Selective uptake of cylindrical poly(2-oxazoline) brush-antiDEC205 antibody-OVA antigen conjugates into DEC-positive dendritic cells and subsequent T-cell activation.

To achieve specific cell targeting by various receptors for oligosaccharides or antibodies, a carrier must not be taken up by any of the very many different cells and needs functional groups prone to clean conjugation chemistry to derive well-defined structures with a high biological specificity. A polymeric nanocarrier is presented that consists of a cylindrical brush polymer with poly-2-oxazoline side chains carrying an azide functional group on each of the many side chain ends. After click conjugation of dye and an anti-DEC205 antibody to the periphery of the cylindrical brush polymer, antibody-mediated specific binding and uptake into DEC205(+) -positive mouse bone marrow-derived dendritic cells (BMDC) was observed, whereas binding and uptake by DEC205(-) negative BMDC and non-DC was essentially absent. Additional conjugation of an antigen peptide yielded a multifunctional polymer structure with a much stronger antigen-specific T-cell stimulatory capacity of pretreated BMDC than application of antigen or polymer-antigen conjugate.

[1]  M. Bros,et al.  Solution Properties and Potential Biological Applications of Zwitterionic Poly(epsilon-N-methacryloyl-L-lysine) , 2013 .

[2]  V. Langlois,et al.  Development of a new azido-oxazoline monomer for the preparation of amphiphilic graft copolymers by combination of cationic ring-opening polymerization and click chemistry , 2013 .

[3]  K. Fischer,et al.  Collapse of cylindrical brushes with 2-isopropyloxazoline side chains close to the phase boundary. , 2013, Macromolecular rapid communications.

[4]  R. Zentel,et al.  Synthesis of maleimide-functionalyzed HPMA-copolymers and in vitro characterization of the aRAGE- and human immunoglobulin (huIgG)-polymer conjugates. , 2013, Macromolecular bioscience.

[5]  U. Schubert,et al.  Aqueous solution behavior of comb-shaped poly(2-ethyl-2-oxazoline) , 2013 .

[6]  J. Kopeček.  Polymer-drug conjugates: origins, progress to date and future directions. , 2013, Advanced drug delivery reviews.

[7]  Yingchao Han,et al.  Macromol. Rapid Commun. 19/2012 , 2012 .

[8]  R. Luxenhofer,et al.  Thermoresponsive Poly(2‐Oxazoline) Molecular Brushes by Living Ionic Polymerization: Modulation of the Cloud Point by Random and Block Copolymer Pendant Chains , 2012 .

[9]  James E Bear,et al.  PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. , 2012, Nano letters.

[10]  F. Caruso,et al.  Targeting cancer cells: controlling the binding and internalization of antibody-functionalized capsules. , 2012, ACS nano.

[11]  S. Akira,et al.  Antibody-Antigen-Adjuvant Conjugates Enable Co-Delivery of Antigen and Adjuvant to Dendritic Cells in Cis but Only Have Partial Targeting Specificity , 2012, PloS one.

[12]  U. Schubert,et al.  A Sugar Decorated Macromolecular Bottle Brush by Carbohydrate-Initiated Cationic Ring-Opening Polymerization , 2012 .

[13]  T. Fahmy,et al.  Nanoparticle Delivery of Mycophenolic Acid Upregulates PD‐L1 on Dendritic Cells to Prolong Murine Allograft Survival , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  C. R. Becer,et al.  Thermal Properties of Oligo(2‐ethyl‐2‐oxazoline) Containing Comb and Graft Copolymers and their Aqueous Solutions , 2011 .

[15]  C. Bertozzi,et al.  From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions , 2011, Accounts of chemical research.

[16]  U. Schubert,et al.  Three-Fold Metal-Free Efficient (“Click”) Reactions onto a Multifunctional Poly(2-oxazoline) Designer Scaffold , 2011 .

