Dissertations / Theses on the topic 'Molecular Imaging'
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DE, BIASIO VALERIA. "Nanosystems for molecular imaging." Doctoral thesis, Università del Piemonte Orientale, 2014. http://hdl.handle.net/11579/45958.
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Zotti, Linda Angela. "Molecular ordering and STM imaging of functionalized organic molecules." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479082.
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Somoza, Eduardo A. Jr. "UTILIZATION OF FLUORESCENCE MOLECULAR IMAGING TO OPTIMIZE RADIONUCLIDE IMAGING." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1338904705.
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Talvik, Mirjam. "Clinical molecular imaging of schizophrenia /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-587-5/.
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Slusarczyk, Adrian L. (Adrian Lukas). "Molecular imaging with engineered physiology." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104229.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 125-133).
Using molecular imaging in vivo, biomolecular and cellular phenomena can be investigated within their relevant physiological context, addressing a central challenge for 21st century biomedicine and basic research. To advance neuroscience in particular, molecular-level measurements across the brain inside the intact organism are required. However, existing imaging strategies and available probes have been limited by serious constraints. Magnetic resonance imaging (MRI) provides deeper tissue penetration depth than optical imaging and better spatial resolution and greater versatility in sensor design than radioactive probes. The most important drawback for MRI probes has been the need for high concentrations in the micromolar to millimolar range, leading to analyte sequestration, complications for noninvasive brain delivery, and toxicity. Efforts to address the sensitivity problem, such as nuclear hyperpolarization, introduce their own technical constraints and so far lack generality. Here, we introduce a conceptually novel molecular imaging technique based on artificially induced physiological perturbations, enabling molecular MRI with nanomolar sensitivity. In this imaging strategy, we take advantage of blood as an abundant endogenous source of contrast compatible with multiple imaging modalities including MRI and optical imaging to decouple the concentration requirement for molecular sensing from the concentration requirement for imaging contrast. Highly potent vasoactive peptides are engineered to respond to specific biomolecular phenomena of interest at nanomolar concentrations by inducing dilation of the microvasculature, increased local bloodflow, and consequently, large changes in T₂*-weighted MRI contrast. This principle is exploited to design activatable probes for protease activity based on the calcitonin gene-related peptide (CGRP) and validate them for brain imaging in live rats; to use CGRP as a genetic reporter for cell tracking; and to create fusions of a vasoactive peptide from flies to previously characterized antibodies capable of crossing the blood-brain barrier (BBB), suggesting the possibility of minimally invasive brain delivery of such probes. We demonstrate the feasibility of highly sensitive molecular MRI with vasoactive probes at concentrations compatible with in situ expression of probes and delivery across the BBB, and show that vasoactive peptides are a versatile platform for MRI probe design which promises unprecedented in vivo molecular insights for biomedicine and neuroscience.
by Adrian L. Slusarczyk.
Ph. D.
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Keasberry, Natasha Ann. "Functionalised nanoparticles for molecular imaging." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/42886.
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This thesis describes the synthesis of iron oxide nanoparticles for use as contrast agents in biomedical imaging, specifically for MRI. The limitations of single imaging modalities can be overcome by the synergistic combination of two or more imaging techniques, e.g. the low sensitivity but high resolution of MRI complements the high sensitivity but low resolution of PET. The large surface area of superparamagnetic iron oxide nanoparticles (SPION) allows relatively simple functionalisation. The large size of a single combined nanoparticle MRI/PET probe would slow down in vivo movement, diminishing radioactivity before reaching its target. Pre-targeting using a magnetic nanoparticle followed by the injection of the radio-labelled molecule at the correct time will ensure radioactivity remains sufficiently high. Thus, the investigation of dual-modality probe development is also a focus of the thesis. Chapter 2 discusses the preparation of iron oxide nanoparticles with a core diameter of 6 nm via the high temperature thermal decomposition of iron salts. Direct modification to the surface of the nanoparticles was carried out using various small molecules with differing anchoring groups, the most successful being sodium alendronate, a bisphosphonate ligand. Chapter 3 describes the further functionalisation of the nanoparticles. One way this was achieved was by the incorporation of PEG chains of different lengths to increase water solubility and biocompatibility. Functionalisation with a strained alkyne for eventual in vitro/in vivo copper-free cycloaddition with an azide group was also achieved. The PET moiety was designed to be a 68Ga-azido-DOTA complex. Prior to radiolabelling with gallium-68, the copper-free cyclised resultant nanoparticles were characterised by the use of lanthanide analogues (Eu, Tb and Gd). Eu and Tb allowed for fluorescence spectroscopy, while the Gd allowed for relaxivity measurements to be carried out. Unexpected fluorescence results were observed for the Eu and Tb analogues. The Gd-NP conjugates are further investigated in Chapter 4. Combination of both a T1 and T2 moiety results in changes to the relaxivity of the resultant nanoparticle which can act as a dual-weighted MRI probe. The relaxivities are found to vary with modifications to the nanoparticle construct. Finally, preliminary in vitro experiments with macrophages were carried out to investigate whether there was significant preferential uptake between M1 and M2 macrophages. A single-chain variable fragment (scFv) specific to Fractalkine, a chemokine important in the progression of atherosclerosis was prepared, for use as a targeting moiety towards the imaging of vulnerable plaque.
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Strand, Joanna. "Affibody Molecules for PET Imaging." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-259410.
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Optimization of Affibody molecules would allow for high contrast imaging of cancer associated surface receptors using molecular imaging. The primary aim of the thesis was to develop Affibody-based PET imaging agents to provide the highest possible sensitivity of RTK detection in vivo. The thesis evaluates the effect of radiolabelling chemistry on biodistribution and targeting properties of Affibody molecules directed against HER2 and PDGFRβ. The thesis is based on five published papers (I-V). Paper I. The targeting properties of maleimido derivatives of DOTA and NODAGA for site-specific labelling of a recombinant HER2-binding Affibody molecule radiolabelled with 68Ga were compared in vivo. Favourable in vivo properties were seen for the Affibody molecule with the combination of 68Ga with NODAGA. Paper II. The aim was to compare the biodistribution of 68Ga- and 111In-labelled HER2-targeting Affibody molecules containing DOTA, NOTA and NODAGA at the N-terminus. This paper also demonstrated favourable in vivo properties for Affibody molecules in combination with 68Ga and NODAGA placed on the N-terminus. Paper III. The influence of chelator positioning on the synthetic anti-HER2 affibody molecule labelled with 68Ga was investigated. The chelator DOTA was conjugated either at the N-terminus, the middle of helix-3 or at the C-terminus of the Affibody molecules. The N-terminus placement provided the highest tumour uptake and tumour-to-organ ratios. Paper IV. The aim of this study was to evaluate if the 68Ga labelled PDGFRβ-targeting Affibody would provide an imaging agent suitable for PDGFRβ visualization using PET. The 68Ga labelled conjugate provided high-contrast imaging of PDGFRβ-expressing tumours in vivo using microPET as early as 2h after injection. Paper V. This paper investigated if the replacement of IHPEM with IPEM as a linker molecule for radioiodination of Affibody molecules would reduce renal retention of radioactivity. Results showed that the use of the more lipophilic linker IPEM reduced the renal radioactivity retention for radioiodinated Affibody molecules. In conclusion, this thesis clearly demonstrates that the labelling strategy is of great importance with a substantial influence on the targeting properties of Affibody molecules and should be taken under serious considerations when developing new imaging agents.
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Rogers, Leon John. "Photofragment ion imaging." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266958.
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Danfors, Torsten. "11C Molecular Imaging in Focal Epilepsy." Doctoral thesis, Uppsala universitet, Neurologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179954.
