Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2016 Targeted nanovaccines against respiratory pathogens Jonathan Tate Goodman Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Allergy and Immunology Commons, Chemical Engineering Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Polymer Chemistry Commons Recommended Citation Goodman, Jonathan Tate, "Targeted nanovaccines against respiratory pathogens" (2016). Graduate Theses and Dissertations. 15023. https://lib.dr.iastate.edu/etd/15023 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. i Targeted nanovaccines against respiratory pathogens by Jonathan Tate Goodman A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Chemical Engineering Program of Study Committee: Balaji Narasimhan, Major Professor Michael J. Wannemuehler Ian C. Schneider Jacqueline V. Shanks Marian L. Kohut Iowa State University Ames, Iowa 2016 Copyright © Jonathan Tate Goodman, 2016. All rights reserved. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ....................................................................................................................... viii CHAPTER 1: INTRODUCTION ................................................................................................................. 1 1.1 References ........................................................................................................................................... 2 1.2 Figures ................................................................................................................................................ 5 CHAPTER 2: LITERATURE REVIEW ...................................................................................................... 6 2.1 Polymeric Vaccine Delivery Systems ................................................................................................. 6 2.1.1 Introduction .................................................................................................................................. 6 2.1.2 Polyesters ..................................................................................................................................... 8 2.1.3 Polyanhydrides ........................................................................................................................... 12 2.1.4 Natural polymers and polysaccharides ....................................................................................... 16 2.1.5 Liposomes .................................................................................................................................. 18 2.2 Targeted Delivery of Vaccines ......................................................................................................... 20 2.2.1 Introduction ................................................................................................................................ 20 2.2.2 Types of PRRs ........................................................................................................................... 21 2.2.3 Co-stimulation and crosstalk ...................................................................................................... 28 2.2.4 Targeting mechanisms ............................................................................................................... 29 2.2.5 Targeted vaccines for respiratory viruses .................................................................................. 36 2.3 Influenza Virus and Influenza Vaccines ........................................................................................... 37 2.3.1 Introduction ................................................................................................................................ 37 2.3.2 Structure and pathogenicity ....................................................................................................... 38 2.3.3 H1N1 Virus ................................................................................................................................ 45 2.3.4 Traditional vaccines and new vaccination approaches .............................................................. 46 2.4 Conclusions ....................................................................................................................................... 53 2.5 References ......................................................................................................................................... 54 2.6 Figures .............................................................................................................................................. 77 2.7 Tables ................................................................................................................................................ 84 CHAPTER 3: RESEARCH OBJECTIVE AND THESIS ORGANIZATION ........................................... 88 3.1 Research Objectives .......................................................................................................................... 88 3.2 Thesis Organization .......................................................................................................................... 90 iii CHAPTER 4: NANOPARTICLE CHEMISTRY AND FUNCTIONALIZATION DIFFERENTIALLY REGULATES DENDRITIC CELL-NANOPARTICLE INTERACTIONS AND TRIGGERS DENDRITIC CELL MATURATION .......................................................................... 91 4.1 Abstract ............................................................................................................................................. 92 4.2 Introduction ....................................................................................................................................... 93 4.3. Materials and Methods ..................................................................................................................... 95 4.3.1 Materials .................................................................................................................................... 95 4.3.2 Monomer and Polymer Synthesis .............................................................................................. 97 4.3.3 Nanoparticle Synthesis: .............................................................................................................. 97 4.3.4 Nanoparticle Functionalization .................................................................................................. 98 4.3.5 Characterization of Functionalized Nanoparticles ..................................................................... 98 4.3.6 Dendritic Cell Culture and Stimulation...................................................................................... 99 4.3.7 Flow Cytometric Analysis and Cytokine Secretion Assays ..................................................... 100 4.3.8 Serum Protein Adsorption onto Nanoparticles ........................................................................ 100 4.3.9 Characterization of Protein Adsorption ................................................................................... 101 4.3.10 Statistical Analysis ................................................................................................................. 102 4.4 Results ............................................................................................................................................. 102 4.4.1 Nanoparticle characterization .................................................................................................. 102 4.4.2 Serum protein adsorption influenced 20:80 CPH:SA nanoparticle internalization ................................................................................................................................... 103 4.4.3 DC surface marker expression is differentially regulated by chemistry and functionalization ............................................................................................................................... 104 4.4.4 DC cytokine production is differentially regulated by nanoparticle chemistry and functionalization ......................................................................................................................... 105 4.4.5 Adsorption of immune activating serum proteins onto polyanhydride nanoparticles ..................................................................................................................................... 106 4.5 Discussion ....................................................................................................................................... 107 4.6 Conclusions ..................................................................................................................................... 114 4.7 Acknowledgments ........................................................................................................................... 115 4.8 References ....................................................................................................................................... 115 4.9 Figures ...........................................................................................................................................