Get this from a library! Molecular imaging: principles and practice. [Ralph Weissleder; Alnawaz Rehemtulla; Sanjiv Sam Gambhir;]. 年12月13日 Author[*] Ralph Weissleder, MD, PhD, Professor of Radiology and Systems Biology, Harvard Medical School, Director, Center for Systems. MOLECULAR IMAGING: PRINCIPLES AND PRACTICE inclusion of MRI contrast agents into the fluorocarbon liquid nanoparticles has made these biocolloids.
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The field of molecular imaging has seen spectacular advances in chemistry, engineering, and biochemical appli- cations in recent years. Comprehensive. Request PDF on ResearchGate | On May 5, , Dustin R Osborne and others published Molecular Imaging: Principles and Practice. The field of molecular imaging of living subjects has evolved considerably and has seen and Practice. Molecular Imaging: Principles and Practice View PDF.
Correspondence should be addressed to Jian Shu ; moc. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Molecular imaging has emerged at the end of the last century as an interdisciplinary method involving in vivo imaging and molecular biology aiming at identifying living biological processes at a cellular and molecular level in a noninvasive manner. It has a profound role in determining disease changes and facilitating drug research and development, thus creating new medical modalities to monitor human health. At present, a variety of different molecular imaging techniques have their advantages, disadvantages, and limitations.
Kircher et al. Overall, magnetic resonance imaging is one of the most important molecular imaging research methods, which can be used for noninvasive monitoring and early diagnosis of diseases at the cellular and molecular level. In recent years, the study of magnetic resonance molecular imaging is increasing and is mainly used for cell tracking, angiogenesis, apoptosis, and in vivo tissue gene imaging.
Although the techniques still have some problems that need an urgent solution, its unique advantages make its application prospect worthy of expectation in clinical medicine and basic research.
Radionuclide Molecular Imaging Radionuclide imaging is one of the four major medical imaging techniques, and it is a radioactive marker in drug, when the body organs and tissue absorb and form radiation source in the body, and then, the nuclide detection device can be used to detect isotope in the process of decay on the rays, which constitute the image of radioactive isotopes in in vivo distribution density [ 75 , 76 ].
In recent years, with the rapid development of molecular biology and nuclear medicine technology, the field of nuclear medicine has formed a new branch of nuclear medicine—molecular nuclear medicine [ 77 ].
SPECT and PET are advanced radionuclide molecular imaging techniques that are able to evaluate biochemical changes and levels of molecular targets within a living subject. SPECT is mainly used for whole body bone imaging [ 78 — 80 ], myocardial blood flow imaging [ 81 — 84 ], cerebral blood flow imaging [ 85 — 89 ], and thyroid imaging [ 90 — 95 ]. PET is mainly used to detect dynamic changes in the metabolic function of substances or drugs in the human body, and it widely used for the nervous system, the cardiovascular system, and the oncology [ 96 — ].
The imaging agents used for PET are the basic elements for the human body, used to easily mark compounds and metabolites, and do not change their biological activity, so as to reflect the molecular level of physiological and biochemical processes of the human body, to achieve the purpose of early diagnosis and guidance of treatment. In clinical practice, PET that enables to locate, stage, and monitor cancer is mainly used to image tumors through the use of the 18F-labeled imaging agent [18F]fluorodeoxy-glucose [18F]-FDG [ — ].
For instance, Brenner et al. Kindred et al. Winther-Larsen et al. In addition to its clinical practicality, PET has extensive applications in the basic and preclinical researches.
PET can be used to study basic physiological and molecular mechanisms of human diseases by using the appropriate radiolabeled-imaging agents [ ]. Bretin et al. Moreover, PET can be employed for the evaluation of novel radiolabeled-PET imaging agents, biodistribution of novel pharmaceuticals in suitable animal models, and effectiveness of new therapies [ 30 , ].
For instance, Nanni et al. SPECT imaging agents use energy between 85 and Kev; radiographic tomography is a technique for projection reconstruction of faulty images, which are similar to X-ray and CT imaging. SPECT uses nuclides such as 99mTc [ — ], and I [ , ] through the emission of single gamma rays decay to obtain different energies. SPECT is one of the most commonly used nuclear medicine modalities in clinical practice [ ].
Some examples of clinical use are the potential usefulness of 99mTc-TRODAT-1 imaging in the evaluation of patients with early-stage Parkinson's disease [ ], the therapeutic effects of In-DTPA-octreotide in tumors of various sizes [ ], and the location and excision of the tumor [ ]. Besides, small-animal SPECT is designed for imaging small animals specifically [ , ], and it has been used for many preclinical studies.