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Epilepsy is a common neurological disease affecting 6 million people in Europe. Early prevention and accurate diagnosis and treatment are of importance to obtain seizure freedom. In this thesis new applications of carbon-11-labelled tracers in PET and autoradiographic studies were explored in focal epilepsy. Patients with low-grade gliomas often experience epileptic seizures. A retrospective PET-study assessing seizure activity, metabolic rate measured with 11C-methionine and other known prognostic factors was performed in patients with glioma. No correlation was found between seizure activity and uptake of methionine. The presence and termination of early seizures was a favourable prognostic factor. Activation of the neurokinin-1 (NK1) receptor by substance P (SP) induces epileptic activity. PET with the NK1 receptor antagonist GR205171 was performed in patients with temporal lobe epilepsy (TLE) and healthy controls. In TLE patients an increased NK1 receptor availability was found in both hemispheres, most pronounced in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptors and seizure frequency was observed in ipsilateral medial structures consistent with an intrinsic network using the NK1-SP receptor system for transmission of seizure activity. The uptake of 18F-fluoro-deoxy-glucose (FDG) is related to cerebral blood flow (CBF). Previously, methods to estimate blood flow from dynamic PET data have been described. A retrospective study was conducted in 15 patients undergoing epilepsy surgery investigation, including PET with 11C-FDG and 11C-Flumazenil (FMZ). The dynamic FMZ dataset and pharmacokinetic modeling with a multilinear reference tissue model were used to determine images of relative CBF. Agreement between data of FDG and CBF was analyzed showing a close association between interictal brain metabolism and relative CBF. Epilepsy often occurs after traumatic brain injuries. Changes in glia and inhibitory neuronal cells contribute to the chain of events leading to seizures. Autoradiography with 11C-PK11195, 11C-L-deprenyl and 11C-Flumazenil in an animal model of posttraumatic epilepsy studied the temporal and spatial distribution of microglia, astrocytes and GABAergic neurons. Results showed an instant increase in microglial activity that subsequently normalized, a late formation of astrogliosis and an instant and prolonged decease in GABA binding. The model can be used to visualize pathophysiological events during the epileptogenesis.
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Morley, Nicholas Christopher Donald. "Molecular targeting for clinical cancer imaging." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15880.
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Modern cancer treatment makes extensive use of clinical imaging methods for diagnosis and response assessment. To this end, there is increasing desire to non-invasively measure various drugs and biomarkers inside a patient on a centimetre scale. Despite undeniable preclinical progress and evaluation of many techniques, few new imaging drugs are emerging into pragmatic clinical cancer imaging. There are many drug targeting strategies, including target-affinity and activation-by-target. Affinity selections can identify binders from combinatorial libraries of heteropolymers such as nucleic-acid sequences and peptides. Using this approach, in combination with next-generation DNA sequencing, I identified sequences as binders of putative cancer biomarkers. In addition, I investigated a target-activated fluorescent probe as a reporter of cancer-associated enzyme activation. Messenger RNA levels for Leucine-rich-repeat containing 15 (LRRC15) are reported to be elevated in human, breast-cancer samples. I analysed a new antibody to LRRC15, which locates this protein in genetically triggered murine breast tumours and in their lysates on Western blot. Antibody staining also showed a distinct pattern in sections of normal murine kidney, and protein expression in human breast-cancer samples. LRRC15 affinity selection of phage peptide and aptamer libraries was performed with immunopurified protein, and this identified consensus sequences. However, specific binding of the peptides or aptamers to the target was not demonstrable. Alpha folate receptor overexpression has been described in many human tumours, particularly ovarian cancer. Cell-lines to enable whole-cell selection of binders to the folate receptor were developed. Specific staining with a folate-fluorophore compound validated these. Selection of peptide and aptamer binders showed early emergence of spurious dominant sequences, triggering abandonment of this approach. The cell-lines were used to test a folate-quantum dot conjugate, with disappointing results. Matrix Metalloproteinase-9 (MMP-9) activity in cancer has previously been described and pursued as a therapeutic target. A novel probe to report activity of MMP-9 was tested using fragments of murine tissue, successfully differentiating normal murine fat pad from pieces of murine mammary tumour. Significant off-target activation was also observed, particularly with kidney. Recombinant proteins based on human MMP-2 and -13 also activated the probe. Expression and activity of equivalent enzymes in the murine tissues and tumours were assessed using RT-PCR, Western blot, immunohistochemistry and zymography, but the basis of spurious activation remains obscure. In conclusion, a new antibody identifies LRRC15 in both human and murine breast cancers, and in the murine kidney. Library affinity selections with LRRC15 and the alpha folate receptor developed consensus sequences, but were unsuccessful. An MMP-9 activated probe successfully differentiated breast tumour from normal tissue but also showed significant off-target activation. Non-invasive detection and measurement of cancer biomarkers remains an important topic, likely to see much progress in coming decades. Some of the practical difficulties in developing reagents to achieve this are discussed.
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Wang, Lei. "Molecular Probes for Pancreatic Cancer Imaging." PDXScholar, 2016. http://pdxscholar.library.pdx.edu/open_access_etds/3108.
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Pancreatic ductal adenocarcinoma (PDAC) has the poorest five-year survival rate of any cancer. Currently, there are no effective diagnostics or chemotherapeutics. Surgical resection is the only curative therapy. However, most patients experience recurrence due largely to challenges in assessing tumor margin status in the operating room. Molecular probes that selectively highlight pancreatic cancer tissue, having the potential to improve PDAC margin assessment intraoperatively, are urgently needed. In this work, a series of red and near-infrared fluorescent probes is reported. Two were found to distribute to normal pancreas following systemic administration. One selectively accumulates in genetically modified mouse models of PDAC, providing cancer-specific fluorescence. In contrast to the small molecule probes reported previously, it possesses inherent affinity for PDAC cells and tissue, and thus does not require conjugation to targeting agents. Moreover, the probe exhibits intracellular accumulation and enables visualization of four levels of structure including the whole organ, tissue, individual cells and subcellular organelles. It can thus promote new strategies for precision image-guided surgery, pancreatic cancer detection, the monitoring of therapeutic outcomes and basic research.
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Oliver, Morag Helen. "Novel gadolinium agents for molecular imaging." Thesis, Imperial College London, 2005. http://hdl.handle.net/10044/1/11852.
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Mills, Bethany. "Molecular imaging of Staphylococcus aureus infections." Thesis, University of Nottingham, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.727640.
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Molecular imaging provides a less invasive means for studying bacterial infections in vivo compared to traditional techniques. However, molecular imaging of infection is currently limited due the lack of suitable imaging tracers. The most widely adopted approach for studying Staphylococcus aureus infections utilises a recombinant bioluminescent strain. However, several environmental requirements and signal attenuation through host tissue render this approach unsuitable for several applications. In order to provide an alternative research tool, the use of SNAP-tag, CLIP-tag and HaloTag was explored. Once expressed, these tags specifically bind fluorescent ligands. The tags were expressed via an inducible plasmid based system, and engineered to covalently attach to the cell surface of S. aureus. The function of the tags was validated in vitro by fluorescence imaging. SNAP-tag was subsequently incorporated into the genome of bioluminescent S. aureus Xen29. This thesis presents the first demonstration of visualising SNAP-tag expressing bacteria in vivo by fluorescent imaging. Potential applications for SNAP-tag imaging were then investigated; such as screening antimicrobials. Imaging of SNAP-tag expressing S. aureus was shown to provide additional information about the infection site compared to bioluminescence imaging alone. Novel [99mTc] SNAP-tag ligands were then developed and evaluated to provide a means for nuclear imaging of SNAP-tag. In addition, tools for infection diagnosis by nuclear imaging currently rely on targeting host immune responses rather than the bacteria directly; resulting in a high false positive rate. In order to develop a tracer with clinical potential to detect infection and not inflammation, the bacterial Universal Hexose Phosphate Transporter (UHPT) was selected as a target. [18F]FDG is an analogue of glucose and is widely used within nuclear medicine. [18F]FDG was phosphorylated, making it a substrate for UHPT. Validations in vitro suggested this probe may be a good tool for specific S. aureus detection; however in vivo biodistribution rendered it an unsuitable candidate.
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Dooley, Patrick W. Corkum Paul B. "Molecular imaging using femtosecond laser pulses." *McMaster only, 2003.
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Misri, Ripen. "Molecular imaging of mesothelin expressing cancers." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/30461.
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Mesothelin is a cell surface glycoprotein highly expressed in mesothelioma, ovarian cancer, pancreatic cancer and some other malignancies. It is a promising candidate for tumour specific therapy and diagnosis, given its limited expression in normal tissues. The purpose of the work presented in this dissertation is to develop and characterize a molecular imaging bioprobe that targets mesothelin.
