Metabolic and Molecular Imaging with Hyperpolarised Tracers

Since reaching the clinic, magnetic resonance imaging (MRI) has become an irreplaceable radiological tool because of the macroscopic information it provides across almost all organs and soft tissues within the human body, all without the need for ionising radiation. The sensitivity of MR, however, is too low to take full advantage of the rich chemical information contained in the MR signal. Hyperpolarisation techniques have recently emerged as methods to overcome the sensitivity limitations by enhancing the MR signal by many orders of magnitude compared to the thermal equilibrium, enabling a new class of metabolic and molecular X-nuclei based MR tracers capable of reporting on metabolic processes at the cellular level. These hyperpolarised (HP) tracers have the potential to elucidate the complex metabolic processes of many organs and pathologies, with studies so far focusing on the fields of oncology and cardiology. This review presents an overview of hyperpolarisation techniques that appear most promising for clinical use today, such as dissolution dynamic nuclear polarisation (d-DNP), parahydrogen-induced hyperpolarisation (PHIP), Brute force hyperpolarisation and spin-exchange optical pumping (SEOP), before discussing methods for tracer detection, emerging metabolic tracers and applications and progress in preclinical and clinical application.     

Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models

Purpose

The purposes of the present study is to evaluate a new ultrasound molecular imaging approach in its ability to image a preclinical tumor model and to investigate the capacity to visualize and quantify co-registered microvascular and molecular imaging volumes.

Procedures

Molecular imaging using the new technique was compared with a conventional ultrasound molecular imaging technique (multi-pulse imaging) by varying the injected microbubble dose and scanning each animal using both techniques. Each of the 14 animals was randomly assigned one of three doses; bolus dose was varied, and the animals were imaged for three consecutive days so that each animal received every dose. A microvascular scan was also acquired for each animal by administering an infusion of nontargeted microbubbles. These scans were paired with co-registered molecular images (VEGFR2-targeted microbubbles), the vessels were segmented, and the spatial relationships between vessels and VEGFR2 targeting locations were analyzed. In five animals, an additional scan was performed in which the animal received a bolus of microbubbles targeted to E- and P-selectins. Vessel tortuosity as a function of distance from VEGF and selectin targeting was analyzed in these animals.

Results

Although resulting differences in image intensity due to varying microbubble dose were not significant between the two lowest doses, superharmonic imaging had significantly higher contrast-to-tissue ratio (CTR) than multi-pulse imaging (mean across all doses 13.98 dB for molecular acoustic angiography vs. 0.53 dB for multi-pulse imaging; p = 4.9 × 10^?10). Analysis of registered microvascular and molecular imaging volumes indicated that vessel tortuosity decreases with increasing distance from both VEGFR2- and selectin-targeting sites.

Conclusions

Molecular acoustic angiography (superharmonic molecular imaging) exhibited a significant increase in CTR at all doses tested due to superior rejection of tissue artifact signals. Due to the high resolution of acoustic angiography molecular imaging, it is possible to analyze spatial relationships in aligned microvascular and molecular superharmonic imaging volumes. Future studies are required to separate the effects of biomarker expression and blood flow kinetics in comparing local tortuosity differences between different endothelial markers such as VEGFR2, E-selectin, and P-selectin.

     

A Molecular Imaging Paradigm to Rapidly Profile Response to Angiogenesis-directed Therapy in Small Animals

Purpose  The development of novel angiogenesis-directed therapeutics is hampered by the lack of non-invasive imaging metrics capable of assessing treatment response. We report the development and validation of a novel molecular imaging paradigm to rapidly assess response to angiogenesis-directed therapeutics in preclinical animal models. Procedures  A monoclonal antibody-based optical imaging probe targeting vascular endothelial growth factor receptor-2 (VEGFR2) expression was synthesized and evaluated in vitro and in vivo via multispectral fluorescence imaging. Results  The optical imaging agent demonstrated specificity for the target receptor in cultured endothelial cells and in vivo. The agent exhibited significant accumulation within 4T1 xenograft tumors. Mice bearing 4T1 xenografts and treated with sunitinib exhibited both tumor growth arrest and decreased accumulation of NIR800-αVEGFR2ab compared to untreated cohorts (p = 0.0021). Conclusions  Molecular imaging of VEGFR2 expression is a promising non-invasive biomarker for assessing angiogenesis and evaluating the efficacy of angiogenesis-directed therapies. Electronic supplementary material    The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Intravital Imaging of Tumor Apoptosis with FRET Probes During Tumor Therapy

Purpose  

The aim of the study is to dynamically and non-invasively monitor the apoptosis events in vivo during photodynamic therapy (PDT) and chemotherapy.     

