Multimodal image-guided interventions using oncological biomarkers

This thesis consists of two parts addressing novel imaging technologies to improve the treatment of cancer patients. In part I, the additional value of real time image guidance during surgery is discussed and the research described in this part of the thesis showed that imaging performed during surgery can be of great value. Nevertheless, the success rate is highly dependent on the choice of imaging modality and biomarker to be targeted. In part II, a necrosis avid probe was successfully evaluated as novel method for early neoadjuvant treatment response monitoring.department of Radiology iThera Medical GmbH MiLabs ChipsoftLUMC / Geneeskund

From Companion Diagnostics to Theranostics:A New Avenue for Alzheimer's Disease?

The recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted

Concurrent fluorescence and volumetric optoacoustic tomography of nanoagent perfusion and bio-distribution in solid tumors

Intravenously administered liposomes and other nano-sized particles are known to passively accumulate in solid tumors via the enhanced permeability and retention (EPR) effect, which is extensively explored toward the improvement of diagnosis and drug delivery in oncology. Agent extravasation into tumors is often hampered by the mononuclear phagocytic and renal systems, which sequester and/or eliminate most of the nanoparticles from the body. Dynamic imaging of the tumor microcirculation and bolus perfusion can thus facilitate optimization of the nanoparticle delivery. When it comes to non-invasive visualization of rapid biological dynamics in whole tumors, the currently available pre-clinical imaging modalities are commonly limited by shallow penetration, lack of suitable contrast or otherwise insufficient spatial or temporal resolution. Herein, we demonstrate the unique capabilities of a combined epi-fluorescence and optoacoustic tomography (FLOT) system for characterizing contrast agent dynamics in orthotopic breast tumors in mice. A liposomal indocyanine green (Lipo-ICG) preparation was administered intravenously with the time-lapse data continuously acquired during and after the injection procedure. In addition to the highly sensitive detection of the fluorescence agent by the epi-fluorescence modality, the volumetric multi-spectral optoacoustic tomography readings further enabled resolving deep-seated vascular structures with high spatial resolution and hence provided accurate readings of the dynamic bio-distribution of nanoparticles in the entire tumor in 3D. The synergetic combination of the two modalities can become a powerful tool in cancer research and potentially aid the diagnosis, staging and treatment guidance of certain types of cancer in the clinical setting

Multi-modal diffuse optical tomography and bioluminescence tomography system for preclinical imaging

The development, characterisation and testing of a novel all-optical, multi-modal preclinical biomedical imaging system is presented. The system aims to provide a new way of accurately visualising the spatial distribution and activity of molecular structures and processes in small animals by combining 3D bioluminescence tomography (BLT; reconstruction-based 3D imaging of internal bioluminescent reporter distributions), diffuse optical tomography (DOT; reconstruction-based imaging of optical parameter distributions) and optical surface capture techniques. The key principle of the imaging system is to use surface capture results to enhance the accuracy of DOT image reconstruction, and to use the results of both surface capture and DOT to enhance the accuracy of BLT. Presented experiments show that the developed system can reconstruct luminescent source distributions and optical parameters accurately and that small animal imaging is feasible with the system

Optical projection tomography for whole organ imaging

In the past twenty years, far-reaching studies of molecular and cellular processes have reached a milestone in their maturation, and the knowledge from these studies was ready to apply at higher organizational levels. At that time, rodent models were long established. However, methods were inappropriate to image a whole rodent organ, such as the mouse brain, which drove the emergence of a new range of imaging techniques, later gathered under the name mesoscopy. Mesoscopic techniques filled a gap between classical microscopy and medical imaging techniques, such as magnetic resonance imaging, and X-ray computed tomography. They allow the acquisition of centimeter-sized samples. In this thesis, we focus on one of these mesoscopic imaging techniques called optical projection tomography, or OPT, and its potential application to Alzheimer's disease (AD) research. We review the fundamentals of OPT and describe the filtered back-projection algorithm, which is the primary tomographic reconstruction method of this technique. We also go through the implementation of OPT for whole mouse brain imaging, including sample preparation. We show that OPT is suitable to image the whole brain anatomy based on endogenous fluorescence, and the whole neural vasculature as well as amyloid plaques (a hallmark of AD) with adequate fluorescent markers. Then, we dwell on the characterization of OPT instruments. We give some insights on the instrument point spread function and discuss the influence of the number of projections on the quality of the reconstructed image. Afterward, we illustrate the application of OPT to study amyloidosis progression in a preliminary cross-sectional study, where we have used supervised learning to quantify the amyloid plaque load. In this study, we show that OPT can be used to quantify amyloidosis in whole mouse brains and that comparison between individuals of different age can be performed. Imaging of a whole mouse brain is unquestionably necessary. At this scale though, it has some constraints. We present the limitations of OPT, and we share how we think they can be circumvented by combining this modality with another microscopy technique, namely structured illumination microscopy. We see that this other microscopy technique has the potential to produce high-resolution zooms in selected regions of interest based on a prior OPT acquisition. The results presented in this work have led to the duplication of our OPT instrument in Lund University, and we hope they will help to foster advances in OPT and broaden its range of application. We also hope that this work will contribute to making OPT more accessible and user-friendly