We radiolabelled fab and f(ab´)₂ fragments of the anti-mesothelin antibody mAbK1 with ⁹⁹mTc- tricarbonyl core using a histidine-modified tridentate ligand, while whole mAbK1 was radiolabelled with ⁹⁹mTc using a direct labelling approach. In vivo evaluation of these ⁹⁹mTc labelled radioimmunoconjugates in mesothelin expressing NCI-H226 tumour model, revealed low mesothelin specific tumour uptake. These findings were attributed to low expression of mesothelin on NCI-H226 cells as well as to the low affinity of mAbK1. An anti-mesothelin antibody mAbMB, with higher mesothelin affinity than mAbK1 was labelled with ¹¹¹In and evaluated in A431K5 tumour model which expresses clinically relevant levels of mesothelin. Biodistribution studies and SPECT imaging revealed specific localization of ¹¹¹In-mAbMB in mesothelin expressing A431K5 tumours. An interesting finding with ¹¹¹In-mAbMB was its preferential localization in spleen, which suggests a role of circulating mesothelin antigen in forming immune complexes with ¹¹¹In-mAbMB. In comparison, control studies with ¹¹¹In-mAbK1 revealed low specific uptake into A431K5 tumours. These studies provided evidence that ¹¹¹In-mAbMB is a better choice than ¹¹¹In-mAbK1 for imaging mesothelin expression in tumours. A dual-modality SPECT/MR imaging bioprobe was further developed by conjugating ¹¹¹In-mAbMB with SPIONs (superparamagnetic iron oxide nanoparticles) which demonstrated specific targeting and MR imaging capability in A431K5 tumour bearing mice.
The work in this dissertation for the first time demonstrates successful SPECT imaging of mesothelin expressing cancers using radiolabelled antibodies. The radiopharmaceutical ¹¹¹In-mAbMB developed in this work holds promise for clinical use as a radioactive imaging bioprobe. Additionally, bioconjugates of ¹¹¹In-mAbMB and SPIONs are promising as dual-modality SPECT/MRI imaging bioprobes, which may be beneficial in improving the imaging outcomes of these difficult to treat tumours. In conclusion, our studies demonstrate that molecular imaging agents targeting mesothelin have a role to play for the detection and monitoring of mesothelin expressing cancers.
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Siepmann, Monica [Verfasser]. "Quantitative Molecular Ultrasound Imaging / Monica Siepmann." München : Verlag Dr. Hut, 2012. http://d-nb.info/1025821548/34.
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Chen, Ian Ying-Li. "Molecular imaging of cardiac gene therapy /." May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Wiśniowska, Agata Elżbieta. "Towards brain-wide noninvasive molecular imaging." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122128.
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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
An intricate interplay of signaling molecules underlies brain activity, yet studying these molecular events in living whole organisms remains a challenge. Magnetic resonance imaging (MRI) is the most promising imaging modality for development of molecular signaling sensors with deeper tissue penetration than optical imaging, and better spatial resolution and more dynamic potential in sensor design, compared to radioactive probes. MRI molecular sensors, however, have largely required micromolar concentrations to achieve detectable signals. In order to detect signaling molecules in the brain at their native low nanomolar concentrations, an improvement in MRI molecular sensors is necessary. Here we introduce a new in vivo imaging paradigm that uses vasoactive probes (vasoprobes) that couple molecular signals to vascular responses. We apply the vasoprobes to detect molecular targets at nanomolar concentrations in living rodent brains, thus satisfying the sensitivity requirement for imaging endogenous signaling events. Even with more sensitive probes, molecular imaging of the brain is further complicated by the presence of the blood-brain barrier (BBB), designed by nature to protect this most vital of organs. We have therefore implemented a means to permit noninvasive delivery of imaging agents following ultrasonic BBB opening. We use the ultrasound technique to deliver another potent class of contrast agents, superparamagnetic iron oxides, and we show that effective permeation of brain tissue is achieved using this approach. We have also designed ultrasensitive vasoprobe variants designed to permeate the brain completely noninvasively, using endogenous transporter-mediated mechanisms. We present preliminary results based on this approach and discuss future directions.
by Agata E. Wiśniowska.
Ph. D. in Medical Engineering and Medical Physics
Ph.D.inMedicalEngineeringandMedicalPhysics Harvard-MIT Program in Health Sciences and Technology
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Fink, Michael Charles. "Molecular Fourier imaging correlation spectroscopy for studies of molecular diffusion /." view abstract or download file of text, 2006. http://wwwlib.umi.com/cr/uoregon/fullcit?p3211214.
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Thesis (Ph. D.)--University of Oregon, 2006.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 104-111). Also available for download via the World Wide Web; free to University of Oregon users.
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Hofström, Camilla. "Engineering of Affibody molecules for Radionuclide Molecular Imaging and Intracellular Targeting." Doctoral thesis, KTH, Molekylär Bioteknologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-116884.
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Affibody molecules are small (7 kDa) affinity proteins of non-immunoglobulin origin that have been generated to specifically interact with a large number of clinically important molecular targets. In this thesis, Affibody molecules have been employed as tracers for radionuclide molecular imaging of HER2- and IGF-1R-expressing tumors, paper I-IV, and for surface knock-down of EGFR, paper V. In paper I, a tag with the amino acid sequence HEHEHE was fused to the N-terminus of a HER2-specific Affibody molecule, (ZHER2), and was shown to enable facile IMAC purification and efficient tri-carbonyl 99mTc-labeling. In vivo evaluation of radioactivity uptake in different organs showed an improved biodistribution, including a 10-fold lower radioactivity uptake in liver, compared to the same construct with a H6-tag. In paper II, it was further shown that an N-terminally placed HEHEHE-tag on ZHER2 provided lower unspecific uptake of radioactivity in liver compared to its H6-tagged counterpart even when radiolabeling was at the C-terminus using alternative chemistries to attach 99mTc, 111In or 125I. In paper III, the H6-tag’s composition and position was varied with regards to charge, hydrophobicity and its C- or N-terminal placement on ZHER2. Among the ten variants investigated, it was found that an N-terminal HEHEHE-tag provided the most favorable overall biodistribution profile and that introduction of hydrophobic and positively charged amino acids provoked liver uptake of radioactivity. In paper IV, the HEHEHE-tag was shown to enable IMAC purification and tri-carbonyl 99mTc-labeling of an IGF-1R-specific Affibody molecule and improved its overall biodistribution when compared to the same construct with a H6-tag. In paper V, the aim was to develop an intracellular receptor-entrapment system to reduce the surface levels of EGFR. An EGFR-specific Affibody molecule was expressed as a fusion to different mutants of an intracellular transport protein in SKOV-3 cells, resulting in a collection of cell lines with 50%, 60%, 80% and 96% reduced surface level of EGFR. Analysis of the proliferation rate of these cell lines showed that a modest reduction (15%) in proliferation occurs between 60% and 80% reduction of the surface level of EGFR.QC 20130129
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Ekblad, Torun. "Chemical synthesis of affibody molecules for protein detection and molecular imaging." Doctoral thesis, Stockholm : Bioteknologi, Kungliga Tekniska högskolan, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-9626.
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Winkler, Amy. "OPTICAL METHODS FOR MOLECULAR SENSING: SUPPLEMENTING IMAGING OF TISSUE MICROSTRUCTURE WITH MOLECULAR INFORMATION." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/195176.
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More and more researchers and clinicians are looking to molecular sensing to predict how cells will behave, seeking the answers to questions like "will these tumor cells become malignant?" or "how will these cells respond to chemotherapy?" Optical methods are attractive for answering these questions because optical radiation is safer and less expensive than alternative methods, such as CT which uses X-ray radiation, PET/SPECT which use gamma radiation, or MRI which is expensive and only available in a hospital setting. In this dissertation, three distinct optical methods are explored to detect at the molecular level: optical coherence tomography (OCT), laser-induced fluorescence (LIF), and optical polarimetry. OCT has the capability to simultaneously capture anatomical information as well as molecular information using targeted contrast agents such as gold nanoshells. LIF is less useful for capturing anatomical information, but it can achieve significantly better molecular sensitivity with the use of targeted fluorescent dyes. Optical polarimetry has potential to detect the concentration of helical molecules, such as glucose. All of these methods are noninvasive or minimally invasive.The work is organized into four specific aims. The first is the design and implementation of a fast, high resolution, endoscopic OCT system to facilitate minimally invasive mouse colon imaging. The second aim is to demonstrate the utility of this system for automatically identifying tumor lesions based on tissue microstructure. The third is to demonstrate the use of contrast agents to detect molecular expression using OCT and LIF. The last aim is to demonstrate a new method based on optical polarimetry for noninvasive glucose sensing.
