Titanium Dioxide Nanoparticles for Photodynamic Therapy A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences Christopher J. Cadman School of Pharmacy and Pharmaceutical Sciences 2013 Contents ____________________________________________________________________ Contents Contents ...................................................................................................................... 2 Abstract ..................................................................................................................... 12 Declaration and Copyright Statement ................................................................... 13 Dedication ................................................................................................................. 14 Acknowledgements ..................................................................................................... 5 List of Figures ............................................................................................................. 5 List of Equations ........................................................................................................ 9 List of Schemes ......................................................................................................... 10 List of Tables ............................................................................................................ 11 List of Abbreviations ............................................................................................... 16 1 Introduction ....................................................................................................... 19 1.1 Nanoparticles ......................................................................................................... 20 1.1.1 What is nano? ................................................................................................ 20 1.1.2 The unique properties of nanoparticles ......................................................... 21 1.1.3 The drive for stimulus responsive nanoparticles in biomedical applications 24 1.1.4 The medical potential for stimulus responsive inorganic nanoparticles ....... 27 1.2 Metal Oxides .......................................................................................................... 29 1.2.1 Overview of synthetic methods ....................................................................... 29 1.2.2 Sol-gel synthesis ............................................................................................. 30 1.2.3 The application of the sol-gel method for TiO2 nanoparticle preparation .... 35 1.3 Titanium dioxide .................................................................................................... 36 1.3.1 Current uses of micro/nano TiO2 .................................................................. 36 1.3.2 The structure of TiO2 ...................................................................................... 38 1.4 Photodynamic therapy............................................................................................ 39 1.5 The design of TiO2 nanoparticles for photodynamic therapy: Chemical, physical and biological aspects ........................................................................................................ 43 1.5.1 TiO2 nanoparticles: Synthesis, size and structure .......................................... 43 1.5.2 TiO2 nanoparticles: Surface composition and biological aspects ................. 45 1.6 Scope of thesis and Authors Contribution ............................................................. 51 1.6.1 Author’s Contributions .................................................................................. 52 1.7 References .............................................................................................................. 53 1.8 Appendix - Nanocharacterisation Techniques and Examples of Their Application 65 2 Contents ____________________________________________________________________ 1.8.1 Introduction .................................................................................................... 65 1.8.2 Experimental Details...................................................................................... 65 1.8.3 X-ray Diffraction (XRD) ................................................................................ 67 1.8.4 Dynamic Light Scattering .............................................................................. 69 1.8.5 Transmission Electron Microscopy................................................................ 76 1.8.6 Atomic Force Microscopy .............................................................................. 80 1.8.7 Appendix References ...................................................................................... 85 2 “Non-aqueous” route to titanium dioxide nanoparticles. Can water really be omitted from the reaction mechanism?............................................................. 87 Abstract .............................................................................................................................. 88 2.1 Introduction ............................................................................................................ 89 2.2 Experimental Section ............................................................................................. 93 2.2.1 Materials ........................................................................................................ 93 2.2.2 Preparation of nanoparticles ......................................................................... 93 2.2.3 Physico-chemical characterization ................................................................ 94 2.3 Results and Discussion .......................................................................................... 95 2.3.1 Role of water in the non-aqueous route. ........................................................ 95 2.3.2 Primary particles (room temp. nucleation). ................................................... 97 2.3.3 Secondary particles (thermal growth). .......................................................... 98 2.3.4 Tertiary particles (solvent-dependent agglomeration). ............................... 100 2.3.5 Internal structure of secondary nanoparticles. ............................................ 103 2.4 Conclusion ........................................................................................................... 108 2.5 References ............................................................................................................ 109 2.6 Supplementary Information ................................................................................. 113 2.6.1 Preparation of Nanoparticles from TiCl4 .................................................... 113 2.6.2 Thermal growth phase at Ti/Cl = 0.5 .......................................................... 113 2.6.3 Nanoparticle growth: surface condensation model ..................................... 114 2.6.4 Static Light Scattering (SLS) measurements ................................................ 115 3 Effect of ligand adsorption and PEGylation on the photoactivity of anatase nanoparticles ........................................................................................................... 117 Abstract ............................................................................................................................ 118 3.1 Introduction .......................................................................................................... 119 3.2 Experimental section ............................................................................................ 121 3.2.1 Materials and methods ................................................................................. 121 3.2.2 Physico-chemical characterization .............................................................. 121 3.2.3 Preparative procedures ................................................................................ 122 3 Contents ____________________________________________________________________ 3.2.4 Surface functionalization of nanoparticles .................................................. 125 3.2.5 Photo-oxidative activity of nanoparticles .................................................... 126 3.2.6 Biological investigations .............................................................................. 127 3.3 Results and Discussion ........................................................................................ 129 3.3.1 Nanoparticle surface functionalization ........................................................ 129 3.3.2 Photoactivity of Nanoparticles ..................................................................... 137 3.4 Conclusions .......................................................................................................... 140 3.5 References ............................................................................................................ 140 3.6 Supplementary Information ................................................................................. 144 3.6.1 Adsorption of catechol ligands on titania nanoparticles ............................. 144 3.6.2 Degradation of methylene blue .................................................................... 147 4 Titania-mediated UV-triggered release from multilayered polymer walled microspheres ..........................................................................................................