The ongoing effort to improve the sensitivity and information content of NMR spectroscopy and MRI has important implications in scientific research and medical diagnostics. In this dissertation, a variety of approaches have been investigated and expanded on in an effort to contribute to this field. First, cryptophanes are cage-shaped molecules that have previously been used to encapsulate molecules of interest for a number of potential applications--including gas sensing and biosensing. In one set of studies, encapsulation of molecular hydrogen gas (H2) has shown different behavior compared to other small organic molecules in C111 (up until now, the smallest cryptophane). The transient, non-covalent binding was studied by variable-temperature NMR at different fields up to 950 MHz. A mathematical model that considers multiple-H2 binding was developed to better understand the physics and binding process, with predictions compared to experimental data (and rationalized in light of quantum chemical calculations on possible H2@C111 complexes). To our knowledge, C111 is the only system to reversibly trap multiple H2 gas molecules non-covalently under mild conditions. In a second series of studies, the interaction of laser-polarized xenon and a water-soluble cryptophane was studied. Despite the low concentration of xenon in aqueous solution, it was possible to achieve polarization transfer from xenon to cryptophane spins via the SPINOE (spin-polarization induced nuclear Overhauser effect). The SPINOE enhancements, along with the 129Xe NMR spectra, provide information about the interaction of the Xe-cryptophane complex (variants of which are now used in so-called xenon biosensors). This was our first in-house successful application of hyperpolarized xenon as a signal source for the spins of other molecules, leading the way to a number of ongoing studies. Although the absolute NMR enhancements obtained via the SPINOE were small, much larger enhancements were studied in a technique that uses para-hydrogen (pH2)--a spin isomer of normal molecular hydrogen)--as the source of spin order. As with the xenon experiments (and the H2 binding experiments), pH2 must be delivered as a gas to a sealed sample prior to performing the NMR experiments. Parahydrogen-induced polarization (PHIP) is an emerging field in enhancing the sensitivity in NMR experiments and may play an important role in MRI studies. Within this field a very recent phenomena of signal amplification by reversible exchange (SABRE) was investigated. The reproducibility of this recent discovery has been examined and new conclusions about the mechanism of this technique are delineated. NMR signal enhancements of nearly ~400-fold are reported. Moreover, a new water soluble NHC-Iridium catalyst was synthesized and investigated in SABRE related studies. We also report the first studies of SABRE-enhancement in biologically tolerable solvents--opening a door to the development of SABRE-hyperpolarized metabolic contrast agents for subsecond molecular imaging in the body. Although much of the above work was motivated by the desire to improve NMR/MRI sensitivity enhancement, other efforts concerned the other side of the equation--improving NMR/MRI information content. The next section concerns our efforts to investigate use of Variable-Angle (VA) NMR to study composite liquid crystal (LC) media comprised of stretched polyacrylamide gels (SAG) and embedded bacteriophage Pf1 particles. This in situ combination exploited the apparent interference between the different solute-aligning properties of the two LC components--yielding composite media with alignment properties that can differ in a tunable manner from those obtained with each medium alone. Characterization of alignment of both large and small molecules provides more insight into the nature of solute alignment that those composite phases introduce--with the goal of developing this approach as a new technique for studying molecular structure and dynamics via the dipolar and quadrupolar couplings that are restored in liquid-crystalline media. Finally the use of SPIONS--superparamagnetic iron oxide nanoparticles--as contrast agents is a relatively new approach to enhance information content in MRI studies; this is particularly true for SPIONs that have been surface-functionalized to achieve an environment-sensitive MR response. Novel surface-functionalized SPIONs were investigated by examining their effect on nuclear spin relaxation in aqueous environments simulating bodily tissues. More specifically, the pH and ionic strength dependent properties of selected dendron-functionalized and polymer-functionalized SPIONs have been examined. Of particular interest to this dissertation is how environment-mediated transient clustering of the SPIONs gives rise to changes in so-called transverse (homogeneous) spin relaxation rates as measured by following the decay of MR signals detected after the application of a series of radio-frequency (RF) pulses. In order to better understand these effects in the context of the SPIONs' behavior, a mathematical model is under development whose predictions are compared with experimental data. Aspects of the model are also compared to transmission electron micrography (TEM) and dynamic light scattering (DLS).