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Gallagher, F. A. "Molecular imaging of tumours using dynamic nuclear polarization and magnetic resonance imaging." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599277.
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Dynamic Nuclear Polarization (DNP) is an emerging technique for increasing the sensitivity of Magnetic Resonance Imaging (MRI) in the liquid state. It has recently been applied to in vivo imaging of carbon metabolism: the spatial distribution of an injected hyperpolarized 13C-labelled molecule can be imaged in an intact living system, as well as the metabolites formed from it. This work demonstrates how this technique could have potential applications in medicine. 13C-labelled bicarbonate was hyperpolarized and the production of hyperpolarized carbon dioxide has been used to image tumour pH in vivo as well as the pH of the murine brain. An adaptation of this experiment allowed the spatial distribution of the enzyme carbonic anhydrase to be imaged in vitro and in vivo. Fumarate, a citric acid cycle intermediate, was hyperpolarized and its subsequent conversion into malate is shown here to increase with cellular necrosis in vitro; this was used as an early marker of response to chemotherapy both in vitro and in vivo. The metabolism of two other molecules is demonstrated: the in vitro metabolism of hyperpolarized 13C-labelled glutamine to glutamate as well as the metabolism of hyperpolarized 13C-labelled glutamate to α-ketoglutarate in vivo. Both of these present new ways to probe the citric acid cycle and the metabolism of glutamine may also act as a marker of cell proliferation. All of the molecules described here are endogenous and some are already administered intravenously into humans. There is therefore a realistic prospect that this technology can be translated into human imaging in the near future.
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GAMBINO, GIUSEPPE. "High-relaxivity systems and molecular imaging probes for Magnetic Resonance Imaging applications." Doctoral thesis, Università del Piemonte Orientale, 2014. http://hdl.handle.net/11579/46171.
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Crisostomo, Ana Goncalves. "Intracellular molecular imaging using multiphoton-excited microscopy." Thesis, University of Salford, 2009. http://usir.salford.ac.uk/26628/.
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Detection of the levels of serotonin (5-HT) present in biofluids may be used for detection of neurological diseases such as Alzheimer's 1 . This project seeks to develop technologies using multiphoton excitation and resultant luminescence of serotonin and related pharmacological drugs (e.g. propranolol) to measure concentrations of serotonin in viable cells and biofluids. Experiments for monitoring real-time serotonin and propranolol (a non-selective beta-blocker) uptake and release have been performed using two-photon (2-PE) 630 nm excitation with ultraviolet fluorescence (340 nm) emission. Excited state lifetimes have been measured using the time-correlated single-photon counting technique adapted for multiphoton microscopy. The solution lifetimes determined were different from those in vivo. The lifetime of serotonin reduced from 3.8 ns in solution to 1.9 ns in cellular systems while propranolol varies between 5 to 10 ns in mammalian cells to 9.8 ns in solution 2 . This technique has shown the potential for evaluation of serotonin and propranolol distribution with high spatial resolution within individual cells as well as to determine its intracellular concentration. Moreover, the use of 630 nm excitation provides a good ratio between signal intensity and background interference (e.g. autofluorescence of other cellular components as flavins, tryptophan). Furthermore in comparison with UV excitation, 2-PE at 630 nm significantly reduces the potential phototoxic effects of exposure to the laser beam. The characteristic hyperluminescence from 5-hydroxyindoles following multiphoton photochemistry was investigated to determine its usefulness in intracellular induction of oxidative stress 3 ' 4 . Solutions of tryptophan and mercaptopyridine-N-oxide (MPNO) were irradiated using 750 nm and observations made on the resultant emission at 500 nm. This emission was much less intense in solutions containing only either MPNO or tryptophan. It is suggested that MPNO generates hydroxyl radicals by 2-photon activation at 750 nm. This was confirmed by the scavenging effects of ethanol as well as kinetic analysis of the results.
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Zhu, Bo Ph D. Massachusetts Institute of Technology. "Acoustical-molecular techniques for magnetic resonance imaging." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103499.
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Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references.
Magnetic resonance imaging (MRI) is a remarkably flexible diagnostic platform due to the variety of clinically relevant physical, chemical, and biological phenomena it can detect. In addition to the host of endogenous contrast mechanisms available, MRI functionality can be further extended by incorporating exogenous factors to attain sensitivity to new classes of indicators. Molecular imaging with targeted injectable contrast agents and MR elastography with externally delivered acoustic vibrations are two such advancements with increasing clinical significance. Conventionally employed separately, this work explores how exogenous components can interact cooperatively in imaging disease and may be combined to more accurately stage disease progression and generate novel mechanisms of MR contrast, using contrast agents and acoustic stimulation as model systems. We imaged hepatic fibrosis in a rat model and found that collagen-binding paramagnetic contrast agents and shear wave MR elastography had partially uncorrelated staging abilities, due to the disease condition's differential timing of collagen production and its stiff cross-linking. This complementary feature enabled us to form a composite multivariate model incorporating both methods which exhibited superior diagnostic staging over all stages of fibrosis progression. We then integrated acoustics and molecular-targeting agents at a deeper level in the form of a novel contrast mechanism, Acoustically Induced Rotary Saturation (AIRS), which switches "on" and "off" the image contrast due to the agents by adjusting the resonance of the spin-lock condition. This contrast modulation ability provides unprecedented clarity in identifying contrast agent presence as well as sensitive and quantitative statistical measurements via rapidly modulated block design experiments. Finally, we extend the AIRS method and show preliminary results for Saturation Harmonic Induced Rotary Saturation (SHIRS), which detects the second harmonic time-oscillation of iron oxide nanoparticles' magnetization in response to an oscillating applied field around B0. We also illustrate an exploratory method of selectively imaging iron oxide agents by diffusion kurtosis measures of freely diffusing water in solutions of magnetic nanoparticles.
by Bo Zhu.
Ph. D. in Biomedical Engineering
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Williamson, Peter. "Strategies for molecular imaging with inorganic nanoparticles." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/strategies-for-molecular-imaging-with-inorganic-nanoparticles(e90cbbe1-2538-407a-b5a5-d1b9dc69e0a9).html.
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If they are to enter routine clinical application, new radiopharmaceuticals must have rapid and simple labelling procedures, ideally inserting the radionuclide at the last synthetic step with no need for further purification. This thesis describes the development of new targeted strategies for molecular imaging. Targeted nanoparticles have great potential for application as radionuclide molecular imaging agents but are subject to several limitations, including complex radiolabelling procedures, slow pharmacokinetics, low uptake in target tissue, and potential toxicity. We have discussed a targeted nanoparticle system comprising biocompatible materials with intrinsic affinity for readily-prepared radiotracers such as 18F-fluoride and 99mTc-technetium bisphosphonate derivatives. Such a system would offer simple labelling, and signal amplification (each particle can deliver many radionuclides). To overcome slow pharmacokinetics we proposed to exploit pretargeting, whereby the radionuclide-nanoparticle bond can form in vivo. Firstly, a large pretargeting agent (nanoparticle) that has affinity for both its target tissue and radionuclide probe, accumulates at the target site slowly over a period of time. This is followed by a chasing step, where a small radionuclide probe (18F-fluoride and 99mTc-bisphosphonate) distributes rapidly to the pretargeting agent, while untargeted circulating radionuclide probe clears rapidly from the blood pool. The reader is first introduced to the topics of radiopharmaceutical particulates and pretargeting, emphasing the requirement for novel radiopharmaceutical targeting methods. A literature review discussing fluoride affine materials was performed to guide initial screening experiments. We screened many inorganic nanoparticulate materials for binding to 18F-fluoride. Of the materials tested, hydroxyapatite (HA) and Alhydrogel showed the most efficient binding to 18F-fluoride. The 18F-HA interaction was highly stable in serum, while the 18F-Alhydrogel interaction was moderately stable in serum. HA materials were prepared via wet chemical precipitation. The effect of synthesis termperature and post-synthesis treatment was investigated. Stabilisation and functionalisation of HA nanoparticles with various ligands was discussed. Synthesis temperature did not greatly affect particle properties, while calcination and hydrothermal post-synthesis treatments controlled particle morphology and crystallinity. HA particles formed stable colloidal solutions when functionalised with sodium hexametaphosphate (SHMP) and polyethyleneglycol-bisphosphonates (PEG-BP). The bisphosphonate -Alendronate was used to link small molecules such as amino acids and fluorescein isothiocyanate to HA surfaces, for potential targeting applications. Porous hollow silica particles were prepared using a novel templating method, using HA as core material. However, 18F-fluoride showed poor affinity for these materials. A novel bifunctional bisphosphonate chelator, A//A/-bis(quinoylmethyl)pamidronate-amine (BQMPA) was prepared and its potential as a probe for SPECT and fluorescence imaging was investigated. A DOTA like bisphosphonate - BPAMD (a literature compound) - and its novel MCu radiolabelled complex were prepared. The preparation of 99mTc and Re-BQMPA complexes resulted in the formation of multiple products. The Cu-BPAMD complex was identified as a single complex and was kinetically stable in serum over 24 h. Both 99mTc-BQMPA and 64Cu-BPAMD showed high affinity for HA materials. We screened inorganic nanoparticulate materials for binding to 99mTc- and 64Cu-bisphosphonates. We identified that 99mTc(CO)3-DPA-Ale (99mTc labelled dipicolylamine-alendronate) and Cu-BPAMD bind to a wide range of metal oxide materials with high efficiency. HA and Alhydrogel were chosen as lead materials for further in vitro and in vivo investigations.
