Temporal and spatial molecular imaging of disease biomarkers using non-invasive MRI with high resolution is largely limited by lack of MRI contrast agents with high sensitivity, high specificity, optimized biodistribution and pharmacokinetics. In this dissertation, I report my Ph. D. work on the development of protein-based MRI contrast agents (ProCAs) specifically targeting different cancer biomarkers, such as grastrin-releasing peptide receptor (GRPR), prostate specific membrane antigen (PSMA), and vascular endothelial growth factor receptor-2 (VEGFR-2). Similar to non-targeted ProCAs, these biomarker-targeted ProCAs exhibit 5 - 10 times higher r1 and r2 relaxivites than that of clinical MRI contrast agents. In addition, these biomarker-targeted ProCAs have high Gd3+ binding affinities and metal selectivities. The highest binding affinity of the three GRPR-targeted contrast reagents obtained by grafting a GRPR ligand binding moiety into ProCA32 for GRPR is 2.7 x 10-9 M. We further demonstrate that GRPR-targeted ProCAs were able to semi-quantitatively evaluate GRPR expression levels in xenograft mice model by MRI. In addition, we have also created a PSMA-targeted ProCA which has a binding affinity to PSMA biomarker of 5.2 x 10-7 M. Further, we developed VEGFR-targeted contrast agent which is able to image VEGFR2 in mice models using T1-weighted and T2-weighted sequences. Moreover, the relaxivities and coordination water numbers of ProCAs can be tuned by protein design of ProCA4. Since disease biomarkers are expressed in various tumors and diseases, our results may have strong preclinical and clinical implications for the diagnosis and therapeutics of cancer and other type of diseases.

No description available.

Heart failure is a complex clinical syndrome in which the heart cannot pump sufficient blood and nutrients to the organs in the body. Increasingly, alterations in cardiac energetics are being implicated as playing an important role in the pathogenesis of heart failure. An understanding of specific metabolic switches which occur during the development of heart failure in patients would be greatly beneficial as a new diagnostic method and for the development of new therapies for patients with failing hearts. This thesis deals with the non-invasive assessment of metabolism in the heart. New magnetic resonance imaging (MRI) methods for metabolic characterization of the heart using hyperpolarized carbon-13 MRI are presented. Spatially resolved images of hyperpolarized 13C substrates and their downstream products can provide insight into real-time metabolic processes occurring in vivo, within minutes of injection of a pre-polarized 13C-labeled substrate. Conventional 3D spectroscopic acquisitions require in excess of 100 excitations, making it challenging to acquire full cardiac and respiratory-gated, whole-heart metabolic volumes. Each of the developments described in this thesis is intended to advance cardiac hyperpolarized 13C metabolic imaging towards a routine, clinical exam which can be used for prognosis and treatment optimization in patients with cardiovascular disease. The major technical development is a new interleaved-frequency, time-resolved MRI pulse sequence that can provide robust and reliable measurements of cardiac metabolic signals. The technique was applied to several realistic pre-clinical models of cardiac disease and the work presented will hopefully lead towards significant improvement in the management of patients with heart failure.

Stem cell therapies hold great promise for diseases such as stroke, where few effective treatment options exist. Clinical translation of experimental stem cell therapies requires the ability to monitor delivery and behaviour of cells non-invasively in-vivo with clinical imaging modalities such as MRI. This thesis presents the translation of established methods for labelling and imaging stem cells with specialized MRI systems to a more clinically relevant setting. A methodology for harvesting and labelling a cell population containing stem cells with iron oxide for detection with a clinical MRI system is presented and single cell detection is demonstrated in-vitro. The feasibility of detecting iron oxide labelled stem cells intravenously delivered in a rat model of stroke is tested. Results demonstrate that while MRI is highly sensitive to the presence and distribution of iron oxide containing cells in-vivo the true origin of these cells remains ambiguous with the current methodology.

Background: To explore normal-appearing white matter (NAWM) in pediatric-onset multiple sclerosis (MS) patients, using diffusion tensor imaging (DTI). DTI study provides measures of WM integrity in adult MS patients. Pediatric MS patients provide a uniquely early window for exploring pathological components of myelin disruption. Methods: DTI data were obtained for 23 pediatric MS patients and 17 healthy children. Images were acquired using GE LX1.5T scanner (DTI parameters: 25 directions, 5mm slice thickness, b=1000s/mm2). Fractional anisotropy (FA) and apparent diffusion co-efficient (ADC) were analyzed in lesions and NAWM throughout corpus callosum (CC) and hemispheres. Results: Altered NAWM integrity in MS patients relative to controls is demonstrated by: reduced FA values (p<0.0001) and elevated ADC values (p<0.05) throughout CC and hemispheres. Conclusions: DTI measures show widespread disruption of WM integrity in children with MS extending beyond visible lesions. These findings implicate diffuse and potentially very early WM degeneration in MS pathobiology.

