Photoacoustic Tomography: Principles and Advances

Photoacoustic tomography (PAT) is an emerging imaging modality that shows great potential for preclinical research and clinical practice. As a hybrid technique, PAT is based on the acoustic detection of optical absorption from either endogenous chromophores, such as oxy-hemoglobin and deoxy-hemoglobin, or exogenous contrast agents, such as organic dyes and nanoparticles. Because ultrasound scatters much less than light in tissue, PAT generates high-resolution images in both the optical ballistic and diffusive regimes. Over the past decade, the photoacoustic technique has been evolving rapidly, leading to a variety of exciting discoveries and applications. This review covers the basic principles of PAT and its different implementations. Strengths of PAT are highlighted, along with the most recent imaging results

Multimodality Imaging of Tumour Pathophysiology and Response to Pharmacological Intervention

This thesis describes the need for imaging the tumour pathophysiological microenvironment in order to understand response to treatment. Specifically looking at tumour vascularisation in in vivo murine xenograft models of disease, response to treatment with vascular disruption is assessed via photoacoustic tomography (PAT) and magnetic resonance imaging (MRI). Photoacoustic imaging is a novel imaging modality based on the detection of ultrasound waves created by the absorption of nano-second pulsed laser energy within tissue chromophores. It has the spectral specificity of optical techniques whilst also achieving the high resolution of ultrasound. Haemoglobin is the main chromophore found in biological tissue and this modality is therefore ideally suited to imaging tumour vascularisation. Using a Fabry-Perot interferometer this thesis demonstrates for the first time the feasibility of using PAT for re-clinical research and the characterisation of typical tumour vascular features in a non-invasive non-ionising manner. Response to different concentrations of a vascular disrupting drug is then demonstrated, with novel insights in to how tumours recover from vascular damage observed. MRI of response to vascular disruption is also presented. As MRI is widely used in the clinic it can serve as a translational tool of novel imaging biomarkers, and serves to further understand the differences in response of pathologically vascularised of tumours. This thesis looks at markers associated with disruption of haemodynamics, using apparent diffusion (ADC) to elucidate onset of necrosis, increase in haemoglobin concentration (R2*) as indication of impaired flow, and arterial spin labelling (ASL) as a marker of tumour blood perfusion. This is shown in both subcutaneous and clinically relevant liver metastasis models. Taken as whole, the results from this thesis indicate that whilst understanding the response of the tumour vasculature to pharmacological intervention is complex, novel imaging techniques can provide invaluable translational information on the pathophysiology of tumours

Molecular Imaging

The present book gives an exceptional overview of molecular imaging. Practical approach represents the red thread through the whole book, covering at the same time detailed background information that goes very deep into molecular as well as cellular level. Ideas how molecular imaging will develop in the near future present a special delicacy. This should be of special interest as the contributors are members of leading research groups from all over the world

Molecular Imaging of Inflammation - current and emerging technologies for diagnosis and treatment

Inflammation is a key factor in multiple diseases including primary immune-mediated inflammatory diseases e.g. rheumatoid arthritis but also, less obviously, in many other common conditions, e.g. cardiovascular disease and diabetes. Together, chronic inflammatory diseases contribute to the majority of global morbidity and mortality. However, our understanding of the underlying processes by which the immune response is activated and sustained is limited by a lack of cellular and molecular information obtained in situ. Molecular imaging is the visualization, detection and quantification of molecules in the body. The ability to reveal information on inflammatory biomarkers, pathways and cells can improve disease diagnosis, guide and monitor therapeutic intervention and identify new targets for research. The optimum molecular imaging modality will possess high sensitivity and high resolution and be capable of non-invasive quantitative imaging of multiple disease biomarkers while maintaining an acceptable safety profile. The mainstays of current clinical imaging are computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) and nuclear imaging such as positron emission tomography (PET). However, none of these have yet progressed to routine clinical use in the molecular imaging of inflammation, therefore new approaches are required to meet this goal. This review sets out the respective merits and limitations of both established and emerging imaging modalities as clinically useful molecular imaging tools in addition to potential theranostic applications

Surveilling the Distinctive Vascular and Metabolic Features of Tumor Progression and Response to Therapy