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Shotbolt, John. "Molecular imaging of dopamine synthesis and release." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11152.
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Positron emission tomography (PET) can be used to measure striatal dopamine synthesis and release, both of which have been shown to be elevated in schizophrenia. One study has demonstrated that first degree relatives of schizophrenia patients exhibit increased dopamine synthesis capacity, suggesting this could be an endophenotype or susceptibility marker. However, the specific relation to schizophrenia was not tested, as the index cases were not studied. In this thesis, I directly tested the hypothesis that both members of twin pairs discordant for schizophrenia show similar increases in dopamine synthesis capacity. I found that striatal dopamine synthesis capacity is not elevated in individuals at genetic risk of schizophrenia or in stable patients with chronic schizophrenia, suggesting that it is not a vulnerability marker for schizophrenia, and is associated with active psychosis only. I also tested whether dopamine synthesis capacity is elevated in otherwise healthy people who report hallucinations. No elevation was found, suggesting that the underlying neurobiology is distinct from schizophrenia. I then considered whether it would be possible to examine similar relationships with measurements of dopamine release. Methodologies for this measurement were still limited: antagonist radioligands such as [11C] raclopride have been used, but the dynamic range for the measure is small, confounding precision. I hypothesised that agonist radioligands could provide a more sensitive measure. [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([11C]-(+)-PHNO) is a D2/D3 agonist PET radioligand. I directly compared the sensitivity of [11C]-(+)-PHNO to amphetamine challenge with that of the antagonist ligand [11C] raclopride. Mass carry-over and cerebellar binding were potential problems with [11C]-(+)-PHNO. I therefore designed a study to quantify these factors. I found that [11C]-(+)-PHNO is superior to [11C]raclopride for studying acute fluctuations in dopamine in the striatum. Use of [11C]-(+)-PHNO will allow quantification of smaller changes in dopamine release, although mass effects and displaceable cerebellar binding are potential confounding factors.
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Caries, Christopher Cain. "Organometallics : a platform for molecular imaging probes /." May be available electronically:, 2009. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Bocharova, Irina A. "Laser coulomb explosion imaging of molecular dynamics." Diss., Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/2279.
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Culberson, Lori. "Molecular Electronic Structure via Photoelectron Imaging Spectroscopy." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/301677.
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This dissertation explores the use of photoelectron imaging spectrometry to probe the molecular electronic structure of various chemical systems, with an emphasis on photoelectron angular distributions. Experimental ion generation, mass selection, laser photodetachment, and photoelectron ion imaging were all done in a photoelectron imaging spectrometer described in detail. Results from simplistic systems, OH- and CH-, are used to illustrate the general and fundamental capabilities of imaging spectroscopy and angular distributions. This illustration is then expanded when both qualitative and quantitative analyses of photoelectron angular distributions are used to aid in the understanding of the electronic structure of several heterocyclic aromatic systems. First a qualitative analysis aids in the exploration of the electronic structure of thiophenide, C₄H₃S⁻, and furanide, C₄H₃O⁻. Ground and excited C₄H₃S and C₄H₃O radical states are observed, and bond dissociation energies are defined. Next, a new model used to qualitatively analyze photoelectron angular distributions resulting from mixed s - p hybrid states is presented and applied to detachment from pyridinide, C₅H₄N⁻; as a benchmark system. Before further exploring this model, the synthesis of several deuterated heterocyclic compounds is presented in order to determine the experimentally produced systems in our experimental setup. The electronic structure of the resultant molecules oxazolide, C₃H₂NO⁻, and thiazolide, C₃H₂NS⁻; are then investigated. Using this new qualitative model, the mixed s - p states model, to evaluate the angular distributions of the systems, the hybridization of the anion molecular orbitals is probed. Comparison of the photoelectron angular distributions that are modeled for each heterocyclic aromatic system yields several trends relating aromatic stabilization, molecular hybridization, and bond dissociation energies. A new qualitative model is then presented to evaluate photoelectron angular distributions resulting from mixed p - d states and applied to detachment from NO⁻. Finally, new ideas and directions are proposed.
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Surber, Sean Eric. "Photoelectron Imaging of Molecular and Cluster Anions." Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/194908.
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Femtosecond negative-ion photoelectron imaging spectroscopy allows the probing of dynamics resulting from solvation and photodissociation in both the time-resolved and solvent domains. First, the basic premise of photoelectron imaging shall be presented, followed by a discussion of qualitative approaches for interpreting photoelectron angular distributions as illustrated by application to the photoelectron images of S₂⁻ and CS₂⁻. The photoelectron images of CS₂⁻ serve as a reference for interpreting the results for homogeneous and heterogeneous solvation in CO₂ and OCS cluster anions. The effects of solvation upon the photoelectron angular distribution and the photoelectron energy spectrum are discussed in relation to (OCS)n⁻, OCS⁻·H₂O, (CO2)n⁻, and (CO₂)n(H₂O)m⁻. The (OCS)₂⁻ cluster anion images show evidence of competition of excited state decay pathways and coexistence of isomers. The evolution of photoelectron images, resulting from I₂Br⁻ dissociation shows the evolving electronic structure of the I⁻ channel as the anion dissociates.
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Albertazzi, Lorenzo. "Dendrimers for drug delivery and molecular imaging." Doctoral thesis, Scuola Normale Superiore, 2011. http://hdl.handle.net/11384/85853.
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Honarvar, Hadis. "Development of Affibody molecules for radionuclide molecular imaging and therapy of cancer." Doctoral thesis, Uppsala universitet, Medicinsk strålningsvetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-298740.
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Affibody molecules are a promising class of scaffold-based targeting proteins for radionuclide-based imaging and therapy of cancer. This thesis work is based on 5 original research articles (papers I-V), which focus on optimization of molecular design of HER2-binding Affibody variants for high contrast imaging of this predictive biomarker as well as development of Affibody molecules suitable for radionuclide-based targeted therapies. Papers I and II were dedicated to evaluation of the influence of the macrocyclic chelator DOTA positioning at N-terminus, in the middle of helix-3 and at C terminus of a synthetic Affibody molecule, ZHER2:S1. These synthetic variants were labelled with different radionuclides i.e. 111In and 68Ga to study also the effect of different labels on their biodistribution properties. In paper III a 2-helix variant, Z342min, was developed using native ligation cyclization to cross-link helices one and two resulting in a stable 2-helix scaffold and characterized in vivo. This study was performed with the aim to obtain structure-properties relationship for development of smaller Affibody molecules. Papers IV and V were devoted to development of therapeutic strategies. In paper IV, a series of peptide based chelators was investigated for labelling of Affibody molecules with 188Re to provide low renal retention. In paper V, a pretargeting approach using peptide nucleic acid was investigated. These studies were performed with the aim to overcome the high renal retention of Affibody molecules when labelled with residualizing therapeutic radionuclides. Otherwise, the particle emitting radiometals could damage the kidneys more than the tumours. The results obtained for anti-HER2 Affibody molecules summarized in this thesis might be of importance for the development of other scaffold protein based targeting agents.
