Multivalent Glycosylation of Fluorescent Gold Nanoclusters Promotes Increased Human Dendritic Cell Targeting via Multiple Endocytic Pathways.
We report the synthesis and characterization of gold nanoclusters (Au NCs) stabilized by a mixture of zwitterionic and multivalent mannose ligands. Characterization of this carbohydrated nanosystem confirms its small size (∼2 nm), intense red-NIR fluorescence, relatively high affinity to lectin (ConA), and stability in physiological media. Cell studies performed using human-monocyte-derived dendritic cells (DCs) show that Au NC uptake efficiency is greatly enhanced by the presence of surface carbohydrate (>250% compared to noncarbohydrated Au NCs), allowing their detection in cells by fluorescence following incubation with concentrations as low as 1 μg mL(-1). Investigation using electron microscopy and pharmacological inhibitors indicates that Au NC uptake is mediated by multiple endocytic pathways involving the engulfment of Au NCs into endosomes and partial transport to lysosomes. Results show that clathrin- and F-actin-dependent pathways play major roles in Au NC uptake by DCs, regardless of whether or not they are coated with carbohydrates. In contrast, a specific C-lectin inhibitor induces a 60% decrease in DC particle uptake only for the carbohydrate-coated Au NCs. This study demonstrates that the combination of ultrasmall gold NCs and functionalization with multivalent mannose ligands results in greatly enhanced human DC targeting, presumably due to increased diffusion and target cell binding, respectively.
Therapeutic Nanosystems, The Andalusian Centre for Nanomedicine and Biotechnology (BIONAND) , 29590 Málaga, Spain.
Xavier
X
Le Guével
Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC-University of Seville , 41092 Seville, Spain.
Monica
M
Perez Perrino
Tahia D
TD
Fernández
Francisca
F
Palomares
Maria-José
MJ
Torres
Miguel
M
Blanca
Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC-University of Seville , 41092 Seville, Spain.
Javier
J
Rojo
Cristobalina
C
Mayorga
D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D000067493:Dynamic Light Scattering; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005453:Fluorescence; D006031:Glycosylation; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D055620:Optical Phenomena; D010316:Particle Size; D013050:Spectrometry, Fluorescence; D014867:Water / Q000737:chemistry
D014867:Water; D006046:Gold
cell uptake; dendritic cells; gold nanoclusters; mannose; targeting