Predicting Response to Therapy for Autoimmune and Inflammatory Diseases Using a Folate Receptor-Targeted Near-Infrared Fluorescent Imaging Agent

Purpose

Although current therapies for many inflammatory/autoimmune diseases are effective, a significant number of patients still exhibit only partial or negligible responses to therapeutic intervention. Since prolonged use of an inadequate therapy can result in both progressive tissue damage and unnecessary expense, methods to identify nonresponding patients are necessary.

Procedures

Four murine models of inflammatory disease (rheumatoid arthritis, ulcerative colitis, pulmonary fibrosis, and atherosclerosis) were induced, treated with anti-inflammatory agents, and evaluated for inflammatory response. The mice were also injected intraperitoneally with OTL0038, a folate receptor-targeted near-infrared dye that accumulates in activated macrophages at sites of inflammation. Uptake of OTL0038 in inflamed lesions was then correlated with clinical measurements of disease severity.

Results

OTL0038 accumulated at sites of inflammation in all four animal models. More importantly, changes in lesion-associated OTL0038 preceded changes in clinical symptoms in mice treated with all anti-inflammatory drugs examined.

Conclusion

OTL0038 has the ability to predict responses to multiple therapies in four murine models of inflammation.

     

Tumor Endothelial Marker Imaging in Melanomas Using Dual-Tracer Fluorescence Molecular Imaging

Purpose

Cancer-specific endothelial markers available for intravascular binding are promising targets for new molecular therapies. In this study, a molecular imaging approach of quantifying endothelial marker concentrations (EMCI) is developed and tested in highly light-absorbing melanomas. The approach involves injection of targeted imaging tracer in conjunction with an untargeted tracer, which is used to account for nonspecific uptake and tissue optical property effects on measured targeted tracer concentrations.

Procedures

Theoretical simulations and a mouse melanoma model experiment were used to test out the EMCI approach. The tracers used in the melanoma experiments were fluorescently labeled anti-Plvap/PV1 antibody (plasmalemma vesicle associated protein Plvap/PV1 is a transmembrane protein marker exposed on the luminal surface of endothelial cells in tumor vasculature) and a fluorescent isotype control antibody, the uptakes of which were measured on a planar fluorescence imaging system.

Results

The EMCI model was found to be robust to experimental noise under reversible and irreversible binding conditions and was capable of predicting expected overexpression of PV1 in melanomas compared to healthy skin despite a 5-time higher measured fluorescence in healthy skin compared to melanoma: attributable to substantial light attenuation from melanin in the tumors.

Conclusions

This study demonstrates the potential of EMCI to quantify endothelial marker concentrations in vivo, an accomplishment that is currently unavailable through any other methods, either in vivo or ex vivo.     

超声微泡及其在分子影像诊断和靶向治疗中的应用

超声微泡是一种超声造影剂,利用超声微泡声学特征和靶向功能可提高超声分子诊断的灵敏性和特异性,利用其药物载体和释放功能可进行靶向药物治疗。现对超声微泡及其在分子影像诊断和靶向治疗中的应用进展作一综述。     

A Preclinical Study to Explore Vasculature Differences Between Primary and Recurrent Tumors Using Ultrasound Doppler Imaging

