title: Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8(+) T cell response: a comparative study.
abstract: Here we demonstrated the importance of targeting antigens (Ags) to dendritic cell (DC) receptors to achieve an efficient cytotoxic T cell response which was associated with a strong activation of DC. Pegylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used to encapsulate ovalbumin (OVA) as a model Ag. This PLGA complex, together with Toll like receptor (TLR) 3 and 7 ligands, was then targeted to distinct DC cell-surface molecules. These cell-surface molecules, including CD40, a TNF-α family receptor, DEC-205, a C-type lectin receptor and CD11c, an integrin receptor, were targeted by means of specific monoclonal antibodies (mAbs) coupled to the NP. The efficiency of these different targeting strategies to activate DC and elicit a potent CD8(+) T cell response was studied. PLGA-(Ag/TLR3+7L) NP was more efficiently targeted to and internalized by DC in vitro compared to the control non-targeted NP. We observed a small but significantly improved internalization of CD40-targeted NP compared to DEC-205 or CD11c targeted NP. In contrast to non-targeted NP, all targeted NPs equally stimulated IL-12 production and expression of co-stimulatory molecules by DC, inducing strong proliferation and IFN-y production by T cells in vitro. Moreover, subcutaneous vaccination with CD40, DEC-205 and CD11c-targeted NP consistently showed higher efficacy than non-targeted NP in stimulating CD8+ T cell responses. However, all targeted NP vaccines showed an equal capacity to prime cytotoxic CD8+ T cells, which subsequently were able to induce targeted cell lysis. In conclusion, delivery of NP-vaccines to DC by targeting via cell-surface molecules leads to strong enhancement of vaccine potency and induction of T cell responses compared to non-specific delivery of NP to DC.
authors: Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands. Electronic address: l.j.cruz_ricondo@lumc.nl.
authors: Luis J
authors: LJ
authors: Cruz
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
authors: Rodney A
authors: RA
authors: Rosalia
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
authors: Jan Willem
authors: JW
authors: Kleinovink
authors: Department of Biochemistry and Molecular Biology, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.
authors: Felix
authors: F
authors: Rueda
authors: Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
authors: Clemens W G M
authors: CW
authors: Löwik
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
authors: Ferry
authors: F
authors: Ossendorp
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016503:Drug Delivery Systems; D019344:Lactic Acid / Q000737:chemistry*; D037181:Lectins, C-Type / Q000276:immunology; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011956:Receptors, Cell Surface / Q000276:immunology
chemical_list: D015703:Antigens, CD; D039521:CD11c Antigen; D019013:CD40 Antigens; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin
keywords: Dendritic cells; Immunotherapy; Molecular imaging; Nanoparticles; PLGA; Targeting