title: The influence of PEG chain length and targeting moiety on antibody-mediated delivery of nanoparticle vaccines to human dendritic cells.
abstract: Targeted delivery of nanoparticles (NPs) carrying vaccine components to dendritic cells (DCs) is a promising strategy to initiate antigen-specific immune responses. Improving the interactions between nanoparticle-carried ligands and receptors on DCs is a major challenge. These NPs are generally coated with poly(ethylene glycol) (PEG), to shield non-specific interactions, and antibodies, to facilitate specific delivery to DC surface receptors. We have devised a strategy to covalently link PEG molecules of various chain length (Mw 2000-20000 g/moL) to poly(lactic-co-)glycolic acid (PLGA) NP vaccines. We coated these NPs with various antibodies recognizing the DC-specific receptor DC-SIGN to study the effects of shielding and antibody type on antibody--receptor interactions. Chemical attachment of PEG to the particle surface was followed by detailed zeta potential, DLS and NMR studies, and analyzed by analytical chemistry. Increasing the PEG chain length increased particle size and polydispersity index and reduced the intracellular degradation rate of encapsulated antigens. Binding and uptake of NPs by human DCs was affected by both PEG chain length and antibody type. NPs coated with PEG-3000 had the optimal chain length for antibody--receptor interactions and induction of antigen-specific T-cell responses. Interestingly, clear differences were observed upon targeting distinct epitopes of the same receptor. Binding and uptake of NPs carrying antibodies recognizing the carbohydrate recognition domain of DC-SIGN was enhanced when compared to those carrying antibodies recognizing the receptor's neck region. In conclusion, our data show that PEG chains cannot be extended beyond a certain length for shielding purposes without compromising the efficacy of targeted delivery. Thereby, the implications of our findings are not limited to the future design of nanovaccines specifically targeted to DC-SIGN, but apply to the general design of targeted nanocarriers.
authors: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, Nijmegen, The Netherlands.
authors: Luis J
authors: LJ
authors: Cruz
authors: Paul J
authors: PJ
authors: Tacken
authors: Remco
authors: R
authors: Fokkink
authors: Carl G
authors: CG
authors: Figdor
mesh_terms: D000906:Antibodies / Q000737:chemistry / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology; D008422:Materials Testing; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000276:immunology; D013499:Surface Properties; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D014612:Vaccines / Q000737:chemistry* / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; D004337:Drug Carriers; D037181:Lectins, C-Type; D011092:Polyethylene Glycols; D011956:Receptors, Cell Surface; D014612:Vaccines; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin