Introduction to the special issue of “Advances in Molecular Imaging”

Abstract

One of the most exciting recent developments in Radiology is molecular imaging. The past decade has seen a gradual increase in the number of scientific publications in this field and the creation of several molecular imaging centers or institutes by funding agencies such as National Institutes of Health (NIH). Molecular imaging is the non-invasive visualization of spatiotemporal distribution of molecular or cellular processes in living animals and humans, either directly or indirectly, for biologic, diagnostic, or therapeutic applications [1Thakur M.L. Lentle B.C. SNM; Radiological Society of North America (RSNA). Joint SNM/RSNA Molecular Imaging Summit Statement.J Nucl Med. 2005; 46 (11N–13N): 42NGoogle Scholar, 2Thakur M. Lentle B.C. Report of a summit on molecular imaging.AJR Am J Roentgenol. 2006; 186: 297-299Crossref PubMed Scopus (19) Google Scholar]. One of its key components is the imaging probe which homes in on the specific target of interest and is detected by clinical or pre-clinical imaging techniques.The concept of molecular imaging is not new. For example, a number of radiotracers have been used in nuclear medicine for decades to detect residual or recurrent tumor; the recent advances made in radiotracer chemistry further fuel the experimentation and development of specific radioactive probes including those based on carbon-11 and copper-64 chemistry with shorter half lives than conventional 18FDG [3Willmann J.K. van bruggen N. Dinkelborg L.M. Gambhir S.S. Molecular imaging in drug development.Nat Rev Drug Discov. 2008; 7: 591-607Crossref PubMed Scopus (934) Google Scholar, 4Hoffman J.M. Gambhir S.S. Molecular imaging: the vision and opportunity for radiology in the future.Radiology. 2007; 244: 39-47Crossref PubMed Scopus (143) Google Scholar]. Meanwhile, probes linking to other imaging modalities, either as a single modality or in hybrid imaging approaches, such as MRI, CT, optical imaging, or PET-CT, PET-MR scanners, are also being investigated [[5]Weissleder R. Pittet M.J. Imaging in the era of molecular oncology.Nature. 2008; 452: 580-589Crossref PubMed Scopus (1948) Google Scholar]. These molecular imaging techniques offer advantages in terms of increased spatiotemporal resolution and better visualization of molecular or cellular processes in vivo. However, the process of molecule imaging in clinics is complex and challenging as the imaging probe must be safe for human use, not perturb or alter the disease process under investigation, and reach the target in sufficient concentration and stay there long enough for detection. For the practicing radiologists who examine gross anatomical or functional manifestations of disease using conventional diagnostic imaging techniques, one would expect they have little concern to the field of molecular imaging. However, the arrival of post-genomic era opens up many new vistas of molecular diagnostics and therapeutics for modern medicine. It now becomes clear that molecular imaging is a serious matter and that radiologists need to get involved in this emerging field in order to maintain their lead in medicine and patient care. Molecular imaging, alone or in concert with other diagnostic and therapeutic techniques, would have the potential to early diagnosis, patient stratification, preventive medicine, early response assessment, and drug development [4Hoffman J.M. Gambhir S.S. Molecular imaging: the vision and opportunity for radiology in the future.Radiology. 2007; 244: 39-47Crossref PubMed Scopus (143) Google Scholar, 5Weissleder R. Pittet M.J. Imaging in the era of molecular oncology.Nature. 2008; 452: 580-589Crossref PubMed Scopus (1948) Google Scholar, 6Pomper M.G. Translational molecular imaging for cancer.Cancer Imag. 2005; (5 Spec no): S16-S26Crossref PubMed Scopus (48) Google Scholar].The discipline of molecular imaging evolved rapidly over the past decade through the integration of cell biology, molecular biology, conjugate chemistry, medical physics, and diagnostic imaging to find new insights to the disease processes and bridge those findings to clinical area. This journey embraces both high technology and scientific approach with a special emphasis on collaboration. Each item is a “sine qua non” to achieve successful and useful results in a much bigger impact of the success. In this special issue dedicated to recent advances in molecular imaging there are articles written by leading molecular imaging researchers and practitioners