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Chapter 1: Introduction and Background…………………………………………….…...1 Synthesis and Characterization of Novel Inorganic Nanoparticles for Diagnostic and Therapeutic Applications A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Vindya S. Perera December, 2014 Dissertation written by Vindya S. Perera B.S., University of Peradeniya, SriLanka, 2006 Ph.D., Kent State University, USA, 2014 Approved by __________________________________ Songping Huang, Professor, Ph.D., Department of Chemistry & Biochemistry, Doctoral Advisor __________________________________ Scott D. Bunge, Professor, Ph.D., Department of Chemistry & Biochemistry __________________________________ Mietek Jaroniec, Professor, Ph.D., Department of Chemistry & Biochemistry __________________________________ Qi-Huo Wei, Professor, Ph.D., Liquid Crystal Institute __________________________________ Ernest Freeman, Professor, Ph.D., Department of Biological Sciences Accepted by __________________________________ Michael J. Tubergen, Professor, Ph.D., Chair, Department of Chemistry & Biochemistry __________________________________ James L. Blank, Professor, Ph.D., Dean, College of Arts and Sciences TABLE OF CONTENTS List of figures……………………………………………………………………….…..iii List of schemes……………………………………………………………………….....ix List of tables……………………………………………………………………………..x Acknowledgments……………………………………………………………………...xi Chapter 1: Introduction and background…………………………………………….…...1 1.1. Magnetic resonance imaging (MRI)………………………………………….…...1 1.1.1 Contrast agents for MRI……………………………………………………..…...6 1.2. X-ray computed tomography (CT)………………………………………….....….9 1.2.1 Contrast agents for X-ray computed tomography (CT)……………………....10 1.3. Contrast agents for dual MRI/CT modalities…………………………………...16 1.4. Targeting intracellular copper ions for selective removal………………….…..17 1.4.1 Intracellular copper removal as a potentially more effective treatment for the Wilson’s disease……………………………………………………………......19 1.4.2. Copper depletion as a novel strategy for angiogenesis inhibition………....…23 Chapter 2: Materials and Methods ……………………………………………….……....28 2.1 Materials…………………………………………………………………….……..28 2.2 Experimental design and techniques…………………………………………......29 2.3 Experimental methodology………………………..................................................29 2.4 Instrumentation…………………………………………………………………....30 2.4.1 Powder X-ray diffraction spectroscopy (PXRD)……………………...30 2.4.2 Transmission electron microscopy (TEM) and energy dispersive X-ray (EDX)…………………………………………………………………...30 2.4.3 Thermogravimetric analysis (TGA)……………………………………31 iii 2.4.4 Fourier transform infrared spectroscopy (FTIR)…………………….31 2.4.5 Confocal microscopy…………………………………………………....31 2.4.6 T1 and T2 measurements…………………………………………….….32 2.4.7 Atomic absorption measurements……………………………………..32 2.5 Experimental calculations………………………………………………………...33 2.5.1 Relaxivity (r1 and r2 values)………………………………………….....33 Chapter 3: Contrast agents for magnetic resonance imaging………………………34 3.1. Gadolinium-based MRI contrast agents………………………………………...34 3.2. Biocompatible nanoparticles of KGd(H2O)2[Fe(CN)6]•H2O with extremely high T1-weighted relaxivity owing to two water molecules directly bound to the Gd(III) center..................................................................................................................38 3.3. Manganese-based MRI contrast agents………………………………………....64 3.4. PVP-coated KMn[Fe(CN)6] nanoparticles as a potential contrast agent for MRI............................................................................................................................66 Chapter 4: Contrast agents for X-ray computed tomography……………………...81 4.1 Nanoparticles of the novel coordination polymer KBi(H2O)2[Fe(CN)6].H2O as a potential contrast agent for computed tomography…………………………...83 4.2. Nanoparticles of KBiXGd(1-X)[Fe(CN)6] as a potential bimodal contrast agent for MRI and CT………………………………………………………………...95 Chapter 5: Nanoparticles for therapeutic applications……………………………….105 5.1. Cell permeable Au@ZnMoS4 core-shell nanoparticles: Towards a novel cellular copper detoxifying drug for Wilson’s disease…………….…………………….......106 5.2. Nanoparticles of ZnMoS4 as novel inhibitors of angiogenesis………………...125 Chapter 6: Conclusions…………………………………………………………………….148 References……………………………………………………………………………….