A multifunctional core-shell nanoparticle for dendritic cell-based cancer immunotherapy.

Dendritic cell-based cancer immunotherapy requires tumour antigens to be delivered efficiently into dendritic cells and their migration to be monitored in vivo. Nanoparticles have been explored as carriers for antigen delivery, but applications have been limited by the toxicity of the solvents used to make nanoparticles, and by the need to use transfection agents to deliver nanoparticles into cells. Here we show that an iron oxide-zinc oxide core-shell nanoparticle can deliver carcinoembryonic antigen into dendritic cells while simultaneously acting as an imaging agent. The nanoparticle-antigen complex is efficiently taken up by dendritic cells within one hour and can be detected in vitro by confocal microscopy and in vivo by magnetic resonance imaging. Mice immunized with dendritic cells containing the nanoparticle-antigen complex showed enhanced tumour antigen specific T-cell responses, delayed tumour growth and better survival than controls.

[1]  C. Figdor,et al.  Multimodal imaging of nanovaccine carriers targeted to human dendritic cells. , 2011, Molecular pharmaceutics.

[2]  K. Foon,et al.  Carcinoembryonic Antigen Transgenic Mouse Models for Immunotherapy and Development of Cancer Vaccines , 2008, Current protocols in immunology.

[3]  E. Allémann,et al.  Nanoprecipitation versus emulsion-based techniques for the encapsulation of proteins into biodegradable nanoparticles and process-related stability issues , 2005, AAPS PharmSciTech.

[4]  Rebekah Drezek,et al.  Evaluation of quantum dot cytotoxicity based on intracellular uptake. , 2006, Small.

[5]  B. Rutt,et al.  Enhanced cell uptake of superparamagnetic iron oxide nanoparticles functionalized with dendritic guanidines. , 2008, Bioconjugate chemistry.

[6]  Craig H Meyer,et al.  Technology Insight: in vivo cell tracking by use of MRI , 2006, Nature Clinical Practice Cardiovascular Medicine.

[7]  L. Leondiadis,et al.  PLA and PLGA microspheres of beta-galactosidase: Effect of formulation factors on protein antigenicity and immunogenicity. , 2004, Journal of biomedical materials research. Part A.

[8]  M. Bock,et al.  Physical and Biological Characterization of Superparamagnetic Iron Oxide- and Ultrasmall Superparamagnetic Iron Oxide-Labeled Cells: A Comparison , 2005, Investigative radiology.

[9]  Bong Hyun Chung,et al.  Biocompatible polymer-nanoparticle-based bimodal imaging contrast agents for the labeling and tracking of dendritic cells. , 2008, Small.

[10]  K. Foon,et al.  Dendritic Cells Pulsed with an Anti-Idiotype Antibody Mimicking Carcinoembryonic Antigen (CEA) Can Reverse Immunological Tolerance to CEA and Induce Antitumor Immunity in CEA Transgenic Mice , 2004, Cancer Research.

[11]  Polly Matzinger,et al.  Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses , 2004, Nature Reviews Immunology.

[12]  D. Keskin,et al.  Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery. , 2011, Biomaterials.

[13]  S. Seong,et al.  Protective anti‐tumour immune responses by murine dendritic cells pulsed with recombinant Tat‐carcinoembryonic antigen derived from Escherichia coli , 2009, Clinical and experimental immunology.

[14]  C Danieli,et al.  Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products , 1995, The Journal of experimental medicine.

[15]  Isabelle Raynal,et al.  Macrophage Endocytosis of Superparamagnetic Iron Oxide Nanoparticles: Mechanisms and Comparison of Ferumoxides and Ferumoxtran-10 , 2004, Investigative radiology.

[16]  M. Schembri,et al.  Sequestration of Zinc Oxide by Fimbrial Designer Chelators , 2000, Applied and Environmental Microbiology.

[17]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[18]  A. Tok,et al.  Chemical Synthesis of ZnO Nanocrystals , 2007, IEEE Transactions on Nanotechnology.

[19]  Arend Heerschap,et al.  Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy , 2005, Nature Biotechnology.