Det här är historien om Robert Hanssen. Mannen som levde ett vanligt liv utåt sett. Istället levde han ett liv av lögner och bedrog både sin familj och sitt land.

This study explored the imaging capability of our frequency-domain photoacoustic (FD-PA) system that utilizes correlation processing alias “photoacoustic radar” and ultrasonic phased array for imaging of soft tissues. The probe imaging capabilities were studied using tissue-mimicking phantoms, tissue samples ex vivo, blood vessels in a human wrist and a rat tumour model in vivo. Our experimental results have shown decent image correlation between our FD-PA and a clinical ultrasound modality. In comparison with ultrasound, we have also demonstrated strong potential of the FD-PA for deep (~15 mm) subsurface imaging with excellent contrast and high signal-to-noise ratio. Additionally, we assessed the potential of silica-coated super paramagnetic iron oxide nanoparticles (SPION) as a novel PA contrast agent. Detection of the nanoparticles up to 24 mm inside an optically tissue-like turbid media and about 5-fold PA signal amplification due to their presence in sheep blood (~1.4 mg/ml) are presented.

This study explored the imaging capability of our frequency-domain photoacoustic (FD-PA) system that utilizes correlation processing alias “photoacoustic radar” and ultrasonic phased array for imaging of soft tissues. The probe imaging capabilities were studied using tissue-mimicking phantoms, tissue samples ex vivo, blood vessels in a human wrist and a rat tumour model in vivo. Our experimental results have shown decent image correlation between our FD-PA and a clinical ultrasound modality. In comparison with ultrasound, we have also demonstrated strong potential of the FD-PA for deep (~15 mm) subsurface imaging with excellent contrast and high signal-to-noise ratio. Additionally, we assessed the potential of silica-coated super paramagnetic iron oxide nanoparticles (SPION) as a novel PA contrast agent. Detection of the nanoparticles up to 24 mm inside an optically tissue-like turbid media and about 5-fold PA signal amplification due to their presence in sheep blood (~1.4 mg/ml) are presented.

No description available.

Ce manuscrit de thèse présente la synthèse de nanoparticules d’oxyde de fer superparamagnétiques couramment appelées SPIONs servant d’agents de contraste pour l’imagerie par résonance magnétique (IRM) et la génération de chaleur pour la thérapie cellulaire par hyperthermie induite par champ magnétique radiofréquence (HMRF). Le contrôle des tailles et de la distribution en tailles des SPIONs et donc de leurs propriétés magnétiques a été obtenu en utilisant un copolymère arborescent G1 (substrat de polystyrène branché en peigne noté G0, greffé avec des groupements pendants poly(2-vinyle pyridine) ) comme milieu « gabarit », tandis que la stabilité colloïdale et la biocompatibilité des SPIONs ont été apportées par un procédé de poly-complexation ionique grâce à un copolymère double-hydrophile acide polyacrylique-bloc-poly(acrylate de 2-hydroxyéthyle) PAA-b-PHEA. / This Ph.D. dissertation describes the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) designed to serve as magnetic resonance imaging (MRI) contrast agents and for heat generation in cellular radiofrequency magnetic field hyperthermia (MFH) treatment. Control over the size and size distribution of the iron oxide nanoparticles (NPs), and thus over their magnetic properties, was achieved using a G1 arborescent copolymer (comb-branched (G0) polystyrene substrate grafted with poly(2-vinylpyridine) side chains, or G0PS-g-P2VP) as a template. Good colloidal stability and biocompatibility of the SPIONs were achieved via the formation of polyion complex (PIC) micelles with a poly(acrylic acid)-block-poly(2-hydroxyethyl acrylate) (PAA-b-PHEA) double-hydrophilic block copolymer.