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite maximal treatment with surgical resection, radiotherapy and temozolomide chemotherapy, prognosis is dismal with median survival around 15 months. GBMs are highly infiltrative tumors that invade into surrounding brain tissue, which makes defining the extent of tumor spread difficult and recurrence common. Radiological identification of GBMs with magnetic resonance imaging (MRI), using transvers (T2) or longitudinal (T1) relaxation contrasts, is a mainstay in the initial diagnosis as well as tracking therapeutic response in GBM. However, there is extreme variability in the structural appearance, size, metabolism, and genetic landscape of GBMs, making imaging characteristics highly heterogeneous and hard to define with tumor progression. Although T2-weighted and contrast-enhanced T1-weighted MRI provides anatomical details of the tumor architecture, these methods can be confounded by pseudoprogression and pseudoresponse in the context of therapy.The GBM microenvironment is characterized by immature vasculature and extracellular acidification due to a metabolic shift towards aerobic glycolysis (Warburg effect). The reduced extracellular pH (pHe) has been associated with promoting angiogenesis and invasion as well as creating an immunosuppressive environment. Given the important contribution of vascular changes and extracellular acidosis to shaping the tumor microenvironment, advanced MRI techniques are needed to better characterize the tumor microenvironment to provide more specific readouts of tumor progression and therapeutic response. Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) is a magnetic resonance spectroscopic imaging (MRSI) technique that utilizes the temperature and pH-dependent hyperfine shifts of paramagnetic agents (e.g., TmDOTP5-) for high resolution, three-dimensional, quantitative temperature and pHe mapping. BIRDS has been used to demonstrate the acidic pH in preclinical models of GBM, where the intratumoral space is highly acidified (pH\u3c6.8) in comparison to healthy brain tissue (pH~7.2) and acidic pH spread beyond the anatomically defined tumor core relates to the invasiveness of the tumors. However, a limitation of the BIRDS technique is the necessity of detectable (\u3e1 mM) levels of contrast agent, which are cleared rapidly by the kidney. To obviate need for surgical intervention (e.g., renal ligation) to stop rapid agent clearance, here we demonstrate that pharmacological inhibition of renal clearance of these agents using probenecid to allow for longitudinal imaging of pHe throughout tumor progression and show that acidosis develops early in tumor progression in human-derived GBM tumors (U87 and U251). Since other tomographic pHe mapping methods are non-quantitative and directly altering pHe in a specific tissue is difficult to implement, we looked to assess the BIRDS-based temperature measurements for verification of the quantitative BIRDS readout. A localized cooling system was used to induce hypothermia in sheep brain to levels suggested to be neuroprotective in hypoxic states. Quantitative temperature mapping using BIRDS showed significantly decreased cerebral temperatures with cooling over all defined brain regions and was in agreement with thermocouple measurements. While pHe is a useful metric, tumor vascularity also shapes tumor metabolism and the microenvironment. BIRDS can be combined with other imaging modalities such as dynamic contrast enhanced (DCE) MRI, which allows quantification of vascular parameters (e.g., permeability) through modeling the dynamic uptake of Gd3+-based contrast agents. Multiparametric characterization of the spatiotemporal changes in cellularity, vascularity and acidosis of U87 and U251 tumors throughout progression showed unique patterns that could be used to identify tumor features and differentiate between tumor types. Finally, pHe readouts have potential as a biomarker of therapeutic response. After finding an increase in pHe after treatment with temozolomide in U251 tumors, we used BIRDS longitudinally to demonstrate normalization of pHe in U87 tumors treated with sorafenib, a nonselective tyrosine kinase inhibitor. Both treatments slowed tumor progression and led to increases of pHe which establishes a role for pHe imaging as an early and sensitive marker of evaluating therapeutic response prior to observable changes in the tumor appearance on standard MRI. The potential of BIRDS is vast and not limited to GBM, or cancer in general. Additional work has demonstrated that an acidic pHe is not limited to preclinical tumor models, but is also found in patient-derived xenograft (PDX) models of metastatic melanoma in the brain. BIRDS can also be utilized in evaluating tumors in any organ, as BIRDS has also shown acidic pHe in models of liver cancer. In summary, this work further expands BIRDS into a broadly applicable longitudinal platform for characterization of the tumor microenvironment and may aid in evaluation of many targeted therapeutic strategies

Application of Nanomaterials in Biomedical Imaging and Cancer Therapy

To mark the recent advances in nanomaterials and nanotechnology in biomedical imaging and cancer therapy, this book, entitled Application of Nanomaterials in Biomedical Imaging and Cancer Therapy includes a collection of important nanomaterial studies on medical imaging and therapy. The book covers recent works on hyperthermia, external beam radiotherapy, MRI-guided radiotherapy, immunotherapy, photothermal therapy, and photodynamic therapy, as well as medical imaging, including high-contrast and deep-tissue imaging, quantum sensing, super-resolution microscopy, and three-dimensional correlative light and electron microscopy. The significant research results and findings explored in this work are expected to help students, researchers and teachers working in the field of nanomaterials and nanotechnology in biomedical physics, to keep pace with the rapid development and the applications of nanomaterials in precise imaging and targeted therapy

Characterization of an Orthotopic Rat Model of Glioblastoma Using Multiparametric Magnetic Resonance Imaging and Bioluminescence Imaging

Glioblastoma multiforme (GBM) is a lethal and incurable disease. The C6 rat model of GBM shares several similarities to human GBM and longitudinal non-invasive imaging may allow tumour features to be studied. In this thesis, a multimodality imaging framework, consisting of bioluminescence imaging (BLI) and multiparametric magnetic resonance imaging (mpMRI), was applied to the C6 rat model to characterize the growth of orthotopic tumours. BLI signal, a measure of cell viability, tended to increase and then decrease in the majority of animals, whereas tumour volume (from MRI) continually increased. Cellular viability and tumour volume did not correlate across all days, highlighting the value of using complimentary imaging modalities. Apparent diffusion coefficient maps and immunohistochemistry suggests decreases in BLI signal are in part due to decreased tumour cellularity (i.e. necrosis). This is the first use of BLI and mpMRI to characterize this model, and highlights the inter-subject variability in tumour growth