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Near-IR plasmonic contrast agents for molecular imaging, cell tracking and clinical translationJoshi, Pratixa Paritosh 11 August 2015 (has links)
Gold nanoparticles attain an intense focus in biomedical imaging applications due to their unique optical properties, facile conjugation with biomolecules, and biocompatibility. Although a considerable amount of work towards the development of gold nanoparticles has been completed, these promising contrast agents have not yet reached the clinic due to several challenges including efficient accumulation at the diseased site, sensitivity of detection in vivo, potential adverse effects, and clearance from the body. High signal-to-background ratio is required to enhance sensitivity of detection. Because near infrared (near-IR) light has the best tissue penetration, contrast agents designed to work in this range can significantly increase imaging sensitivity. Moreover, efficient targeting of the molecular biomarkers on diseased cells can decrease the required dosage, increase the site-specific accumulation, and enhance the imaging sensitivity. Molecular-specific contrast agents developed in this project use directional attachment of antibody molecules to the nanoparticle surface, enhancing the targeting efficacy. Additionally, cell-based delivery of diagnostic and therapeutic agents is gaining much interest due to the immune cells’ special access to the avascular, diseased regions. The contrast agents developed in this project enable detection of just a few cells per unit of imaging volume, enable multiplex imaging, and open up a possibility for tracking different cell populations with noninvasive photoacoustic and ultrasound imaging. Finally, the clearance of nanoparticles from the body dictates their clinical translation. The in vivo pharmacokinetics study along with the proposed in vitro model explored in this project will enable fast, reliable, and cost-efficient screening of promising agents and facilitate quick optimization of nanoparticles for their potential use in the clinic. / text
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Novel functional nano-coatings on glass by spray depositionWang, Weiliang January 2010 (has links)
Nanocomposite thin films with gold nanoparticles embedded in a host metal oxide prepared by spray pyrolysis deposition have been investigated. A single-step process has been developed using a one-pot solution containing precursors for both gold nanoparticles and host metal oxides. The films obtained display combined features of colouration, electrical conductivity and solar control. In this study two precursors for gold nanoparticles were used: preformed gold colloids and HAuCl<sub>4</sub>. Three metal oxide host materials, TiO<sub>2</sub>, SnO<sub>2</sub> and ZnO, were investigated. These films were deposited at a substrate temperature of 200-600 °C. Powder X-ray diffraction analysis reveals the presence of metallic gold. SEM inspection typically showed particulate gold of 5-20 nm in diameter, distributed at the surface or within the host matrix. Optical spectroscopy showed an intense absorption in the visible region due to the characteristic surface plasmon resonance (SPR) effects of gold nanoparticles. The wavelength of the SPR peaks varies depending on the refractive index of surrounding host material which is significantly influenced by the substrate deposition temperature. On the other hand, SnO<sub>2</sub> and ZnO, together with the introduction of dopants, were further investigated as suitable materials for transparent conducting oxides (TCO). SnO<sub>2</sub>:F films were found to attain very low electrical resistivity, while ZnO films exhibit higher transparency in the visible. A double layered structure with a TCO layer of SnO<sub>2</sub>:F on top of a layer embedded with gold nanoparticles has been employed to achieve the combined functionalities of conductivity and colouration. The electrical conductivity is significantly enhanced compared to a nanocomposite single layer film due to the introduction of the TCO top layer. In this thesis, spray pyrolysis deposition has demonstrated a simple and rapid approach to the production of a variety of thin films. It can be immediately integrated with current industrial coating equipment and scaled up for large-scale production process.
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SELECTIVE TRIPODAL TITANIUM SILSESQUIOXANE CATALYSTS FOR THE EPOXIDATION OF UNACTIVATED OLEFINSPeak, Sarah M. 01 January 2015 (has links)
Regiomeric mixture of HMe2Si(CH2)3(i-Bu)6Si7O9(OH)3 (6), containing a Si-H group in one of the ligands of the silsesquioxane, was tethered onto a vinyl terminated hyperbranched poly(siloxysilane) polymer via a hydrosilation reaction to generate extremely active catalysts, P1-8 and c-P1-8. The synthesis of 6, in good yield, was accomplished via hydrosilation of CH2=CHCH2(i-Bu)7Si8O12 (1) to generate ClMe2Si(CH2)3(i-Bu)7Si8O12 (3) followed by the reduction of 3 with LiAlH4 to afford HMe2Si(CH2)3(i-Bu)7Si8O12 (4) where the base-catalyzed excision of one framework silicon was employed to generate a regiomeric mixture of 6.