While many investigations have been performed to establish a better understanding of the effects that magnetic fields and nanoparticles have on cells, the fundamental mechanisms behind the interactions are still yet unknown, and investigations on concurrent exposure are quite limited in scope. This study was therefore established to investigate the biological impact of concurrent exposure to magnetic nanoparticles and extremely-low frequency magnetic fields using an in-vitro CHO-K1 cell line model, in an easily reproducible manner to establish grounds for further in-depth mechanistic, proteomic, and genomic studies. Cells were cultured and exposed to 10nm Fe3O4 nanoparticles, and DC or low frequency (0Hz, 50Hz, and 100Hz) 2.0mT magnetic fields produced by a Helmholtz coil pair. The cells were then observed under confocal fluorescence microscopy, and subject to MTT biological assay to determine the synergistic effects of these concurrent exposures. No effects were observed on cell morphology or microtubule network; however, cell viability was observed to decrease more drastically under the combined effects of magnetic field and nanoparticle exposures, as compared to independent exposures alone. It was concluded that no significant difference was observed between the types of magnetic fields, and their effects on the nanoparticle exposed cells, but quite clearly there are deleterious synergistic effects of these concurrent magnetic field and nanoparticle exposure conditions.

<p>Multifunctional drug delivery systems incorporated with stimuli-sensitive drug release, magnetic nanoparticles and magnetic resonance (MR) <em>T</em>₂ contrast agents is attracting increasing attention recently. In this thesis, works on polymer nanospheres response to temperature change, superparamagnetic iron oxide nanoparticles (SPION)/polymeric composite materials for MR imaging contrast agents are summarized.</p><p>A “shell-in-shell” polymeric structure has been constructed through a “modified double-emulsion method”. Thermosensitive inner shell is comprised of poly(<em>N</em>-isopropylacrylamide) which undergoes phase transition at body temperature. Such a feature could facilitate drug release at an elevated temperature upon administration. Furthermore, the dual-shell structure is covered by a layer of gold nanoparticles. According to the cytotoxicity tests, the biocompatibility is shown to be enhanced due to the layer of gold.</p><p>SPION have been prepared using a high temperature decomposition method. Particle growth of SPION is monitored by transmission electron microscope and synchrotron X-ray diffraction. Poly(L,L-lactide)@SPION (PLLA@SPION) composite particles have been prepared through surface-initiated ring-opening polymerization which has been developed in our lab. For biomedical applications, it is essential to transfer the particles to physiological solutions from organic solutions. Phase transfer of SPION has been carried out by utilizing small molecules. Stability at the neutral pH is of large concern for such transfer systems. A novel phase transfer agent, Pluronic F127 (PF127), a triblock copolymer has been applied and the stability of the aqueous PF127@oleic acid (OA)@SPION solution has been greatly enhanced over a broad pH range. Most interestingly, PF127@OA@SPION show remarkable efficacy as T2 contrast agents as indicated by relaxometric measurements compared with commercially available products.</p>

