Multivalency Beats Complexity: A Study on the Cell Uptake of Carbohydrate Functionalized Nanocarriers to Dendritic Cells.

Matthias Krumb,Volker Mailänder,Till Opatz,Jens Langhanki,Marie-Luise Frey,Katharina Landfester,Danuta Kowalczyk,Robert Forster

doi:10.3390/cells9092087

Abstract

Herein, we report the synthesis of carbohydrate and glycodendron structures for dendritic cell targeting, which were subsequently bound to hydroxyethyl starch (HES) nanocapsules prepared by the inverse miniemulsion technique. The uptake of the carbohydrate-functionalized HES nanocapsules into immature human dendritic cells (hDCs) revealed a strong dependence on the used carbohydrate. A multivalent mannose-terminated dendron was found to be far superior in uptake compared to the structurally more complex oligosaccharides used.

Highlights

The synthesis and characterization of nanocarrier systems is an emerging discipline in modern nanomedicine, where bioavailability, biodegradability, adequate release, efficient coupling of the drug to the nanocarrier and targeted delivery of the drug to its destination play key roles and need to be finely tuned [1]
A key study by Holla and Skerra revealed that simple mannose-units, and especially branched oligomannosidic structures, in particular a trimannose structure (3,6-di-(α-d-mannopyranosyl)-α-d-mannopyranose) as well as fucose-containing saccharides, in particular a disaccharide (3-(β-l-fucopyranosyl)-2-acetamido-2-deoxy-β-d-glucopyranose), are recognized by dendritic cells (DCs)-SIGN [25]
We selected four different potential ligands for dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) that carry a poly(ethylene glycol) (PEG)-based, azide-terminated linker to enable covalent binding through azide-alkyne click reactions to nanocarriers as the target structures for total synthesis (Figure 1) A simple d-mannose monosaccharide 1 and the mentioned trimannose structure 2, which were available from earlier studies [4,26,27], as well as a fucose containing disaccharide 3 and a mannose-terminated glycodendron 4, were chosen as potential ligands

Summary

Introduction

The synthesis and characterization of nanocarrier systems is an emerging discipline in modern nanomedicine, where bioavailability, biodegradability, adequate release, efficient coupling of the drug to the nanocarrier (e.g., by encapsulation) and targeted delivery of the drug to its destination play key roles and need to be finely tuned [1]. Targeted drug delivery to certain cell types is a highly desirable strategy and the targeting of dendritic cells (DCs) in terms of tumor immunotherapy has gained wide attention in recent years [2]. Due to their ability to activate the adaptive immune response, DCs play a key role in delivering information to the immune system. They can serve as important mediators in nanomedicine to deliver antigens upon targeting and cell uptake of antigen-loaded nanocarriers [3]. It can be deduced that multivalency might be a universal promising strategy to maximize the carbohydrate lectin interactions in terms of DC-SIGN targeting with nanocarriers

Objectives

Methods

Results

Discussion

Conclusion