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Biomedical Nanocrystal Agents: Design, Synthesis, and ApplicationsCho, Minjung 16 September 2013 (has links)
In these days, nanomaterials are applied in a variety of biomedical applications including magnetic resonance imaging (MRI), cell imaging, drug delivery, and cell separation. Most MRI contrast agents affect the longitudinal relaxation time (T1) and transverse relaxation time (T2) of water protons in the tissue and result in increased positive or negative contrast. Here, we report the optimization of r1 (1/T1) or r2 (1/T2) relaxivity dynamics with diameter controlled gadolinium oxide nanocrystals (2~22 nm) and iron based magnetic nanocrystals (4 ~33 nm). The r1 and r2 MR relaxivity values of hydrated nanocrystals were optimized and examined depending on their core diameter, surface coating, and compositions; the high r1 value of gadolinium oxide was 40-60 S-1mM-1, which is 10-15 fold higher than that of commercial Gd (III) chelates (4.3~4.6 S-1mM-1). Moreover, in vitro toxicological studies revealed that polymer coated nanocrystals suspensions had no significant effect on human dermal fibroblast (HDF) cells even at high concentration. Towards multimodal imaging or multifunctional ability, we developed the iron oxide/QDs complexes, which consist of cores of iron oxide that act as nucleation sites for fluorescent QDs. The choice of variable QDs helped to visualize and remove large iron oxide materials in a magnetic separation. Additionally, diluted materials concentrated on the magnet could be fluorescently detected even at very low concentration. The designed MRI or multifunctional nanomaterials will give great and powerful uses in biomedical applications.
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Engineering nanoparticles using chemical and biological approaches for tumor targeted deliveryNguyen, Tuyen January 1900 (has links)
Doctor of Philosophy / Department of Chemistry / Santosh Aryal / Nanotechnology offers exciting options for the site-selective delivery of chemotherapeutics and diagnostic agents using nanoparticles. Varieties of organic and inorganic nanomaterials have been explored extensively as a delivery system either in the form of drug carriers or imaging agents. Successful stories include the clinical translation of anticancer nanomedicines such as PEGylated liposomal doxorubicin (DOXIL®), albumin-bound paclitaxel (Abraxane®), and polymeric micelle loaded paclitaxel (Genexol®), which are currently used in the clinic as one of the first lines for cancer chemotherapies. These conventional nanomedicines rely on passive-drug targeting taking advantage of leaky tumor vasculature, called the Enhanced Permeability and Retention (EPR) effect. However, delivering biologically active components selectively to the diseased cell, for example, cancer, is highly challenging due to the biological barriers in the body including blood pool cells/proteins, heterogeneous microenvironment, and intracellular degradation. Therefore, the goal of this dissertation is to develop nanoplatforms that can deliver the agents of interest in targeted fashion to cancer while bypassing or collaborating with the biological barriers. The design consideration of these nanoplatforms centralizes on using simple chemical reactions and cell biology to engineer nanoparticles. The presented nanoparticles were extensively studied and evaluated for their biological functions using in vitro and in vivo models. These nanoconstructs described herein address current limitations of conventional nanomedicine such as (1) the lack of understanding of the interaction of nanoparticle and biological system, and (2) the lack of an effective targeting strategy to deliver drugs to the cancer cell in the tumors. The significant findings of each system will be highlighted and discussed throughout this dissertation. Results obtained highlight key findings such as NP intracellular fate, maximized tumor accumulation, and unique pharmacokinetics could open the avenues for systemic investigations for personalized medicine and lay the foundation for nanomedicine design to accelerate clinical translation.