The purpose of this preclinical study was to perform a longitudinal investigation of the function and morphology of the vasculatures of primary and recurrent tumors, because recurrent tumors have lower curability. Thus, elucidating differences in the features of the vasculatures of primary and recurrent tumors could help to improve tumor therapies. The transgenic adenocarcinoma of the mouse prostate tumors were transplanted in nonirradiated and with 25 Gy of preirradiation normal tissues to produce the primary and recurrent tumor models, respectively. The perfusion and branching index of tumor vasculatures were characterized to reveal the function and morphology information, respectively. The blood vessels were more dilated and continuous in recurrent tumors than in primary tumors. During tumor progression, the perfusion increased in primary tumors but did not change significantly in recurrent tumors. The tumor perfusion was lower in recurrent tumors than in primary tumors, whereas branching index in 2-D ultrasound images did not differ between the two tumor models. Furthermore, the introducing 3-D volumetric power Doppler image may have the potential for accurately revealing the morphologic features within tumors. The results of this study suggest that power Doppler imaging is an easily applied and rapid method for noninvasively assessing the vascular features of primary and recurrent tumors and for exploring differences between their vasculature pathways.     

Preclinical ImmunoPET Imaging of Glioblastoma-Infiltrating Myeloid Cells Using Zirconium-89 Labeled Anti-CD11b Antibody

Molecular Imaging and Biology - Glioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). TAMCs are emerging as a promising therapeutic target as they...     

Noninvasive Imaging of Cardiac Gene Expression and Its Future Implications for Molecular Therapy

Innovative approaches for cardiovascular molecular therapy are rapidly evolving, and translational efforts from experimental to clinical application are increasing. Gene and cell therapy hold promise for treatment of heart disease, but despite progress, some basic principles are still under development. Open issues are, e.g., related to the optimal method for delivery, to therapeutic efficacy, to time course and magnitude of gene expression, and to the fate of transplanted cells in target and remote areas. The use of reporter genes and labeled reporter probes for noninvasive imaging provides the methodology to address these questions by assessment of location, magnitude, and persistence of transgene expression in the heart and the whole body. Coexpression of a reporter gene allows for indirect imaging of the expression of a therapeutic gene of choice. Furthermore, reporter genes can be transferred to stem cells prior to transplantation for serial monitoring of cell viability using gene product imaging. Additionally, functional effects of therapy on the tissue level can be identified using established imaging approaches to determine blood flow, metabolism, innervation, or cell death. Measures of transgene expression can then be linked to physiologic effects and will refine the understanding of basic therapeutic mechanisms. Noninvasive gene-targeted imaging will thus enhance the determination of therapeutic effects in cardiovascular molecular therapy in the future.     

Preclinical Dosimetry,Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding,PSMA-Targeted CTT1403

Molecular Imaging and Biology - Prostate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition,...     

Incongruity of Imaging Using Fluorescent 2-DG Conjugates Compared to 18F-FDG in Preclinical Cancer Models

Purpose

We compared the use of near-infrared conjugates of 2-deoxyglucose (NIR 2-DG) to 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG) for the purposes of imaging tumors, as well as response to therapy.

Procedures

Uptake of both ¹⁸F-FDG and NIR 2-DG within gastrointestinal stromal tumor xenografts were imaged before and after nilotinib treatment. Confocal microscopy was performed to determine NIR 2-DG distribution in tumors.

Results

Treatment with nilotinib resulted in a rapid reduction in ¹⁸F-FDG uptake and reduced tumor cell viability which was predictive of long-term antitumor efficacy. In contrast, optical imaging with NIR 2-DG probes was unable to differentiate control from niltonib-treated animals, and microscopic analysis revealed no change in probe distribution as a result of treatment.

Conclusions

These results suggest that conjugation of large bulky fluorophores to 2-DG disrupts the facilitated transport and retention of these probes in cells. Therefore, optical imaging of NIR 2-DG probes cannot substitute for ¹⁸F-FDG positron emission tomography imaging as a biomarker of tumor cell viability and metabolism.     

代谢综合征的防治

随着人类社会文明的发展，生活方式的改变，以代谢综合征（Metabolic syndrome，MS）为代表的代谢异常疾病已成为当前影响人类健康和生命最主要的非传染性疾病。据报道，美国24％的成年人患有MS，我国MS患病率已达13％。MS的主要后果是增加糖尿病、心血管病的发生．而其中80％糖尿病患者死于心血管并发症，因此，加强对MS患者的综合防治，特别是早期干预，将会起到从“上游”源头上防止心血管并发症的效果。MS防治重点是改善生活方式；全面控制各项代谢危险因素；改善胰岛素抵抗等治疗。综述如下。