[Ti(NMe2){Et3Si(CH2)3(i-Bu)6Si7O12}] (7), [Ti(NMe2){HMe2Si(CH2)3(i-Bu)6Si7O12}] (8), [Ti(NMe2){(i-C4H9)7Si7O12}] (9) and [Ti(NMe2){(c-C6H11)7Si7O12}] (10) were synthesized via protonolysis of Ti(NMe2)4 with one equivalent of the trisilanol precursor in order to determine if the presence of isomers would be intrinsically different as compared to the uniformly substituted catalysts. Isomers 8 and 9, demonstrated lower activity as compared to the uniformly substituted catalysts 9 and 10, however the isomers still exhibited extremely high catalytic activity for the epoxidation of 1-octene using tert-butyl hydroperoxide (TBHP) relative to titanium catalysts used in industry. Additionally, 9, 10, P1-8 and c-P1-8 were very selective catalysts for the epoxidation of various olefins such as terminal (1-octene), cyclic (cyclohexene or 1-methylcyclohexene), and more demanding olefins (limonene or α-pinene) employing TBHP as the oxidant. Furthermore, P1-8 and c-P1-8 were recyclable with minimal loss of titanium however the catalysts could also be repaired if a loss in activity was observed.
Preliminary epoxidation reactions employing P1-8 and c-P1-8 along with hydrogen peroxide (H2O2) as the oxidant were also explored using different solvents. P1-8 degraded quickly due to the hydrolysis of the titanium from the large amount of water present in the reaction mixture however c-P1-8 showed activity for the epoxidation of cyclohexene. Finally, regiomeric mixture of Ti(NMe2)(HS(CH2)3)(i-C4H9)6Si7O12) (13), was tethered onto gold nanoparticles for the conversion of propene to propylene oxide using molecular hydrogen and oxygen. While the catalysts showed low activity under our reaction conditions, numerous improvements can be investigated in order to improve upon the catalysts.
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Characterization of atherosclerotic plaques using ultrasound guided intravascular photoacoustic imagingWang, Bo, 1981- 01 June 2011 (has links)
Rupture of atherosclerotic plaque is closely related to plaque composition. Currently, plaque composition cannot be clinically characterized by any imaging modality. The objective of this dissertation is to use a recently developed imaging modality – ultrasound-guided intravascular photoacoustic (IVPA) imaging – to detect the distribution of two critical components in atherosclerotic plaques: lipid and phagocytically active macrophages. Under the guidance of intravascular ultrasound imaging, spectroscopic IVPA imaging is capable of detecting the spatially resolving optical absorption property inside a vessel wall. In this study, contrast in spectroscopic IVPA imaging was provided by either the endogenous optical property of lipid or optically absorbing contrast agent such as gold nanoparticles (Au NPs). Using a rabbit model of atherosclerosis, this dissertation demonstrated that ultrasound guided spectroscopic IVPA imaging could simultaneously image lipid deposits as well as macrophages labeled in vivo with Au NPs. Information of macrophage activity around lipid rich plaques may help to identify rupture-prone or vulnerable plaques. The results show that ultrasound guided IVPA imaging is promising for detecting plaque composition in vivo. Clinical use of ultrasound guided IVPA imaging may significantly improve the accuracy of diagnosis and lead to more effective treatments of atherosclerosis. / text
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Probing Single Cell Gene Expression in Tissue Morphogenesis and AngiogenesisWang, Shue January 2015 (has links)
The fascinating capability of cellular self-organization during tissue development and repair is a central question in developmental biology and regenerative medicine. Understanding the dynamic morphogenic and regenerative processes of biological tissues will have important implications in biology and medicine. Nevertheless, the elucidation of the cellular self-organization processes is hindered by a lack of effective tools for monitoring the spatiotemporal gene expression distribution and a lack of ability to perturb the self-organization processes in living cells and tissues. Multimodal modularities that allow both single cell perturbation and gene detection are required to enable a new paradigm in the investigation of complex tissue morphogenic processes. To address this critical challenge in the field of developmental and regenerative medicine, we are developing a multimodal gold