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Expanded porphyrins as experimental anticancer agents and MRI contrast agentsPreihs, Christian 04 March 2014 (has links)
Texaphyrins represent the vanguard of experimental anticancer drugs and also symbolize a well-known example of expanded porphyrins, a class of oligopyrrolic macrocycles with tumor localization properties and powerful metal chelating properties. Chapter 1 of this thesis describes the unique structural characteristics of this complex synthetic molecule along with the biological relevance and scientific justifications for studying its anticancer properties and powerful MRI contrast ability. This Chapter also serves to underscore the need to improve further and refine the efficacy of texaphyrins as compounds that may be applied in the struggle against cancer. Chapter 2 details the synthesis of bismuth(III) and lead(II)-texaphyrin complexes that could potentially find use as [alpha]-core emitters for radiotherapy. In principle, porphyrins would ostensibly appear to be ideal ligands for use in radiotherapy due to their tumor-localizing ability. However, Bi(III)- and Pb(II)-porphyrin complexes are extremely rare, most reflecting the vastly challenging synthesis of these compounds as well as their general lack of stability. These limitations provided an incentive for us to use texaphyrins as more versatile ligands to prepare and fully characterize stable bismuth(III) and lead(II) complexes. To be of interest in future medical applications, we needed to prepare these complexes quickly as compared to the relevant time scales set by the half-lives of the isotopes targeted for use in radiotherapy. This goal was successfully realized. As mentioned above, texaphyrin is able to form stable complexes with a large variety of metals particularly in the lanthanide series. Gadolinium(III) complexes of texaphyrin have been studied in considerable detail. Chapter 3 details the synthesis and conjugation methods used to develop a texaphyrin conjugated dual mode nanoparticle contrast agent. This project has been done in collaboration with the group of Prof. Jinwoo Cheon (Yonsei University, Seoul, Korea), who demonstrated fascinating results with the texaphyrin functionalized nanoparticles. Not only do these conjugates act as improved magnetic resonance contrast agents displaying enhanced signals in both the T1 and T2 MRI modes, but also serve to sensitize apoptotic hyperthermia. It is this latter, double effector feature, that has been most extensively studied to date. Chapter 4 of this dissertation describes work done in close collaboration with Dr. Natalie Barkey and Dr. David Morse (Moffitt Cancer Center, Tampa, FL) where a gadolinium texaphyrin complex was developed that is able to target the melanocortin 1 receptor (MC1R) when encapsulated in a micellar system. As detailed in this Chapter, these collaborateurs demonstrated that these gadolinium-texaphyrin micelles are able to target MC1R-expressing xenograft tumors in vivo. This work relied on the supply of a new set of texaphyrin derivatives that were prepared and characterized as part of this dissertation work Chapter 5 of this disseration introduces sapphyrins, another class of expanded porphyrins with tumor selectivity. This project is based on the hypothesis that a direct linkage of sapphyrin with an anticancer agent based on ruthenium(II) could improve the efficacy of both compounds. Since sapphyrins exhibit limited ability to form stable complexes with transition metals, an appended 1,10-phenanthroline unit was chosen as an efficient N-donor aromatic ligand for ruthenium(II). Therefore, extensive synthetic efforts were made to form this sapphyrin-1,10-phenanthroline construct in an effort to stabilize a mixed sapphyrin-metallo-phenanthroline complex. Finally, Chapter 6 of this dissertation demonstrates the author's efforts to synthesize a planar rosarin species. Non-aromatic and non-planar rosarins have been known for over two decades. Through structural modification of the compound, namely through linking of both [Beta] positions on the bipyrrole unit, a new planar rosarin species has been synthesized exhibiting Hückel antiaromaticity. / text
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Development of photoswitchable charge-transfer materials with photochromic spirooxazines: from molecular systems to surfacesKurimoto, Aiko 28 February 2018 (has links)
Optical modulation of the physical properties of materials is important for future development of optical memories and switches, optoelectronics, and smart surfaces. Incorporation of an optically bistable photochromic compound into an electronically bifunctional material is a promising strategy for a development of photoswitchable materials. Photochromic spirooxazine ligands undergo light-induced ring-opening and closure between the closed-spirooxazine (SO) and open-photomerocynanine (PMC) forms. The structural reorganization leads to accompanying changes in electronic structure which can lead to a change in the oxidation/reduction potentials and spin state of a bound metal center. Changes in the ligand field about a metal center in turn can lead to “non-classical” photoinduced magnetic (PIM) effects. The “non-classical” PIM effect is an effect that occurs through ligand-centered processes via the metal center, rather than direct excitation at the metal center. The structural change of the photochromic compounds also results in a change in the frontier orbital energies and donor-acceptor character, which may lead to optically-gated charge-transfer and energy-transfer processes.