highlighting different perspectives of the techniques and disease application areas that can use molecular imaging in an efficient manner.We first begin with Dr. King Li, on his perspective on the concept of systems diagnostics in radiology. After a brief discussion with the historical steps towards what we call imaging today, he describes the evolution of biology into molecular biology and introduces the era of genomic medicine relating it with molecular imaging and radiologists for providing systems diagnostics.It has been nearly 30 years since metabolism, angiogenesis and various disease mechanisms have been explored with non-invasive imaging modalities, especially in animal models. Drs. Franklin Wong and Edmund Kim review the molecular imaging studies reaching the clinical stage in nuclear medicine which is of course one of the most critical goals of this effort. The problems of imaging response in cancer patients, especially with targeted drugs, the properties of an ideal imaging technique, the importance of functional imaging techniques especially in stroke patients and various aspects of imaging modalities used in molecular imaging in clinical context are presented in this review article.The article “New Horizons in Prostate Imaging” by Dr. Choyke et al. provides an excellent basic understanding of conventional and novel imaging modalities on the diagnosis, local staging, and monitoring response to treatment in prostate cancer with images. The readers can find the progress of advanced MRI and PET techniques and novel radiotracers being eloquently described in the rest of the article.“Noninvasive in vivo spectroscopic nanorod-contrast photoacoustic mapping of sentinel lymph nodes” by Drs. Lihong Wang and Kwanghyun Song can be considered as the next step in clinics for sentinel lymph node detection. The technique can be used before surgery and has the advantage of being non-invasive and also lacks radioactivity. To overcome the poor spatial resolution of the pure optical imaging methods, hybrid imaging modalities such as photoacoustic (PA) imaging is used which is capable of detecting ultrasound instead of light. The ultrasonic waves are created by the thermo-elastic expansion of the tissue which absorbs the optical energy from the short pulsed laser. The technique and the features of the equipment are fully described with the experiment performed on a rat model.In their article, Drs. Rutman and Kuo are trying to decrease the gap between the genomic and radiologic imaging characteristics of tissues and ease the need interventions for histopathological examinations. After a detailed explanation of high throughput methods and their new roles in molecular biology, the authors are concentrating on novel methods of associating gene expression patterns obtained with high throughput methods such as microarray analysis with radiographic imaging phenotypes.A promising local treatment strategy utilizes ultrasound especially high intensity focused ultrasound (HIFU) which can precisely focus the thermal energy to a small volume. The resulting local hyperthermia causes cell death via coagulative necrosis. Ultrasound energy can also be used non-destructively for increasing the efficacy for delivery of drugs and genetic material; both with heat and pressure activated particles. Both techniques integrate imaging with therapy. Microbubbles and their extended use in targeted imaging as well as formation of pores in cell membranes (sonoporation) and methods of drug and genetic material incorporation into those microbubbles is also extensively discussed by Böhmer et al. in their article. Clinical perspectives in cardiologic and oncologic applications are also provided.The paper from Dr. Anna Moore summarizes recent progress of in vivo beta-cell imaging from two aspects. One is multimodality imaging techniques (MRI, PET, and optical) in molecular imaging application while the other is different approaches in identifying specific imaginable beta-cell markers; an important measure for tracking the effectiveness of pancreatic beta-cell transplantation in treating Type-1 diabetes in particular. The paper provides important information of principal, limitation, and expectation on the frontier of this specific field.MR imaging techniques are also actively developed to improve the sensitivity and specificity to detect the small number of labeled cells in in vivo pathology. The review article by Drs. Wei Liu and Joseph Frank provide a concise and excellent summary of the development and practice