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Kujala, Naresh Gandhi Yu Ping. "Frequency domain fluorescent molecular tomography and molecular probes for small animal imaging." Diss., Columbia, Mo. : University of Missouri--Columbia, 2009. http://hdl.handle.net/10355/7021.
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Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 26, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Ping Yu. Vita. Includes bibliographical references.
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Stöckmann, Henning. "The development of new agents for molecular imaging in cancer." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610030.
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Zurkiya, Omar. "Magnetic Resonance Molecular Imaging Using Iron Oxide Nanoparticles." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/19848.
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Magnetic resonance imaging (MRI) is regularly used to obtain anatomical images, greatly advancing biomedical research and clinical health care today, but its full potential in providing functional, physiological, and molecular information is only beginning to emerge. The goal of magnetic resonance molecular imaging is to utilize MRI to acquire information on the molecular level. This dissertation is focused on ways to increase the use of MRI for molecular imaging using superparamagnetic iron oxide (SPIO) nanoparticle induced MRI contrast. This work is divided into three main sections: 1) Elucidation of the contribution of size and coating properties to magnetic nanoparticle induced proton relaxation. To maximize contrast generated without increasing particle size, new methods to increase effects on relaxivity must be developed. Experimental data obtained on a new class of biocompatible particles are presented, along with simulated data. The effects of coating size, proton exchange, and altered diffusion are examined. Simulations are presented confirming the effect of particle coatings on clustering-induced relaxivity changes, and an experimental system demonstrating the clustering effect is presented. 2) Development of a diffusion-dependent, off-resonance imaging protocol for magnetic nanoparticles. This work demonstrates an alternative approach, off-resonance saturation (ORS), for generating contrast sensitive to SPIO nanoparticles. This method leads to a calculated contrast that increases with SPIO concentration. Experimental data and a mathematical model demonstrate and characterize this diffusion-dependent, off-resonance effect. Dependence on off-resonance frequency and power are also investigated. 3) Development of a genetic MRI marker via in vivo magnetic nanoparticle synthesis. This work seeks to provide a gene expression marker for MRI based on bacterial magnetosomes, tiny magnets produced by naturally occurring magnetotactic bacteria. Here, magA is expressed in a commonly used human cell line, 293FT, resulting in the production of magnetic, iron oxide nanoparticles by these cells. MRI shows these particles can be formed in vivo utilizing endogenous iron and can be used to visualize cells positive for magA. These results demonstrate magA alone is sufficient to produce magnetic nanoparticles and that it is an appropriate candidate for an MRI reporter gene.
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Asayesh, Amir. "Spleno-pancreatic development assessed by 3D molecular imaging." Doctoral thesis, Umeå universitet, Umeå centrum för molekylär medicin (UCMM), 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-987.
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The development of different organs and tissues along the gastrointestinal tract, including the pancreas, depends on signalling between the endoderm and the adjacent mesenchyme. The Nkx gene Bapx1 is involved in spatial control of organ-positioning in the spleno-pancreatic region, and deficiency in this gene results in unacceptable proximity of the splenic mesenchyme to the pancreas. This permits agitating signals from the splenic mesenchyme to induce an in vivo (and in vitro) transformation of pancreatic epithelium to a cystic structure with gut like features. Also, wild type splenic mesenchyme is competent to induce a similar transformation. These findings illustrate the importance for strict control of organ positioning during spleno-pancreatic development. Several growth factors and receptors involved in pancreatic development are activated by protease processing. Some of these growth factors have been implicated as substrates for members of the A Disintegrin And Metalloprotease (ADAM) family. The ADAMs 9, 10, and 17 are expressed during pancreatic development and in the adult pancreas, suggesting a possible role for these ADAMs in pancreatic development and function. Animal model systems are widely used to investigate gene function during development and disease. However, spatial, molecular, and quantitative phenotype screening in animals is a time consuming effort. Optical Projection Tomography is a 3-dimensional imaging technique that, in combination with improvements in sample preparation and computer processing, can be used to visualize and quantify characteristics of intact adult mouse organs such as the total β-cell content in the pancreas.
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Tegler, Gustaf. "Abdominal Aortic Aneurysm : Molecular Imaging Studies of Pathophysiology." Doctoral thesis, Uppsala universitet, Kärlkirurgi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-194663.
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The pathological process behind abdominal aortic aneurysm (AAA) formation is poorly understood and difficult to study. The aim of the thesis was to study the pathophysiology of AAA formation with positron emission tomography (PET) technology, a molecular imaging technique, allowing in vivo studies of pathophysiological changes. In study I 18F-FDG, a glucose analogue, was tested. It had previously been reported as a useful tracer studying inflammation in AAAs. These studies included, however, foremost large, symptomatic, and inflammatory AAAs. In the present study on five small and seven large asymptomatic AAAs, no increase in 18F-FDG uptake could be revealed in vivo. In study II 11C-PK11195, a macrophage tracer, and 11C-D-deprenyl, an unspecific inflammatory tracer, previously never tested on asymptomatic AAAs, were tested in vivo on five and 10 AAA-patients respectively, without signs of increased levels of inflammatory activity in the aorta. In study III several tracers were screened in vitro through autoradiography on AAA tissue. [18F]fluciclatide, targeting the integrin αVβ3 receptor upregulated in angiogenesis, was the only tracer with an increased uptake. In study IV [18F]fluciclatide-autoradiography was performed on AAA tissue from five patients and non-aneurysmal aortic tissue obtained from five age and sex matched organ donors. The study showed a 56% increased specific uptake in AAA, although not significant (P=0.136). Immunohistochemical revealed inflammatory cell foci in close relation to the vessels. In conclusion, PET has potential to elucidate the pathophysiology of AAA formation. For the large group of small asymptomatic AAAs, 18F-FDG is not suitable, as the chronic inflammation in asymptomatic AAA is not sufficiently metabolically active. Furthermore, 11C-PK11195 and 11C-D-deprenyl were unable to show the chronic inflammation seen in asymptomatic AAA. The interesting finding with uptake of [18F]fluciclatide showed that angiogenesis may be imaged in large asymptomatic AAAs in vitro, through the integrin αVβ3 receptor. Thus, it is likely that future studies of the role of angiogenesis in AAA formation in vivo, in small AAAs, could use this target site. The development of an integrin αVβ3 receptor tracer, preferably with higher affinity, is in progress for further in vitro and in vivo studies.
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Reininger, Katrin [Verfasser]. "Imaging strong-field induced molecular dynamics / Katrin Reininger." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/117670575X/34.
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Webb, Alexander. "Imaging the photodissociation dynamics of molecular hydride cations." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492462.
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The work presented in this thesis constitutes an imaging study of the photodissociation of state-selected molecular cations, each of which was prepared by (2+1) resonance-enhanced multiphoton ionisation (REMPI).
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Waghorn, Philip A. "Investigations into porphyrins as potential molecular imaging agents." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526421.
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Joshi, Nikhil Vilas. "Novel molecular imaging of cardiovascular disease in man." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25394.