To name a few, Wang et al. Moscaroli et al. Tang et al. This weakness may be eliminated through the combination of these instruments with either CT or MRI, producing a single scanner capable of accurately identifying molecular events with precise correlation to anatomical findings [ ].
For example, Glaus et al. Chen et al. Xing et al. Thus, the nuclear medical imaging is associated with near-infrared imaging.
Finally, the authors show that the PET signal is highly coincided with quantum dot near-infrared image. So far, nuclear medicine molecular imaging technology is one of the widely used technologies in clinical molecular imaging technology and plays an important role in the study of personalized medical care due to its unique technology [ — ]. PET and SPECT are not only powerful tools for basic medicine and pharmacy but also the best tools for detecting and guiding the treatment of various diseases and tumors [ , , ].
They contribute to developing treatment programs on the tumor and other diseases, which are made by clinicians more scientific, more comprehensive, and more reasonable.
Their application will have a profound impact on clinical practice. Medical ultrasound imaging is a unique imaging modality that exploits the properties and behavior of high-frequency sound waves as they travel through biological tissue, and it can be used both for diagnostic imaging and as a therapeutic tool. Compared with traditional imaging techniques such as radionuclide imaging and optical imaging, ultrasound imaging has some advantages such as economy, convenience, and real-time imaging [ , ].
Furthermore, ultrasound molecular imaging of contrast agents which combine with the target organ can be used as a carrier for therapeutic drugs or genes, so as to achieve a multiplier effect [ — ]. Traditional ultrasound contrast agents, that are a few micrometers in diameter and in the terms of gas-filled microbubbles, are often coated with lipids or biopolymers, and they are available for enhancing the reflection signal-to-noise ratio for blood [ ]. These contrast agents have provided useful imaging data, but they do not enable imaging of specific molecular events.
However, by attaching certain antibodies [ — ], peptides [ , ], or other targeting moieties [ ] to the surface of microbubbles, those particles can target specific biochemical processes to achieve ultrasound molecular imaging. Ultrasound molecular imaging that uses in vivo simulation of immunohistochemistry or in situ hybridization techniques targets biomolecules to highlight the pathological changes of diseased tissue.
Thus, it can visualize the real pathogenesis and significantly improve the sensitivity and accuracy of imaging diagnosis. These aspects are actually the current clinical research central issues.
At present, targeted microbubbles are being used in preclinical investigations of both inflammation and angiogenesis.
For example, microbubble shells have been attached to endothelial cell adhesion molecules for visualization of P-selectin, supplying foresight on molecular aspects of inflammation [ ]. Deshpande et al.
After using either targeted microbubbles or control microbubbles in tumor-bearing nude mice, ultrasound imaging studies can be performed. Compared with studies using only control microbubbles, imaging results demonstrated a significantly higher average intensity in images from studies using targeted microbubbles. Liu et al. With the emergence of ultrasound molecular imaging, the early diagnosis and specific treatment of malignant tumors gained some research achievements.
Cochran et al. Wang et al. Hu et al. In the near future, ultrasound molecular imaging is expected to pass from a preclinical modality to a fully clinically useful technique through the use of different clinically translatable instrumentation, such as endoscopes and novel US-compatible imaging agents that are able to exudate [ , ].
Among the agent-based molecular imaging techniques, targeted ultrasound imaging has promising huge developments. Optical Molecular Imaging Optical imaging is a method of obtaining biological information by using optical detection means combined with optical detection molecules to imaging cells or tissues or even organisms.
If the biological optical imaging is limited to the visible and near-infrared range, different biological optical imaging methods can be divided into fluorescence imaging, bioluminescence imaging, photoacoustic imaging, and optical tomography. Nowadays, molecular imaging becomes more popular and is combined with classical optical imaging techniques. Fluorescence imaging technology is marked with a fluorescent report group including inorganic materials, such as upconversion, quantum dots, and other organic materials, such as green fluorescent protein, red fluorescent protein, or fluorescent dye.
It uses excitation light to make the report group reach a higher level of molecular level and then emit a longer wavelength visible light to form biological light source in vivo and detect it.
At present, common fluorescent groups include various small molecule fluorescent dyes, green fluorescent protein, and red fluorescent protein. In recent years, fluorescence technology has been extensively used in the study of molecular biology and the metabolism of small molecules in small molecules.
There is a rapidly expanding list of fluorescent agents which includes near-IR Cy 5. Besides, lanthanide-based imaging agents were added to this list [ ]. There are numerous strengths of these agents which are better than the aforementioned dyes and proteins. They have narrow, nonoverlapping emission bands, long luminescence lifetimes, and allow multiplexed quantitative measurements of the intracellular analysis concentrations [ , ].