In this dissertation, the structural factors that govern thermal relaxation of spirooxazines, as optical control units, was investigated toward controlling the photostationary states of this important class of photochromes. The electronic structure of the PMC form of azahomoadamantyl-based spirooxazines was found to control the thermal coloration/decoloration rates of photochromic spirooxazines. A significant charge-separated character of the PMC form was correlated with the slow thermal coloration/decoloration rates in spirooxazines. This concept was then extended to an investigation of the effect of Lewis-acidic metal complexation. Solution study of the charge-separated character of the PMC form via metal complexation of the photochromic spirooxazines supported the correlation between the charge-separated character of the PMC form and the rate of the thermal coloration/decoloration. The studies provide a potential pathway for modulating PMC thermal relaxation rates through optimization of the structure of the spirooxazines and metal complexation. The studies were then extended to an investigation of the photomodulation of charge-transfer processes in cobalt multinuclear clusters by photoisomerization of photochromic spirooxazines. Incorporation of optically bistable phenanthroline-spirooxazine ligands into a magnetically bistable cobalt-dioxolene valence tautomeric cluster resulted in large magnetic moments in the solid and solution states. This study suggests that the redox-isomeric behavior of the cobalt dioxolenes can be coupled to isomerization of the photochromic ligand in the solution state when the π-acceptor ability of the photochromic ligands align with the direction of charge transfer of the cobalt dioxolene components. The potential of these cobalt multinuclear clusters to enhance the relaxivity of water in MRI for biological imaging was investigated. A cobalt tetranuclear cluster was prepared and found to exhibit high magnetic moments in solution at room temperature, and large relaxivities relative to commercially available gadolinium based MRI contrast agents. Lastly, the photomodulation of ionic doping of graphene organic field-effect transistors (OFETs) by photochromic spirooxazines was investigated. The electron donor or acceptor nature of the photochromic isomers modulates the direction and magnitude of ionic doping of graphene, and in turn the gate voltages of graphene OFETs, leading to optical modulation of OFET gate voltages for data processing and memory technologies. / Graduate / 2020-02-08
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Siloxane Based Cellular Labeling: Functional Applications in 1H MRIJanuary 2014 (has links)
abstract: Modern medical conditions, including cancer, traumatic brain injury, and cardiovascular disease, have elicited the need for cell therapies. The ability to non-invasively track cells in vivo in order to evaluate these therapies and explore cell dynamics is necessary. Magnetic Resonance Imaging provides a platform to track cells as a non-invasive modality with superior resolution and soft tissue contrast. A new methodology for cellular labeling and imaging uses Nile Red doped hexamethyldisiloxane (HMDSO) nanoemulsions as dual modality (Magnetic Resonance Imaging/Fluorescence), dual-functional (oximetry/ detection) nanoprobes. While Gadolinium chelates and super paramagnetic iron oxide-based particles have historically provided contrast enhancement in MRI, newer agents offer additional advantages. A technique using 1H MRI in conjunction with an oxygen reporter molecule is one tool capable of providing these benefits, and can be used in neural progenitor cell and cancer cell studies. Proton Imaging of Siloxanes to Map Tissue Oxygenation Levels (PISTOL) provides the ability to track the polydimethylsiloxane (PDMS) labeled cells utilizing the duality of the nanoemulsions. 1H MRI based labeling of neural stem cells and cancer cells was successfully demonstrated. Additionally, fluorescence labeling of the nanoprobes provided validation of the MRI data and could prove useful for quick in vivo verification and ex vivo validation for future studies. / Dissertation/Thesis / Masters Thesis Bioengineering 2014
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MOLECULAR IMAGING OF BREAST CANCER USING PARACEST MRIYoo, Byunghee 06 July 2007 (has links)
No description available.
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Imaging neuroinflammatory processes with USPIO-MRIBrown, Andrew Peter January 2009 (has links)
This thesis examines the utility of USPIO-MRI to provide a tool of tracking macrophage recruitment to sites of neuroinflammation within the CNS. Recruited macrophages and microglia resident in CNS tissue play a key role in the pathophysiology of a number of neuroinflammatory diseases such as neuropathic pain and multiple sclerosis. Under activated conditions, microglia and macrophages will phagocytose invading cells and CNS debris. It has been shown that ultrasmall superparamagnetic particles of iron oxide (USPIO), such as Sinerem, injected systemically, are engulfed by macrophages, which in turn migrate to sites of tissue injury. USPIOs can be visualised as a distinct reduction in signal intensity on T2* weighted MR images. However, there are still some issues regarding the distinction between iron-laden recruited macrophages and the entry of free iron across a permeable blood brain barrier (BBB) in disease cases. Hence, it was shown that intravenously injected Sinerem is cleared from the peripheral circulation within 24 hours, indentifying this as a time point as suitable for MCP-1 injection. Data showed that free USPIO can be visualised in the brain and that there is a linear relationship between Sinerem concentration and T2* signal intensity changes. MCP-1 induces macrophage recruitment to the site of microinjection and causes BBB breakdown at between 3 and 4 hours. In particular it was shown that T2* signal intensity changes are seen, in the presence of an intact BBB, as a result of Sinerem laden macrophages. This finding was verified by the co-localisation of ED-1 positive cells and Prussian blue positive regions. It was demonstrated that there is a strong correlation between T2* signal changes and the number of macrophages. This demonstrates that USPIO-MRI can be used to characterise macrophage infiltration in neuroinflammation in the presence of an intact BBB.