Effective early detection and monitoring of patient response to cancer therapy is important for improved patient outcomes, avoiding unnecessary procedures and their associated toxicities, as well as the development of new therapies. Dynamic contrast-enhanced magnetic resonance imaging shows promise as a way to evaluate tumour vasculature and assess the efficacy of new anti-angiogenic drugs. However, unavoidable patient motion can decrease the accuracy of subsequent analyses rendering the data unusable. Motion correction algorithms are challenging to develop for contrast-enhanced data since intensity changes due to contrast-enhancement and patient motion must somehow be differentiated from one another. A novel method is presented that employs a motion-informed intensity correction in order to facilitate the registration of contrast enhanced data. The intensity correction simulates the presence or absence of contrast agent in the image volumes to be registered in an attempt to emulate the level of contrast-enhancement present in a single reference image volume.

Stem cell therapies hold great promise for diseases such as stroke, where few effective treatment options exist. Clinical translation of experimental stem cell therapies requires the ability to monitor delivery and behaviour of cells non-invasively in-vivo with clinical imaging modalities such as MRI. This thesis presents the translation of established methods for labelling and imaging stem cells with specialized MRI systems to a more clinically relevant setting. A methodology for harvesting and labelling a cell population containing stem cells with iron oxide for detection with a clinical MRI system is presented and single cell detection is demonstrated in-vitro. The feasibility of detecting iron oxide labelled stem cells intravenously delivered in a rat model of stroke is tested. Results demonstrate that while MRI is highly sensitive to the presence and distribution of iron oxide containing cells in-vivo the true origin of these cells remains ambiguous with the current methodology.

Heart failure is a complex clinical syndrome in which the heart cannot pump sufficient blood and nutrients to the organs in the body. Increasingly, alterations in cardiac energetics are being implicated as playing an important role in the pathogenesis of heart failure. An understanding of specific metabolic switches which occur during the development of heart failure in patients would be greatly beneficial as a new diagnostic method and for the development of new therapies for patients with failing hearts. This thesis deals with the non-invasive assessment of metabolism in the heart. New magnetic resonance imaging (MRI) methods for metabolic characterization of the heart using hyperpolarized carbon-13 MRI are presented. Spatially resolved images of hyperpolarized 13C substrates and their downstream products can provide insight into real-time metabolic processes occurring in vivo, within minutes of injection of a pre-polarized 13C-labeled substrate. Conventional 3D spectroscopic acquisitions require in excess of 100 excitations, making it challenging to acquire full cardiac and respiratory-gated, whole-heart metabolic volumes. Each of the developments described in this thesis is intended to advance cardiac hyperpolarized 13C metabolic imaging towards a routine, clinical exam which can be used for prognosis and treatment optimization in patients with cardiovascular disease. The major technical development is a new interleaved-frequency, time-resolved MRI pulse sequence that can provide robust and reliable measurements of cardiac metabolic signals. The technique was applied to several realistic pre-clinical models of cardiac disease and the work presented will hopefully lead towards significant improvement in the management of patients with heart failure.

Background: To explore normal-appearing white matter (NAWM) in pediatric-onset multiple sclerosis (MS) patients, using diffusion tensor imaging (DTI). DTI study provides measures of WM integrity in adult MS patients. Pediatric MS patients provide a uniquely early window for exploring pathological components of myelin disruption. Methods: DTI data were obtained for 23 pediatric MS patients and 17 healthy children. Images were acquired using GE LX1.5T scanner (DTI parameters: 25 directions, 5mm slice thickness, b=1000s/mm2). Fractional anisotropy (FA) and apparent diffusion co-efficient (ADC) were analyzed in lesions and NAWM throughout corpus callosum (CC) and hemispheres. Results: Altered NAWM integrity in MS patients relative to controls is demonstrated by: reduced FA values (p<0.0001) and elevated ADC values (p<0.05) throughout CC and hemispheres. Conclusions: DTI measures show widespread disruption of WM integrity in children with MS extending beyond visible lesions. These findings implicate diffuse and potentially very early WM degeneration in MS pathobiology.

Effective early detection and monitoring of patient response to cancer therapy is important for improved patient outcomes, avoiding unnecessary procedures and their associated toxicities, as well as the development of new therapies. Dynamic contrast-enhanced magnetic resonance imaging shows promise as a way to evaluate tumour vasculature and assess the efficacy of new anti-angiogenic drugs. However, unavoidable patient motion can decrease the accuracy of subsequent analyses rendering the data unusable. Motion correction algorithms are challenging to develop for contrast-enhanced data since intensity changes due to contrast-enhancement and patient motion must somehow be differentiated from one another. A novel method is presented that employs a motion-informed intensity correction in order to facilitate the registration of contrast enhanced data. The intensity correction simulates the presence or absence of contrast agent in the image volumes to be registered in an attempt to emulate the level of contrast-enhancement present in a single reference image volume.