title: Influence of ligand valency on the targeting of immature human dendritic cells by mannosylated liposomes.
abstract: An important challenge for the development of new generations of vaccines is the efficient delivery of antigens to antigen presenting cells such as dendritic cells. In the present study we compare the interaction of plain and targeted liposomes, containing mono-, di-, and tetraantennary mannosyl lipid derivatives, with human monocyte-derived immature dendritic cells (iDCs). Whereas efficient mannose receptor-mediated endocytosis by iDCs was observed for the mannosylated liposomes, in contrast, only nonspecific interaction with little uptake was observed with plain liposomes. In accordance with the clustering effect, liposomes prepared with multibranched mannosylated lipids displayed higher binding affinity for the mannose receptor than vesicles containing the monomannosylated analogs. Importantly, we have found that dimannosylated ligands present at the surface of the liposomes were as efficient as tetramannosylated ones to engage in multidentate interactions with the mannose receptor of iDCs, resulting in both cases in an effective uptake/endocytosis. This result will greatly facilitate, from a practical standpoint, the design of mannose-targeted vaccination constructs. Moreover, we showed that mannose-mediated uptake of liposomes did not result in an activation of iDCs. Altogether, our results suggest that antigen-associated targeted liposomes containing diantennary mannosylated lipids could be effective vectors for vaccines when combined with additional DC activation signals.
authors.affiliation: Institut Gilbert Laustriat, UMR 7175-LC01 CNRS/Universite Louis Pasteur, Departement de Chimie Bioorganique, Laboratoire de Chimie Enzymatique et Vectorisation, Faculte de Pharmacie, 74 route du Rhin, 67400 Illkirch, France.
authors.forename: Socorro
authors.initials: S
authors.lastname: Espuelas
authors.forename: Christine
authors.initials: C
authors.lastname: Thumann
authors.forename: Béatrice
authors.initials: B
authors.lastname: Heurtault
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
authors.forename: Benoît
authors.initials: B
authors.lastname: Frisch
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004002:Clodronic Acid / Q000737:chemistry; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004705:Endocytosis; D005452:Fluoresceins / Q000737:chemistry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D008358:Mannose / Q000737:chemistry*
chemical_list: D005452:Fluoresceins; D008024:Ligands; D008081:Liposomes; D004002:Clodronic Acid; C024098:6-carboxyfluorescein; D008358:Mannose