Fluorescence molecular tomography FMT has been applied to visualize and quantitate a variety of cellular and molecular events. In opposition to planar fluorescence imaging, FMT can produce quantitative information and allows imaging at greater depths, up to several centimeters [ 10 ]. In , Hyde et al. Lin et al. Bioluminescence imaging technology uses luciferase gene to label cells or DNA and exploits sensitive optical detection instrument to directly monitor cell activity and gene behavior in living subjects.
This technique has these following advantages: 1 noninvasive, 2 continuous repeated detection, 3 fast real-time scanning imaging, and 4 high sensitivity. Bioluminescence imaging has been used to study numerous enigmatic protein-protein interactions.
One such study uses a firefly luciferase-based protein fragment complementation assay to visualize luciferase-expressing bone marrow cells in brain inflammation in living mice [ ]. In , Wang et al. Photoacoustic imaging PA by using optical absorption and transformation between the tissues of the light and sound energy is a nondestructive imaging method developed in recent years. Advances in molecular imaging for tracking stem cell therapy Stem cell therapies offer enormous potential for the treatment of a wide range of diseases and injuries including neurodegenerative diseases, cardiovascular disease, diabetes, arthritis, spinal cord injury, stroke, and burns.
More research teams are accelerating the use of other types of adult stem cells, in particular neural stem cells for diseases where beneficial outcome could result from either in-lineage cell replacement or extracellular factors. At the same time, the first three trials using cells derived from pluripotent cells have begun [ 12 ]. These early trials are showing roles for stem cells both in replacing damaged tissue as well as in providing extracellular factors that can promote endogenous cellular salvage and replenishment [ 26 ].
Clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease [ 10 ]. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair [ 27 ]. Although early clinical trials of stem cell therapy have showed positive effect, there remains much controversy about which cell type holds the most promise for clinical therapeutics and by what mechanism stem cells mediate a positive effect, and further research should be able to answer these questions.
Imaging of embryonic stem cells driven regeneration Embryonic stem cells ESCs are pluripotent stem cells capable of self-renewal and differentiation into virtually all cell types [ 28 ]. Various lineages have been derived from human and mouse ESCs, including cardiomyocytes, neurons, hematopoietic cells, osteogenic cells, hepatocytes, insulin-producing cells, keratinocytes, and endothelial cells.
Given their unlimited self-renewal and pluripotency capacity, ESCs have been regarded as a leading candidate source for novel regenerative medicine therapy. So far, ESCs transplantation has been widely investigated as a potential therapy for cell death-related heart disease, ischemic diseases, CNS disorders and diabetes. However, the bottleneck of application of ESC driven regeneration is high risk of teratoma formation in vivo [3, 6].
The concurrent development of accurate, sensitive, and noninvasive technologies capable of monitoring ESCs engraftment in vivo has greatly accelerated basic research prior to future clinical translation. Numerous imaging modalities have analyzed the behavior of embryonic stem cells that have been transplanted to regenerate tissues, which include MRI, bioluminescence imaging BLI , fluorescence, PET, and multimodality approaches.
Two main PET strategies for embryonic stem cell has been used——direct imaging [ 29 ] and indirect imaging [ 30 ]. Although the value of PET lies in its easy accessibility and high-sensitivity tracking of biomarkers, potential disadvantages of PET include repeated injection of radioactive substances into an organism with the potential to radiation accumulation [ 31 ] and adverse effect on ESCs viability and pluripotency capacity [ 32 ]. Additionally, the short half-lives of most current available radiotracers have limited their use for long-term tracing [ 33 ].
Meanwhile, MRI is accessible for tracking ESCs engraftment, providing detailed morphological and functional information. Drawbacks of MRI include low sensitivity and being unable to quantify cell population. Holding the significant advantage of high sensitivity cells, for more superficial anatomical sites , safety, low cost and the repeated tracking of small numbers of labeled cells in whole body distribution without background signal, BLI is widely used in this field.
Zongjin Li, et al. Nevertheless, at present, bioluminescence imaging still lacks adequate tomographic resolution because of attenuation of photons within tissues [ 3 ].
An innovative approach to combine the strengths of optical fluorescence, bioluminescence, and PET is the creation and use of a fusion reporter [ 36 ] construct composed of RFP, Fluc, and HSV-tk. This fusion reporter construct has been adapted to research the spatio-temporal kinetics of hESC engraftment and proliferation in living subjects, without significant adverse effects on mouse ESC viability, proliferation, differentiation, or proteomic expression [ 37 ].
Imaging of mesenchymal stem cells driven regeneration Mesenchymal stem cells MSCs are a heterogeneous subset of stromal stem cells that can differentiate into cells of the mesodermal lineage, such as bone, fat and cartilage cells, but they also have endodermic and neuroectodermic differentiation potential.
