title: Targeting human dendritic cells via DEC-205 using PLGA nanoparticles leads to enhanced cross-presentation of a melanoma-associated antigen.
abstract: Targeting antigen to dendritic cells (DCs) is a powerful and novel strategy for vaccination. Priming or loading DCs with antigen controls whether subsequent immunity will develop and hence whether effective vaccination can be achieved. The goal of our present work was to increase the potency of DC-based antitumor vaccines by overcoming inherent limitations associated with antigen stability and cross-presentation. Nanoparticles prepared from the biodegradable polymer poly(lactic-co-glycolic acid) have been extensively used in clinical settings for drug delivery and are currently the subject of intensive investigation as antigen delivery vehicles for vaccine applications. Here we describe a nanoparticulate delivery system with the ability to simultaneously carry a high density of protein-based antigen while displaying a DC targeting ligand on its surface. Utilizing a targeting motif specific for the DC-associated surface ligand DEC-205, we show that targeted nanoparticles encapsulating a MART-127-35 peptide are both internalized and cross-presented with significantly higher efficiency than isotype control-coated nanoparticles in human cells. In addition, the DEC-205-labeled nanoparticles rapidly escape from the DC endosomal compartment and do not colocalize with markers of early (EEA-1) or late endosome/lysosome (LAMP-1). This indicates that encapsulated antigens delivered by nanoparticles may have direct access to the class I cytoplasmic major histocompatibility complex loading machinery, overcoming the need for "classical" cross-presentation and facilitating heightened DC stimulation of anti-tumor CD8(+) T-cells. These results indicate that this delivery system provides a flexible and versatile methodology to deliver melanoma-associated antigen to DCs, with both high efficiency and heightened potency.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Saluja
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hanlon
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Sharp
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: Enping
authors.initials: E
authors.lastname: Hong
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Khalil
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Robinson
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tigelaar
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA ; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Edelson
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry* / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D058965:MART-1 Antigen / Q000008:administration & dosage* / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011956:Receptors, Cell Surface / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D058965:MART-1 Antigen; C548667:MLANA protein, human; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: DEC-205; PLGA nanoparticles; cross-presentation; dendritic cells; melanoma-associated antigen