issues of cellular MRI and different cell labeling methods, including superparamagnetic iron oxide (SPIO) nanoparticles, paramagnetic contrast agent (gadolinium) or perfluorocarbons to track and quantitate single or clusters of labeled cells within target tissues. They consider that quantitative image analysis methods to reveal the presence and migration of labeled cells in host system is required in addition to the qualitative assessment of cellular MRI alone.The article by Dr. Mukherjee et al. list and discuss several oncogenes and their roles in the genetic diagnosis of certain cancers. The basic properties of in vivo gene imaging agents, with a special focus on antisense agents are presented with an outline of the role of molecular imaging in in vivo oncogene expression.In their article Dr. Pan et al. comment on nanomedicine and its role in ligand-directed molecular imaging. They describe a number of advanced molecular imaging methods and targeted nano-sized contrast agents for ultrasound, MRI, and CT imaging modalities for detection and treatment of cardiovascular and related diseases. Targeted molecular imaging using different modalities is introduced with a special emphasis on perfluorocarbon nanoemulsion. The article also contains basic information about the conjugation strategies.The treatment approach and options of available cancer therapeutic agents have significantly changed from cytotoxic agents towards more selective and local treatments relying on targets. In their article, Alves et al. are introducing major considerations in antibody directed enzyme prodrug therapy (ADEPT). The major issue in ADEPT is discovering tumor-specific antibodies, so that we can obtain high retention within the tumor and fast clearance from the circulation. In addition, the near infrared frequency (NIRF) imaging can be used to assess the binding kinetics of such antibodies, flat-panel volume computed tomography (fpVCT) can be used to analyse the anatomical structures, and the fusion of them gives us clear visualization of both functional and structural effects. This approach will give us insights about the efficacy of novel agents in pre-clinical studies.The paper from Dr. Chen et al. addresses heat shock proteins and their role in cancer treatment via Hsp70 (heat shock protein 70) promoter-driven gene therapy and inhibition of Hsp90 (heat shock protein 90) activity with small molecule inhibitors. In this review, most recent information related to heat shock proteins is described. The article provides a balanced summary of a broad spectrum of applications using molecular imaging approaches that have been applied to understand Hsp70 and Hsp90 in the past two decades.It is not possible to think of a special issue on the subject of molecular imaging without a discussion on vascular targeting. In their article Drs. Lyubomir Zagorchev and Mary J. Mulligan-Kehoe provide an overview on the general characteristics of complexity of angiogenesis mechanisms in cellular level. After that, they focus on the use of microCT, ultrasound, microPET, and confocal microscopy for imaging of angiogenesis and molecular vascular targets in a mouse tumor model of angiogenesis. One of the most exciting recent developments in Radiology is molecular imaging. The past decade has seen a gradual increase in the number of scientific publications in this field and the creation of several molecular imaging centers or institutes by funding agencies such as National Institutes of Health (NIH). Molecular imaging is the non-invasive visualization of spatiotemporal distribution of molecular or cellular processes in living animals and humans, either directly or indirectly, for biologic, diagnostic, or therapeutic applications [1Thakur M.L. Lentle B.C. SNM; Radiological Society of North America (RSNA). Joint SNM/RSNA Molecular Imaging Summit Statement.J Nucl Med. 2005; 46 (11N–13N): 42NGoogle Scholar, 2Thakur M. Lentle B.C. Report of a summit on molecular imaging.AJR Am J Roentgenol. 2006; 186: 297-299Crossref PubMed Scopus (19) Google Scholar]. One of its key components is the imaging probe which homes in on the specific target of interest and is detected by clinical or pre-clinical imaging techniques. The concept of molecular imaging is not new. For example, a number of radiotracers have been used in nuclear medicine for decades to detect residual or recurrent tumor; the recent advances made in radiotracer chemistry further fuel the experimentation and development of specific radioactive probes including those based on carbon-11 and copper-64 chemistry with shorter half lives than conventional 18FDG [3Willmann J.K. van bruggen N. Dinkelborg L.M. Gambhir S.S. Molecular imaging in drug development.Nat Rev Drug Discov. 