nanorod-locked nucleic acid (GNR-LNA) composite for single cell gene expression analysis in living cells and tissues at the transcriptional level. Using antisense RNA sequences, we design LNA probes for detecting specific molecular targets in living cells. The LNA probes bind to the GNR spontaneously due to the intrinsic affinity between the GNR and LNA. In close proximity, the fluorescent probes are effectively quenched by the GNR. Therefore, a fluorescent signal is only observed when the specific target thermodynamically displaces the LNA probe from the GNR. Furthermore, the GNR also serves as a transducer for photothermal ablation. Thus, we established a novel modularity for imaging the spatiotemporal gene expression distribution in living cells and tissues. The single cell analysis capability of our techniques enables us to adopt a unique approach to study the tissue regenerative processes during normal development and diseases, and this will have a profound impact on regenerative medicine and disease treatment in future. Moreover, we applied this GNR-LNA probe to explore the endothelial cell mRNA dynamics during capillary morphogenesis. Three different types of cells were identified due to their different roles during endothelial cell capillary-like formation process. Our findings indicated that the endothelial cell behavior is directly related to the Dll4 mRNA expression, and Dll4 expression in ECs determine the cell fate. Our GNR-LNA probe enable us to investigate the correlations between Dll4 mRNA expression and cell behavior during capillary morphogenesis. Experimental results indicated that: (1) When the endothelial cells aggregate, the cells migrate with certain displacement, the Dll4 mRNA expression decreases. (2) When the endothelial cells sprout, the cells migrate with small displacement but the cell shape changes to an ellipse shape, the Dll4 mRNA expression begin to increase. (3) When the endothelial cells elongate and form cell-cell contract with adjacent cells, the Dll4 expression decreased to a certain level and keep stable until the cell activity change to another stage. Furthermore, it has been demonstrated endothelial cells compete for the leader cell position during wound healing, collective cell migration, and tip cell formation during angiogenic process. It has been demonstrated that endothelial cells compete for the tip cell formation through Notch signaling pathway. However, how the mechanical force regulates tip cell formation is still unclear, and if mechanoregulation of tip cell formation through Notch pathway still unknown. Mechanical and chemical regulations of tissue morphogenesis and angiogenesis are being investigated in both in vitro capillary-like network formation assay and in vivo mice retina angiogenesis assay. Here, we investigated the mechanoregulation of mechanotransduction of tissue morphogenesis and angiogenesis using both in vitro endothelial cell tube formation model and in vivo mice retina blood vessel development model. Our results demonstrated that (1) Notch pathway negatively regulates tip cell formation: inhibition of Notch pathway (DAPT) enhances tip cell formation, induces Dll4 and Notch1 activity, activation of Notch pathway (Jag1 peptide) inhibits tip cell formation, suppresses Dll4 and Notch1 activity. (2) Mechanical force negatively regulate tip cell formation: (a) Decrease mechanical force via Rho kinase inhibitor Y-27632, myosin II inhibitor Blebbistatin, or laser ablation, enhances tip cell formation and induces Dll4 activity through mediation of Dll4-Notch1 lateral inhibition, (b) increase mechanical force via traction force inducer Nocodazole and Calyculin A, suppresses tip cell formation and inhibits Dll4 activity through activation of Notch pathway. (3) Mechanical force negatively regulates tip cell formation partially via mediation of Notch pathway. Mechanical force is necessary for tip cell formation and negatively regulate tip/stalk selection via Dll4-Notch1 lateral inhibition. Interruption of mechanical force enhance tip cell formation via suppression of Dll4-Notch1 lateral inhibition, thus resulting the increase of Dll4 expression. Enhance of mechanical force inhibits tip cell formation via activation of Dll4-Notch1 lateral inhibition, thus resulting the decreases of Dll4 expression. All these finding wills have great significance for various biomedical applications, such as tissue engineering, cancer, and drug screening.