[20]  T. Strachowski,et al.  Luminescence of ZnO nanopowders , 2004 .

[21]  Jerry S. H. Lee,et al.  Magnetic nanoparticles in MR imaging and drug delivery. , 2008, Advanced drug delivery reviews.

[22]  C. Melief.  Cancer immunotherapy by dendritic cells. , 2008, Immunity.

[23]  U. Şeker,et al.  Material Binding Peptides for Nanotechnology , 2011, Molecules.

[24]  Haosen Zhang,et al.  A New Nano-sized Iron Oxide Particle with High Sensitivity for Cellular Magnetic Resonance Imaging , 2011, Molecular Imaging and Biology.

[25]  Benjamin Gilbert,et al.  Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. , 2008, ACS nano.

[26]  Young Keun Kim,et al.  Synthesis of streptavidin-FITC-conjugated core-shell Fe3O4-Au nanocrystals and their application for the purification of CD4+ lymphocytes. , 2008, Biomaterials.

[27]  Nuria Sanvicens,et al.  Multifunctional nanoparticles--properties and prospects for their use in human medicine. , 2008, Trends in biotechnology.

[28]  C. Figdor,et al.  Dendritic cell immunotherapy: mapping the way , 2004, Nature Medicine.

[29]  K. Ahn,et al.  Simultaneous in vivo tracking of dendritic cells and priming of an antigen-specific immune response. , 2011, Biomaterials.

[30]  Y. Liu,et al.  Preparation of ZnO colloids by aggregation of the nanocrystal subunits. , 2005, Journal of colloid and interface science.

[31]  J. Schlom,et al.  Carcinoembryonic Antigen as a Vaccine Target , 2001 .

[32]  F. Baneyx,et al.  MATERIALS ASSEMBLY AND FORMATION USING ENGINEERED POLYPEPTIDES , 2004 .

[33]  Jing Sun,et al.  Stable aqueous dispersion of ZnO quantum dots with strong blue emission via simple solution route. , 2007, Journal of the American Chemical Society.

[34]  Alke Petri-Fink,et al.  Biomedical nanoparticles modulate specific CD4+ T cell stimulation by inhibition of antigen processing in dendritic cells , 2011, Nanotoxicology.

[35]  J. Gore,et al.  Multimodal imaging of dendritic cells using a novel hybrid magneto-optical nanoprobe. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[36]  W. Oyen,et al.  Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. , 2003, Cancer research.

[37]  Mehmet Sarikaya,et al.  Identification and characterization of Cu2O‐ and ZnO‐binding polypeptides by Escherichia coli cell surface display: toward an understanding of metal oxide binding , 2004, Biotechnology and bioengineering.

[38]  E. Gilboa.  DC-based cancer vaccines. , 2007, The Journal of clinical investigation.

[39]  J. Bulte,et al.  Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes. , 2009, Cancer research.

[40]  Katharina Landfester,et al.  Interaction of nanoparticles with cells. , 2009, Biomacromolecules.

[41]  T. D. Schneider,et al.  Sequence logos: a new way to display consensus sequences. , 1990, Nucleic acids research.

[42]  Bengt Fadeel,et al.  Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells. , 2011, Toxicology and applied pharmacology.

[43]  R. Sékaly,et al.  Semiquantitation of Mouse Dendritic Cell Migration In Vivo Using Cellular MRI , 2009, Journal of immunotherapy.

[44]  Andreas Hess,et al.  In vivo magnetic resonance imaging of dendritic cell migration into the draining lymph nodes of mice , 2006, European journal of immunology.

[45]  M. Loudovaris,et al.  In Vivo Tracking of Dendritic Cells in Patients With Multiple Myeloma , 2008, Journal of immunotherapy.

[46]  J. Marshall,et al.  Carcinoembryonic antigen as a vaccine target , 2008, Expert review of vaccines.

[47]  H. Ueno,et al.  Taming cancer by inducing immunity via dendritic cells , 2007, Immunological reviews.

[48]  David Pozo,et al.  Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[49]  Jeff W M Bulte,et al.  In vivo MRI cell tracking: clinical studies. , 2009, AJR. American journal of roentgenology.