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Cardiovascular disease remains the commonest cause of death worldwide. The majority of deaths are caused by atherosclerotic plaque rupture with resultant myocardial infarction or stroke, or rupture of abdominal aortic aneurysms. Conventional imaging modalities have consistently failed to identify atherosclerotic plaques or aneurysms with high-risk pathological features that are at highest risk of rupture or progression. The development of modern molecular imaging techniques targeted at these features could lead to the identification of such high-risk plaques and aneurysms in vivo and guide the development of novel treatment strategies. The aim of this thesis was to evaluate whether novel molecular modalities have a role in providing new insights into biological disease processes, and identify high-risk plaques and aneurysms. Using positron emission tomography-computed tomography (PET-CT), 18F-fluorodeoxyglucose and 18F-fluoride were utilised as markers of metabolic inflammation and active calcification. Cellular inflammation was assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) enhanced magnetic resonance imaging (MRI). In a prospective trial, 80 patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-fluoride and 18F-fluorodeoxyglucose PET-CT, and invasive coronary angiography (Chapter 3). Intense 18F-fluoride uptake localised to recently ruptured plaque in patients with acute myocardial infarction. In patients with stable coronary artery disease, 18F-fluoride uptake identified coronary plaques with high-risk features on intravascular ultrasound. 18F-fluoride PET-CT is the first noninvasive imaging method to identify and localise ruptured and high-risk coronary plaques. Aortic vascular uptake of 18F- fluorodeoxyglucose was studied in patients with myocardial infarction and stable angina (Chapter 4). In a separate outcome of 1,003 patients enrolled in the Global Registry of Acute Coronary Events, we further evaluated whether infarct size predicted recurrent coronary events. Patients with myocardial infarction had higher remote atherosclerotic tracer uptake that correlated with the degree of myocardial necrosis, and exceeded that observed in patients with stable coronary disease. The outcome cohort demonstrated that patients with higher degree of myocardial necrosis had the highest risk of early recurrent myocardial infarction. This supports the hypothesis that acute myocardial infarction exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: myocardial infarction begets myocardial infarction. In a prospective imaging cohort, the role inflammation and calcification was assessed in 63 patients with abdominal aortic aneurysms and 19 age and sex matched patients with atherosclerosis (Chapter 5). Compared to non-aneurysmal segments, enhanced inflammation and calcification was observed within the wall of aortic aneurysmal segments. In comparison to matched controls with atherosclerosis, the entire aorta in those with aortic aneurysm appears more highly inflamed, suggesting presence of a global aortopathy rather than a disease confined only to the abdominal region of the aorta. Aortic aneurysms have greater active inflammation and calcification than atherosclerotic controls suggesting a more intense, destructive and transmural pathological process. A subgroup of fifteen patients with aortic aneurysms underwent imaging with both PET-CT with 18F-fluorodeoxyglucose, and T2*- weighted MRI before and 24 h after administration of USPIO (Chapter 6). Whilst there was a moderate correlation between the two tracers, there were distinct differences in the pattern and distribution of uptake suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively. These studies provide novel insights into vascular biological processes involved in the initiation, progression and rupture of atherosclerotic plaques and aortic aneurysms. Future longitudinal studies are needed to establish whether these techniques have a role in improving the clinical management and treatment of patients with coronary artery disease and aortic aneurysms.
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Rao, Vinay P. "Molecular imaging of gene transduction in cardiac transplantation." Thesis, University of Hull, 2012. http://hydra.hull.ac.uk/resources/hull:7165.
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This thesis is based on a series of experiments aimed at designing a model of gene transfer to the transplanted heart. The use of viral vector-based gene therapy to target pathological processes following cardiac transplantation faces many challenges including the potential effects of the virus on the host as well as the need to establish the presence of the gene in the target organ. In the first set of experiments (Chapter 2), concerns over the effects of adenoviral gene transfer on the later development of cardiac allograft vasculopathy (CAV) were addressed. Heterotopically transplanted cardiac allografts from Brown Norway to Lewis rats revealed the presence of CAV at 120 days. Ex vivo adenoviral serotype 5 perfusion of the donor heart did not affect the later development of allograft vasculopathy. In the second series of experiments, the feasibility of visualizing the presence of the sodium iodide symporter (hNIS) non-invasively following its gene transduction was established with the use of SPECT imaging. Following gene transfer, the recipients were injected with ⁹⁹mTc in the first set of experiments (Chapter 3) or with radioactive ¹²³I (Chapter 4) and imaged under a SPECT scanner. Radioactive isotope uptake in the Ad-NIS group was significantly higher than in the group of animals whose hearts were perfused with just University of Wisconsin solution or with blank adenovirus without a marker gene. Sequential imaging of Ad-NIS-perfused hearts between post-operative days 2 and 14 revealed peak image intensity at day 5. Overall, image intensities correlated with ex vivo counts of radioactivity. These data demonstrate that hNIS is an excellent reporter gene whose expression can be accurately and non-invasively monitored by serial radioisotope single photon emission computed tomography (SPECT) imaging.
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Waghorn, Philip Alan. "Investigations into porphyrins as potential molecular imaging agents." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669974.
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Yoo, Byunghee. "MOLECULAR IMAGING OF BREAST CANCER USING PARACEST MRI." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1183658257.
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Wang, Changning. "DEVELOPMENT OF NOVEL MOLECULAR IMAGING AGENTS FOR MYELINATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1317992169.
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DONG, YONGHUI. "Mass spectrometry imaging: looking fruits at molecular level." Doctoral thesis, country:IT, 2014. http://hdl.handle.net/10449/24270.
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Mass spectrometry imaging (MSI) is a MS-based technique. It provides a way of ascertaining both spatial distribution and relative abundance of a large variety of analytes from various biological sample surfaces. MSI is able to generate distribution maps of multiple analytes simultaneously without any labeling and does not require a prior knowledge of the target analytes, thus it has become an attractive molecular histology tool. MSI has been widely used in medicine and pharmaceutical fields, while its application in plants is recent although information regarding the spatial organization of metabolic processes in plants is of great value for understanding biological questions such as plant development, plant environment interactions, gene function and regulatory processes.
The application of MSI to these studies, however, is not straightforward due to the inherent complexity of the technique. In this thesis, the issues of plant sample preparation, surface properties heterogeneity, fast MSI analysis for spatially resolved population studies and data analysis are addressed. More specifically, two MSI approaches, namely matrix assisted laser desorption ionization (MALDI) imaging and desorption electrospray ionization (DESI) imaging, have been evaluated and compared by mapping the localization of a range of secondary and primary metabolites in apple and grapes, respectively. The work based on MALDI has been focused on the optimization of sample preparation for apple tissues to preserve the true quantitative localization of metabolites and on the development of specific data analysis tool to enhance the chemical identification in untargeted MSI (chapter 3). MALDI imaging allows high-spatial localization analysis of metabolites, but it is not suitable for applications where rapid and high throughput analysis is required when the absolute quantitative information is not necessary as in the case of screening a large number of lines in genomic or plant breeding programs. DESI imaging, in contrast, is suitable for high throughput applications with the potential of obtaining statistically robust results. However, DESI is still in its infancy and there are several fundamental aspects which have to be investigated before using it as a reliable technique in extensive imaging applications. With this in mind, we investigated how DESI imaging can be used to map the distribution of the major organic acids in different grapevine tissue parts, aiming at statistically comparing their distribution differences among various grapevine tissues and gaining insights into their metabolic pathways in grapevine. Our study demonstrated that this class of molecules can be successfully detected in grapevine stem sections, but the surface property differences within the structurally heterogeneous grapevine tissues can strongly affect their semi-quantitative detection in DESI, thereby masking their true distribution. Then we decided to investigate this phenomenon in details, in a series of dedicated imaging studies, and the results have been presented in chapter 4. At the same time, during DESI experiments we have observed the production of the dianions of small dicarboxylates acids. We further studied the mechanism of formation of such species in the ion source proposing the use of doubly charged anions as a possible proxy to visualize the distributions of organic acid salts directly in plant tissues (chapter 5). The structural organization of the PhD thesis is as below:
Chapter one and Chapter two describe the general MSI principle, compare the most widely used MSI ion sources, and discuss the current status in MSI data pre-processing and statistical methods. Due to the importance of sample preparation in MSI, sample handling for plant samples is independently reviewed in chapter two, with all the essential steps being fully discussed. The first two chapters describe the comprehensive picture regarding to MSI in plants.
Chapter three presents high spatial and high mass resolution MALDI imaging of flavonols and dihydrochalcones in apple. Besides its importance in plant research, our results demonstrate that how data analysis as such Intensity Correlation Analysis could benefit untargeted MSI analysis.
Chapter four discusses how sample surface property differences in a structurally/biologically heterogeneous sample affect the quantitative mapping of analytes in the DESI imaging of organic acids in grapevine tissue sections.
Chapter five discusses the mechanism of formation of dicarboxylate dianions in DESI and ESI
Chapter six summarizes the work in the thesis and discusses the future perspectives.
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Boase, Nathan R. B. "Hyperbranched polymers for in vivo multimodal molecular imaging." Thesis, University of Queensland, 2015. https://eprints.qut.edu.au/96267/1/96267.pdf.
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For the development of the next generation of polymeric nanomedicines, it is crucial to gain a fundamental understanding of their behaviour and interactions with and within biological systems. Moving beyond in vitro models, into in vivo models, earlier in the development process will greatly aid in the advancement of the next generation of nanomedicines. By moving to whole animal models, our understanding of these systems progresses beyond cell targeting and uptake, to developing mechanisms for how these materials will distribute through tissues and their pharmacokinetic profile. This information is important for truly assessing the performance of a nanomedicine. One possible set of tools for obtaining this information is molecular imaging.
