglyconic moiety. A self-contingent strategy that overcomes previous synthetic limitations was used to produce neoglycolipids that have a single exposed α-D-mannopyranoside residue, an aromatic scaffold, and two lipid tails with varied alkyl chains. The lipid tails were built from 3,5-dihydoxybenzoic acid possessing two alkyl chains of twelve to sixteen carbons (C₁₂–C₁₆). The azido-ending carbohydrate precursor, harboring a hydrophilic triethylene glycol, was prepared by glycosidation of mannose pentaacetate with triethylene glycol monotosylate using standard Lewis acid-catalysed conditions. The carboxylic acid-ending lipid tails were directly ligated to the azido mannopyranoside residue using a modified Staudinger chemistry. The formation of stable spherical vesicles of controllable sizes (≈100 nm) was confirmed by dynamic light scattering (DLS), TEM, and AFM experiments. The values of critical micelle concentration (CMC) of mannnolipids were also determined by DLS using variations of scattered light as a function of concentrations. The CMC values obtained from the C₁₂ to the C₁₆ alkyl chains were 1.76 × 10⁻⁶, 3.87 × 10⁻⁶, and 3.86 × 10⁻⁶ mol L⁻¹, respectively. The bio-relevance of the mannosylated glycolipids were also demonstrated using their cross-linking abilities with the leguminous lectin Concanavalin A from Canavalia ensiformis which is a homotetrameric mannose-binding protein. In addition, the glycolipids were biocompatible, enhanced cell uptake of lipophilic cargos, and improved the human plasma stability of entrapped quercetin.