The use of MSCs for clinical purposes takes advantage of their poor immunogenicity in vitro. Preclinical [ 38 ] and clinical [ 39 , 40 ] studies have supported the possible use of MSCs obtained from allogeneic donors in the clinic. In preclinical researches, MSCs have been applied in tissue regeneration, including haematopoietic organs, heart, CNS, skin, kidney, liver, lung, joint, eye, pancreas and renal glomeruli.
The current data indicate that bone-marrow-derived MSCs were first proposed for therapeutic purposes in regenerative medicine on the basis of their stem-cell-like qualities [ 41 ]. The versatility of the molecular imaging method could allow cellular tracking using single or multimodal imaging modalities.
Noninvasive MRI is fast becoming a clinical favorite, though there is scope for improvement in its accuracy and sensitivity. Indirect labeling relies on the expression of imaging reporter genes transduced into cells before transplantation. A classic example of using reporter gene tracing MSCs transplantation is the research by Zachary Love, et al. Signals from the cubes loaded with reporter-transduced hMSCs were visible by BLI over 3 mo, meanwhile, PET data provided confirmation of the quantitative estimation of the number of cells at one spot cube [ 44 ].
The reporter gene approach resulted in a reliable method of labeling stem cells for investigations in small-animal models by use of both BLI and small-animal PET imaging. Imaging of neural stem cell therapy Neural stem cells NSCs -driven regeneration has been proposed as a promising potential treatment option for CNS-related disease processes, including everything from cerebrovascular disease to traumatic brain injury to degenerative diseases of the CNS.
Grafted NSCs differentiated into neurons, into oligodendrocytes undergoing remyelination and into astrocytes extending processes toward damaged vasculatures [ 45 ].
In contrast to most tissues in adults, the central nervous system has a low regenerative activity, and neural stem cells reside in regions of the adult brain that are difficult to access by most imaging modalities [ 5 ] owning to tissue depth and the blood-brain barrier BBB. MRI has been used in clinical practice for the past 30 years to diagnose brain lesions and is therefore already a standard clinical adjunct for neuropathologies.
However, this technique is still in its infancy, further study into the possibility of magnetic resonance reporter genes is needed before this technology can be used for NSCs. The hypointense signal generated by the cells demonstrated cell trace from the implantation site to the periphery of the lesion the first week, and then disappeared by the seventh week, which the group attributed to NSC proliferation.
A solution to the BBB problem could be the use of the xanthine phosphoribosyl transferase reporter enzyme PET system, which employs xanthine reporter probes that can cross the BBB [ 48 ]. With regard to in vivo NSCs imaging, bioluminescence is the most studied of the optical imaging techniques and has been employed in numerous small animal studies. Improvement of the existing imaging modalities, assessment of the effect of imaging modalities on cellular biology, and development of new techniques for in vivo NSC imaging, would open up the window of the use of NSCs for various neuropathologies.
Imaging of hematopoietic stem cell transplantation Hematopoiesis is described to be the production of all types of fully differentiated daughter blood cells from ancestral great-grandmother hematopoietic stem cells HSCs. HSCs studies and clinical applications have historically been ahead of other tissue stem cells and have generated most stem cell biology models.
However, hematopoiesis is arguably among the most difficult of the mammalian stem-cell systems to image real-time in vivo [ 5 ]. In homeostatic conditions, the different short-lived cell types of blood are regenerated from a small population of HSCs [ 49 ], while a significant proportion of HSCs with long-term reconstitution potential is predominantly quiescent or divides infrequently. The HSC niche is most likely a complex, multi-component microenvironment of which the osteoblast is just one of the major constituents identified so far.
Thus, non-invasive long-term imaging is more challenging in the bone marrow.
Hematopoiesis is better understood than other stem-cell systems and has important clinical significance, but despite intensive research in the past decade, many basic questions are still unresolved [ 50 ]. MRI [ 51 ], bioluminescence imaging [ 52 ], and multiphoton fluorescence microscopy [ 53 ] had been applied in continuous observation of cellular behavior of HSCs.
The field of molecular imaging of living subjects has evolved considerably and has seen spectacular advances in chemistry, engineering and biomedical applications. This textbook was designed to fill the need for an authoritative source for this multi-disciplinary field. Given the multidisciplinary nature of the field, the book is broken into six different sections: Molecular Imaging technologies , Chemistry , Molecular Imaging in Cell and Molecular Biology , Applications of Molecular Imaging , Molecular Imaging in Drug Evaluation with the final section comprised of chapters on computation, bioinformatics and modeling.
The organization of this large amount of information is logical and strives to avoid redundancies among chapters. It encourages the use of figures to illustrate concepts and to provide numerous molecular imaging examples.