Molecular imaging is a field of research dedicated to the real time monitoring of biological processes in vivo, without the use of invasive techniques such as biopsies and dissections. Molecular imaging has been used extensively to follow the in vivo behaviour of a labelled material. This is advantageous because the performance of a single material in one subject can be monitored and mapped against the progression of disease. It can help to provide the pharmacokinetic information necessary for preclinical development of nanomedicines. Nanomedicines can be designed to combine molecular imaging with targeting molecules and therapeutic agents to create a theranostic, which can be used for simultaneous imaging and treatment of disease.
This thesis aims to synthesise novel multimodal molecular imaging agents based on a hyperbranched polymer architecture, and to gain a deeper understanding of how these materials behave in vivo. To achieve this, biocompatible hyperbranched polymers with defined architectures were synthesised using RAFT polymerisation techniques. These materials were extensively characterised using a wide range of spectroscopic techniques to thoroughly understand their physical and chemical properties. A variety of synthetic strategies were investigated for functionalising both the α- and ω-chain ends of these polymers with multiple imaging ligands to form multimodal imaging agents. Far-red and near-infrared fluorophores provided for fluorescence imaging and radiometal chelators allowed for positron emission tomography (PET) imaging.
These hyperbranched polymer systems were first evaluated as molecular imaging agents in C57 BL/6J mice using whole animal fluorescence and PET-CT imaging. It was shown that the rate of excretion was dependent on the size and level of branching of the hyperbranched polymer cores. The larger more highly branched material showed extended circulation times, making it suitable for use as a passive targeting agent for cancer. It was demonstrated in a murine model for melanoma, that the material showed significant uptake within the tumour after 24 hours and that the material was not cleared from the tissue within 72 hours.
To gain a deeper understanding of the behaviour of these materials in vivo, PET imaging was combined with gadolinium contrast enhanced MRI, in order to gain both molecular and physiological information. Using this technique, we were able to show that while a folic acid targeted hyperbranched polymer did accumulate in the tumour tissue, its distribution was concentrated in highly vascularised areas of the tumour. This is the first time that this phenomenon has been demonstrated at a macroscopic level, in a living animal. This has important implications for using these materials as theranostics, because heterogeneous distribution of the nanomaterial, and therefore delivery of a therapeutic, can lead to ineffective treatment of the cancer and thus lead to tumour recurrence.
In further development of these imaging agents into theranostics, targeting of the hyperbranched polymers by conjugating single chain fragment antibodies (scFv) was explored. Two potential routes to improve efficiency of conjugation were investigated. Both approaches used novel bifunctional oligoethylene glycol (OEG) linkers to introduce the required chemical functionality to either the hyperbranched polymer or scFv. The first approach utilised a heterobifunctional OEG which was synthesised with a pentafluorophenol ester at one end for coupling with amines and an ω-azide group at the other end to allow for the copper catalysed Huigsen 1,3-dipolar cycloaddition reactions. This linker was first attached to the scFv via activated ester chemistry, to provide the necessary azide functionality for coupling of the scFv to the alkyne end groups of the hyperbranched polymer. The second route used an enzymatic cross coupling approach using the sortase enzyme. In order to achieve this, a triglycine functionalised OEG ligand was synthesised and attached to the hyperbranched polymer. The triglycine could then be used as a substrate for enzymatic cross coupling to scFv bioengineered to possess the required recognition sequence (LPETG). Despite both OEG linkers being demonstrated to be able to undergo conjugation to both the hyperbranched polymers and scFv independently, further optimisation is required to achieve conjugation of the two macromolecules.
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Boase, Nathan, Kristofer James Thurecht, and Idriss Blakey. "Hyperbranched polymers for in vivo multimodal molecular imaging." Thesis, University of Queensland, 2015.
Find full textAbstract:
For the development of the next generation of polymeric nanomedicines, it is crucial to gain a fundamental understanding of their behaviour and interactions with and within biological systems. Moving beyond in vitro models, into in vivo models, earlier in the development process will greatly aid in the advancement of the next generation of nanomedicines. By moving to whole animal models, our understanding of these systems progresses beyond cell targeting and uptake, to developing mechanisms for how these materials will distribute through tissues and their pharmacokinetic profile. This information is important for truly assessing the performance of a nanomedicine. One possible set of tools for obtaining this information is molecular imaging.Molecular imaging is a field of research dedicated to the real time monitoring of biological processes in vivo, without the use of invasive techniques such as biopsies and dissections. Molecular imaging has been used extensively to follow the in vivo behaviour of a labelled material. This is advantageous because the performance of a single material in one subject can be monitored and mapped against the progression of disease. It can help to provide the pharmacokinetic information necessary for preclinical development of nanomedicines. Nanomedicines can be designed to combine molecular imaging with targeting molecules and therapeutic agents to create a theranostic, which can be used for simultaneous imaging and treatment of disease.
This thesis aims to synthesise novel multimodal molecular imaging agents based on a hyperbranched polymer architecture, and to gain a deeper understanding of how these materials behave in vivo. To achieve this, biocompatible hyperbranched polymers with defined architectures were synthesised using RAFT polymerisation techniques. These materials were extensively characterised using a wide range of spectroscopic techniques to thoroughly understand their physical and chemical properties. A variety of synthetic strategies were investigated for functionalising both the α- and ω-chain ends of these polymers with multiple imaging ligands to form multimodal imaging agents. Far-red and near-infrared fluorophores provided for fluorescence imaging and radiometal chelators allowed for positron emission tomography (PET) imaging.
These hyperbranched polymer systems were first evaluated as molecular imaging agents in C57 BL/6J mice using whole animal fluorescence and PET-CT imaging. It was shown that the rate of excretion was dependent on the size and level of branching of the hyperbranched polymer cores. The larger more highly branched material showed extended circulation times, making it suitable for use as a passive targeting agent for cancer. It was demonstrated in a murine model for melanoma, that the material showed significant uptake within the tumour after 24 hours and that the material was not cleared from the tissue within 72 hours.
To gain a deeper understanding of the behaviour of these materials in vivo, PET imaging was combined with gadolinium contrast enhanced MRI, in order to gain both molecular and physiological information. Using this technique, we were able to show that while a folic acid targeted hyperbranched polymer did accumulate in the tumour tissue, its distribution was concentrated in highly vascularised areas of the tumour. This is the first time that this phenomenon has been demonstrated at a macroscopic level, in a living animal. This has important implications for using these materials as theranostics, because heterogeneous distribution of the nanomaterial, and therefore delivery of a therapeutic, can lead to ineffective treatment of the cancer and thus lead to tumour recurrence.
In further development of these imaging agents into theranostics, targeting of the hyperbranched polymers by conjugating single chain fragment antibodies (scFv) was explored. Two potential routes to improve efficiency of conjugation were investigated. Both approaches used novel bifunctional oligoethylene glycol (OEG) linkers to introduce the required chemical functionality to either the hyperbranched polymer or scFv. The first approach utilised a heterobifunctional OEG which was synthesised with a pentafluorophenol ester at one end for coupling with amines and an ω-azide group at the other end to allow for the copper catalysed Huigsen 1,3-dipolar cycloaddition reactions. This linker was first attached to the scFv via activated ester chemistry, to provide the necessary azide functionality for coupling of the scFv to the alkyne end groups of the hyperbranched polymer. The second route used an enzymatic cross coupling approach using the sortase enzyme. In order to achieve this, a triglycine functionalised OEG ligand was synthesised and attached to the hyperbranched polymer. The triglycine could then be used as a substrate for enzymatic cross coupling to scFvs bioengineered to possess the required recognition sequence (LPETG). Despite both OEG linkers being demonstrated to be able to undergo conjugation to both the hyperbranched polymers and scFvs independently, further optimisation is required to achieve conjugation of the two macromolecules.
In summary, this thesis has explored aspects of design, synthesis and characterisation of hyperbranched polymers as novel multimodal molecular imaging agents. A range of synthetic strategies have been combined for the production of hyperbranched polymers with controlled architecture, and for the incorporation of imaging moieties and targeting molecules. The imaging agents synthesised in this thesis have been used to gain significant insight into the in vivo biological behaviour of these hyperbranched polymer materials. All of this new knowledge will greatly progress the development of hyperbranched polymers as a class of materials into working theranostics.