Diagnostic ultrasound (US) is safer, quicker and cheaper than other diagnostic imaging modalities. Over the past two decades, the applications of US imaging has been widened due to the development of injectable, compressible and encapsulated microbubbles (MBs) that provide an opportunity to improve conventional echocardiographic imaging, blood flow assessment and molecular imaging. The encapsulating material is manufactured by different biocompatible materials such as proteins, lipids or polymers. In current research, researchers modify the encapsulated shell with the help of advanced molecular chemistry techniques to load them with dyes (for fluorescent imaging), nanoparticles and radioisotopes (for multimodal imaging) or functional ligands or therapeutic gases (for local drug delivery). The echogenicity and the radial oscillation of MBs is the result of their compressibility, which undoubtedly varies with the encapsulated shell characteristics such as rigidity or elasticity. In this thesis, we present acoustic properties of novel type of polyvinyl alcohol (PVA)-shelled microbubble (PVA-MB) that was further modified with superparamagnetic iron oxide nanoparticles (SPIONs) to work as a dual-modal contrast agent for magnetic resonance (MR) imaging along with US imaging. Apparently, the shell modification changes their mechanical characteristics, which affects their acoustic properties. The overall objective of the thesis is to investigate the acoustic properties of modified and unmodified PVA-MBs at different ultrasound parameters. The acoustic and mechanical characterization of SPIONs modified PVA-MBs revealed that the acoustical response depends on the SPION inclusion strategy. However they retain the same structural characteristics after the modification. The modified MBs with SPIONs included on the surface of the PVA shell exhibit a soft-shelled behavior and produce a higher echogenicity than the MBs with the SPIONs inside the PVA shell. The fracturing mechanism of the unmodified PVA-MBs was identified to be different from the other fracturing mechanisms of conventional MBs. With the interaction of high-pressure bursts, the air gas core is squeezed out through small punctures in the PVA shell. During the fracturing, the PVA-MBs exhibit asymmetric (other modes) oscillations, resulting in sub- and ultra-harmonic generation. Exploiting the US imaging at the other modes of the oscillation of the PVA-MBs would provide an opportunity to visualize very low concentrations of (down to single) PVA-MBs. We further introduced the PVA-MBs along with particles mimicking red blood cells in an acoustic standing-wave field to observe the acoustic radiation force effect. We observed that the compressible PVA-MBs drawn toward pressure antinode while the solid blood phantoms moved toward the pressure node. This acoustic separation method (acoustophoresis) could be an efficient tool for studying the bioclearance of the PVA-MBs in the body, either by collecting blood samples (in-vitro) or by using the extracorporeal medical procedure (ex-vivo) at different organs. Overall, this work contributes significant feedback for chemists (to optimize the nanoparticle inclusion) and imaging groups (to develop new imaging sequences), and the positive findings pave new paths and provide triggers to engage in further research. / <p>QC 20150827</p> / 3MiCRON

Multifunctional drug delivery systems incorporated with stimuli-sensitive drug release, magnetic nanoparticles and magnetic resonance (MR) T2 contrast agents is attracting increasing attention recently. In this thesis, works on polymer nanospheres response to temperature change, superparamagnetic iron oxide nanoparticles (SPION)/polymeric composite materials for MR imaging contrast agents are summarized. A “shell-in-shell” polymeric structure has been constructed through a “modified double-emulsion method”. Thermosensitive inner shell is comprised of poly(N-isopropylacrylamide) which undergoes phase transition at body temperature. Such a feature could facilitate drug release at an elevated temperature upon administration. Furthermore, the dual-shell structure is covered by a layer of gold nanoparticles. According to the cytotoxicity tests, the biocompatibility is shown to be enhanced due to the layer of gold. SPION have been prepared using a high temperature decomposition method. Particle growth of SPION is monitored by transmission electron microscope and synchrotron X-ray diffraction. Poly(L,L-lactide)@SPION (PLLA@SPION) composite particles have been prepared through surface-initiated ring-opening polymerization which has been developed in our lab. For biomedical applications, it is essential to transfer the particles to physiological solutions from organic solutions. Phase transfer of SPION has been carried out by utilizing small molecules. Stability at the neutral pH is of large concern for such transfer systems. A novel phase transfer agent, Pluronic F127 (PF127), a triblock copolymer has been applied and the stability of the aqueous PF127@oleic acid (OA)@SPION solution has been greatly enhanced over a broad pH range. Most interestingly, PF127@OA@SPION show remarkable efficacy as T2 contrast agents as indicated by relaxometric measurements compared with commercially available products. / QC 20101115