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Regiospecifické deriváty cyklamu pro radiomedicinské a MRI aplikace / Regiospecific cyclam derivatives for radiomedical and MRI utilizationsBlahut, Jan January 2013 (has links)
Cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives are widely used for various purposes. In a medicine they are applied as ligands for radiometals applied as diagnostic or therapeutic agents against tumours, hypoxic brain tissues etc. In this thesis a new method for asymmetric cyclam derivati- ves preparation was developed. New cyclam derivatives with trifluoroethyl groups were prepared too. Paramagnetic metal complexes with these fluori- nated ligands can be used as contrast agents for 19 F-MRI. Keywords: Cyclam; Non-symmetric protection; Contrast agents; Trifluoroethylamines; Paramagnetic relaxation; 19 F-MRI.
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Engineering magnetic properties of nanoparticles for biomedical applications and magnetic thin film composite heterostructures for device applications.Hunagund, Shivakumar 01 January 2019 (has links)
The motivation of this study is to investigate the size dependent properties of Gadolinium silicide nanoparticles and their potential applications in Biomedicine. We use two approaches in our investigation - size dependence and possible exchange interaction in a core-shell structure. Past results showed Gd5Si4 NPs exhibit significantly reduced echo time compared to superparamagnetic iron oxide nanoparticles (SPION) when measured in a 7 T magnetic resonance imaging (MRI) system. This indicates potential use of Gd5Si4 ferromagnetic nanoparticles as T2 contrast agents for MRI.
Until recently most contrast agents (CA) that are used in Magnetic Resonance Imaging (MRI) studies have been paramagnetic. However, ferromagnetic CAs are potentially more sensitive as T2 CAs than T1 paramagnetic compounds due to their large magnetic moments. Furthermore, the need for better MRI images without the need of upgrading to the higher magnetic field strength can be achieved using better CA such as Gd5Si4 NP. The quality of the image contrast in MRI is improved by shortening T1 and T2 relaxation times at the site or close proximity to the CA. In this study, effect of Gd5Si4 NP of varying sizes and with different concentrations are investigated on T1, T2 and T2* (effective/observed T2) relaxations times.
Further study was carried out on possible exchange interaction between Fe3O4 and Gd5Si4 to enhance the magnetic properties of the Gd5Si4 which could be later used to synthesize core-shell structures. Exchange interaction / bias is a phenomena associated with the exchange anisotropy created at the interface between the two magnetic materials. Therefore, thin films of varying thickness was deposited and studied for their magnetic properties.
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MRI Signal Intensity Analysis of Novel Protein-based MRI Contrast AgentsQian, Yan 12 August 2014 (has links)
Contrast agents are of great importance in clinical applications of Magnetic Resonance Imaging (MRI) to improve the contrast of internal body structures and to obtain tissue-specific image. However, current approved contrast agents still have limitations including low relaxivity, low specificity and uncontrolled blood circulation time, which motivated researchers to develop novel contrast agents with higher relaxivity, improved targeting abilities and optimal retention time. This thesis uses animal experimental data from Dr. Jenny J. Yang’s lab at the Department of Chemistry in Georgia State University to study effects of a class of newly designed protein-based MRI contrast agents (ProCAs). Models for the longitudinal data on MRI intensity are constructed to evaluate the efficiency of different MRI contrast agents. Statistically significant results suggest that ProCA1B14 has the great potential to be a tumor specific contrast agent and ProCA32 could be a promising MRI contrast agent for the liver imaging in clinical applications.
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