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The Use of Nanoparticles on Nanometer Patterns for Protein IdentificationPowell, Tremaine Bennett January 2008 (has links)
This dissertation describes the development of a new method for increasing the resolution of the current protein microarray technology, down to the single molecule detection level. By using a technique called size-dependent self-assembly, different proteins can be bound to different sized fluorescent nanostructures, and then located on a patterned silicon substrate based on the sized pattern which is closest to the size of the bead diameter.The protein nanoarray was used to detect antibody-antigen binding, specifically anti-mouse IgG binding to mouse IgG. The protein nanoarray is designed with the goal of analyzing rare proteins. However, common proteins, such as IgG, are used in the initial testing of the array functionality. Mouse IgG, representing rare proteins, is conjugated to fluorescent beads and the beads are immobilized on a patterned silicon surface. Then anti-mouse IgG binds to the mouse IgG on the immobilized beads. The binding of the antibody, anti-mouse IgG, to the antigen, mouse IgG is determined by fluorescent signal attenuation.The first objective was to bind charged nanoparticles, conjugated with proteins, to an oppositely charged silicon substrate. Binding of negatively charged gold nanoparticles (AuNP), conjugated with mouse IgG, to a positively charged silicon surface was successful.The second objective was to demonstrate the method of size-dependent self-assembly at the nanometer scale (<100 >nm). Different-sized, carboxylated, fluorescent beads and AuNP, which were conjugated with proteins, were serially added to a patterned polymethyl methacrylate (PMMA) coated silicon surface. Size-dependent self-assembly was successfully demonstrated, down to the nanometer scale.The final objective was to obtain a signal from antibody-antigen binding within the protein array. Conjugated fluorescent beads were bound to e-beam patterns and signal attenuation was measured when the antibodies bound to the conjugated beads. The size-dependent self-assembly is a valuable new method that can be used for the detection and quantification of proteins.
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A Monte Carlo-based Model Of Gold Nanoparticle RadiosensitizationLechtman, Eli 10 January 2014 (has links)
The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization.
A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10^3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther.
A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm AuNPs, and 100 and 300 kVp source energies. The impact of AuNP localization was most significant for low-energy sources. At equal mass concentrations, AuNP size did not impact radiosensitization unless the AuNPs were localized in the nucleus. This novel predictive model of AuNP radiosensitization could help define the optimal use of AuNPs in potential clinical strategies by determining therapeutic AuNP concentrations, and recommending when active approaches to cellular accumulation are most beneficial.
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Design of Raman Active Phopsholipid Gold Nanoparticles for Plasmonics based Tumour Detection and ImagingTam, Natalie Chin Mun 20 December 2011 (has links)
Cancer is the leading cause of death worldwide and one third of its burden can be decreased with early detection. Surface enhanced Raman spectroscopic (SERS) based imaging is a promising new technique for non-invasive detection of tumours due to its ultra-sensitivity and multiplexing capabilities. For in vivo SERS molecular imaging, a biocompatible, robust and targeted nanoparticle is required to attain high sensitivity and specificity. In this thesis, a SERS capable gold nanoparticle was rationally designed by encapsulation with a phospholipid bilayer which conferred biocompatibility, colloidal stability and versatility to changing surface chemistry. Moreover, validation of this SERS probe with a specific targeting ligand for carcinoma cells was studied through the targeting of a commonly overexpressed cancer receptor, epidermal growth factor receptor. Using this phospholipid design, optimizations with differing chemistries, targeting ligand or modifications for additional functionalities can be achieved for further development as a viable in vivo molecular imaging tool.
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Design of Raman Active Phopsholipid Gold Nanoparticles for Plasmonics based Tumour Detection and ImagingTam, Natalie Chin Mun 20 December 2011 (has links)
Cancer is the leading cause of death worldwide and one third of its burden can be decreased with early detection. Surface enhanced Raman spectroscopic (SERS) based imaging is a promising new technique for non-invasive detection of tumours due to its ultra-sensitivity and multiplexing capabilities. For in vivo SERS molecular imaging, a biocompatible, robust and targeted nanoparticle is required to attain high sensitivity and specificity. In this thesis, a SERS capable gold nanoparticle was rationally designed by encapsulation with a phospholipid bilayer which conferred biocompatibility, colloidal stability and versatility to changing surface chemistry. Moreover, validation of this SERS probe with a specific targeting ligand for carcinoma cells was studied through the targeting of a commonly overexpressed cancer receptor, epidermal growth factor receptor. Using this phospholipid design, optimizations with differing chemistries, targeting ligand or modifications for additional functionalities can be achieved for further development as a viable in vivo molecular imaging tool.
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A Monte Carlo-based Model Of Gold Nanoparticle RadiosensitizationLechtman, Eli 10 January 2014 (has links)
The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization.
A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10^3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther.
A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm AuNPs, and 100 and 300 kVp source energies. The impact of AuNP localization was most significant for low-energy sources. At equal mass concentrations, AuNP size did not impact radiosensitization unless the AuNPs were localized in the nucleus. This novel predictive model of AuNP radiosensitization could help define the optimal use of AuNPs in potential clinical strategies by determining therapeutic AuNP concentrations, and recommending when active approaches to cellular accumulation are most beneficial.
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