[17]  R. Luxenhofer,et al.  Structure-property relationship in cytotoxicity and cell uptake of poly(2-oxazoline) amphiphiles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[18]  L. Bockenstedt,et al.  The impact of nanoparticle ligand density on dendritic-cell targeted vaccines. , 2011, Biomaterials.

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

[20]  Jason Park,et al.  Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery. , 2011, Molecular pharmaceutics.

[21]  C. Amiel,et al.  Click‐Chemistry: An Alternative Way to Functionalize Poly(2‐methyl‐2‐oxazoline) , 2011 .

[22]  Frank Caruso,et al.  Targeting of cancer cells using click-functionalized polymer capsules. , 2010, Journal of the American Chemical Society.

[23]  Karl Fischer,et al.  Evaluation of nanoparticle aggregation in human blood serum. , 2010, Biomacromolecules.

[24]  C. Loquai,et al.  Release of IL‐12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy , 2010, Journal of leukocyte biology.

[25]  Pilar M. Dominguez,et al.  Differentiation and function of mouse monocyte‐derived dendritic cells in steady state and inflammation , 2010, Immunological reviews.

[26]  J. Kopeček,et al.  HPMA copolymers: origins, early developments, present, and future. , 2010, Advanced drug delivery reviews.

[27]  R. Luxenhofer,et al.  Cylindrical Molecular Brushes of Poly(2-oxazoline)s from 2-Isopropenyl-2-oxazoline , 2009 .

[28]  M. Nolte,et al.  Inflammatory signals in dendritic cell activation and the induction of adaptive immunity , 2009, Immunological reviews.

[29]  A. Enk,et al.  Inhibition of Melanoma Growth by Targeting of Antigen to Dendritic Cells via an Anti-DEC-205 Single-Chain Fragment Variable Molecule , 2008, Clinical Cancer Research.

[30]  M. Textor,et al.  Poly-2-methyl-2-oxazoline: a peptide-like polymer for protein-repellent surfaces. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[31]  Samir Mitragotri,et al.  Shape Induced Inhibition of Phagocytosis of Polymer Particles , 2008, Pharmaceutical Research.

[32]  M. Essler,et al.  Synthesis, biodistribution and excretion of radiolabeled poly(2-alkyl-2-oxazoline)s. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[33]  Kandaswamy Vijayan,et al.  Micelles of Different Morphologies—Advantages of Worm-like Filomicelles of PEO-PCL in Paclitaxel Delivery , 2007, Pharmaceutical Research.

[34]  D. Discher,et al.  Shape effects of filaments versus spherical particles in flow and drug delivery. , 2007, Nature nanotechnology.

[35]  N. Shastri,et al.  In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Binder,et al.  Essential role of CD91 in re-presentation of gp96-chaperoned peptides. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[37]  K. Ulbrich,et al.  HPMA copolymers with pH-controlled release of doxorubicin: in vitro cytotoxicity and in vivo antitumor activity. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[38]  Michel C. Nussenzweig,et al.  Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance , 2002, The Journal of experimental medicine.

[39]  M. Garnett,et al.  Targeted drug conjugates: principles and progress. , 2001, Advanced drug delivery reviews.

[40]  H. Chéradame,et al.  Synthesis of polymers containing pseudohalide groups by cationic polymerization 15. Study of the functionalizing living cationic polymerization of 2-methyl-2-oxazoline in the presence of trimethylsilylazide , 2000 .

[41]  W. Binder,et al.  Block copolymers derived from photoreactive 2-oxazolines, 1. Synthesis and micellization behavior , 2000 .

[42]  K. Fischer,et al.  Amphipolar core-shell cylindrical brushes , 1999 .

[43]  T. Allen,et al.  Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes. , 1996, Journal of pharmaceutical sciences.

[44]  M. Woodle,et al.  New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes. , 1994, Bioconjugate chemistry.

[45]  L. Hutchinson,et al.  Soluble polymeric carriers for drug delivery. Part 2. Preparation and in vivo behaviour of N-acylethylenimine copolymers , 1989 .