……150 iv List of figures Figure 3.1: TEM image of as prepared nanoarticles of KGdPB nanoparticles…………………40 Figure 3.2: EDX spectrum on a PVP-coated nanoparticle……………………………………...41 Figure 3.3: The FT-IR spectra of sodium citrate, PVP, bulk compound and nanoparticles alone……………………………………………………………………………………………..42 Figure 3.4: Powder X-ray diffraction spectra for the as-prepared KGd [Fe(CN)6].3H2O………44 Figure 3.5: The unit-cell packing diagram of KGd(H2O)2[Fe(CN)6]•H2O (left) with the K+ ion and zeolitic water molecule omitted for clarity. The coordination environment of the Gd3+ ion (middle and right) showing two water molecules directly bound to the metal center……………………………………………………………………………………...44 II Figure 3.6: The TGA curve of bulk KGd(H2O)2[Fe (CN)6] H2O sample……………………....45 3+ Figure 3.7: The graph of 1/T1 (i=1,2) versus Gd -concentration at the magnetic field strength of 1.4 T………………………………………………………………………………....47 3+ Figure 3.8: The graph of 1/T1 (i=1,2) versus Gd -concentration at the magnetic field strength of 7.0 T………………………………………………………………………………....48 3+ Figure 3.9: The plot of 1/Ti (i=1,2) versus Gd -concentration at the magnetic field strength of 1.4 T for PVP coated nanoparticles……………………………………………….....49 Figure 3.10: The plot of r1 vs the hydrodynamic particle size for KGdPB nanoparticles……..50 Figure 3.11: The plot of r2 vs the hydrodynamic particle size for KGdPB nanoparticles……...50 Figure 3.12: T1-weighted MR phantom images of KGdPB nanoparticles with various Gd3+-concentrations using a 7.0-T scanner………………………………………………….…...53 Figure 3.13: T2-weighted MR phantom images of KGdPB nanoparticles with various Gd3+-concentrations using a 7.0-T scanner……………………………………………………....55 v Figure 3.14: Fluorescence spectra of carboxyfluorescein dye and dye labeled nanoparticles....56 Figure 3.15: Confocal microscopic images of Hela cell line (A) Fluorescence image of cells incubated with dye conjugated nanoparticles for 3 hrs (B) Bright field image of cells incubated with dye conjugated nanoparticles for 3 hrs (C) flurescence image of untreated cells. (D) Bright field image of untreated cells………………………….………………………………….……..58 Figure 3.16: Viability of Hela cells after incubation with KGdPB nanoparticles for 24 hrs and 48 hrs (Trypan Blue exclusion assay)…………………………………………………….....59 Figure 3.17: CN- releasing test for different conditions…………………………………………61 Figure 3.18: Gd3+ releasing test for different conditions………………………………………..62 Figure 3.19: T1-weighted MRI phantoms of PC3 cells incubated in PBS buffer (left), 0.13 mM nanoparticles (central), and 0.25 mM nanoparticles (right) for 6 hours. The images were collected using a Bruker 9.4-T scanner………………………………………………………....63 Figure 3.20: TEM images of PVP-coated KMn[Fe(CN)6 nanoparticles……………………......68 Figure 3.21: PXRD pattern of bulk MnPB……………………………………………………...69 Figure 3.22: Crystal structure of bulk MnPB, color code: red=K, dark yellow=Fe and Mn, yellow=C, blue=N…………………………………………………………………………….....70 Figure 3.23: Overlay of the IR spectra of bulk (red) and nanoparticles (blue) of MnPB and PVP (green) alone…………………………………………………………………………...71 −1 Figure 3.24: Longitudinal relaxation rates (1/T1, s ) of MnPB NPs as a function of the manganese concentration (mM)………………………………………………………………....72 −1 Figure 3.25: Transverse relaxation rates (1/T2, s ) of MnPB NPs as a function of the manganese concentration (mM)………………………………………………………………....73 vi 2+ Figure 3.26: T2-weighted MRI phantoms of NPs with various Mn -concentrations using a 9.4-T scanner…………………………………………………………………………………..74 Figure 3.27: Mn2+ leaching results of MnPB NPs under different conditions……………….....75 - III Figure 3.28: CN leaching results of KMn[Fe (CN)6 under different conditions……………...76 Figure 3.29: Viability of Hela cells after incubation with MnPB NPs for 24 hrs and 48 hrs (Trypan Blue exclusion viability assay)………………………………………………………....77 Figure 3.30: Confocal microscopic images of Hela cell line (A) Bright field image of cells incubated with dye conjugated nanoparticles for 4 hrs. (B) Fluorescence image of cells incubated with dye conjugated nanoparticles for 4 hrs. (C) Bright field image of untreated cells. (D) Fluorescence image of untreated cells……………………………………………………....79 Figure 3.31: T2-weighted MRI phantoms of Hela cells incubated in PBS buffer (left), 0.2 mM NPs (central), and 0.5 mM NPs (right) for 6 hours. The images were collected using a Bruker 9.4-T scanner……………………………………………………………………80 Figure 4.1: TEM image of KBi(H2O)2[Fe(CN)6].H2O nanoparticles………………………......84 Figure 4.2: EDX spectrum on a typical PVP-coated nanoparticle………………………….…..85 Figure 4.3: Rietveld refinement plot: difference between observed and calculated patterns is shown at the bottom; reflection positions are shown as vertical lines…………………………..87 Figure 4.4: Crystal structure of KBi(H2O)2[Fe(CN)6].H2O with Bi and Fe shown in yellow and blue polyhedra, respectively. Cyanide ions are shown as thick cylinders (N, blue; C, gray balls). K ions are depicted as large balls………………………………………………..…...…..88 Figure 4.5: The FT-IR spectrum of PVP-coated nanoparticles……………………………........89 vii Figure 4.6: The TGA curve of bulk KBi(H2O)2[Fe(CN)6]·H2O sample…………….……….....90 Figure 4.7: Viability
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