2008; 7: 591-607Crossref PubMed Scopus (934) Google Scholar, 4Hoffman J.M. Gambhir S.S. Molecular imaging: the vision and opportunity for radiology in the future.Radiology. 2007; 244: 39-47Crossref PubMed Scopus (143) Google Scholar]. Meanwhile, probes linking to other imaging modalities, either as a single modality or in hybrid imaging approaches, such as MRI, CT, optical imaging, or PET-CT, PET-MR scanners, are also being investigated [[5]Weissleder R. Pittet M.J. Imaging in the era of molecular oncology.Nature. 2008; 452: 580-589Crossref PubMed Scopus (1948) Google Scholar]. These molecular imaging techniques offer advantages in terms of increased spatiotemporal resolution and better visualization of molecular or cellular processes in vivo. However, the process of molecule imaging in clinics is complex and challenging as the imaging probe must be safe for human use, not perturb or alter the disease process under investigation, and reach the target in sufficient concentration and stay there long enough for detection. For the practicing radiologists who examine gross anatomical or functional manifestations of disease using conventional diagnostic imaging techniques, one would expect they have little concern to the field of molecular imaging. However, the arrival of post-genomic era opens up many new vistas of molecular diagnostics and therapeutics for modern medicine. It now becomes clear that molecular imaging is a serious matter and that radiologists need to get involved in this emerging field in order to maintain their lead in medicine and patient care. Molecular imaging, alone or in concert with other diagnostic and therapeutic techniques, would have the potential to early diagnosis, patient stratification, preventive medicine, early response assessment, and drug development [4Hoffman J.M. Gambhir S.S. Molecular imaging: the vision and opportunity for radiology in the future.Radiology. 2007; 244: 39-47Crossref PubMed Scopus (143) Google Scholar, 5Weissleder R. Pittet M.J. Imaging in the era of molecular oncology.Nature. 2008; 452: 580-589Crossref PubMed Scopus (1948) Google Scholar, 6Pomper M.G. Translational molecular imaging for cancer.Cancer Imag. 2005; (5 Spec no): S16-S26Crossref PubMed Scopus (48) Google Scholar]. The discipline of molecular imaging evolved rapidly over the past decade through the integration of cell biology, molecular biology, conjugate chemistry, medical physics, and diagnostic imaging to find new insights to the disease processes and bridge those findings to clinical area. This journey embraces both high technology and scientific approach with a special emphasis on collaboration. Each item is a “sine qua non” to achieve successful and useful results in a much bigger impact of the success. In this special issue dedicated to recent advances in molecular imaging there are articles written by leading molecular imaging researchers and practitioners highlighting different perspectives of the techniques and disease application areas that can use molecular imaging in an efficient manner. We first begin with Dr. King Li, on his perspective on the concept of systems diagnostics in radiology. After a brief discussion with the historical steps towards what we call imaging today, he describes the evolution of biology into molecular biology and introduces the era of genomic medicine relating it with molecular imaging and radiologists for providing systems diagnostics. It has been nearly 30 years since metabolism, angiogenesis and various disease mechanisms have been explored with non-invasive imaging modalities, especially in animal models. Drs. Franklin Wong and Edmund Kim review the molecular imaging studies reaching the clinical stage in nuclear medicine which is of course one of the most critical goals of this effort. The problems of imaging response in cancer patients, especially with targeted drugs, the properties of an ideal imaging technique, the importance of functional imaging techniques especially in stroke patients and various aspects of imaging modalities used in molecular imaging in clinical context are presented in this review article. The article “New Horizons in Prostate Imaging” by Dr. Choyke et al. provides an excellent basic understanding of conventional and novel imaging modalities on the diagnosis, local staging, and monitoring response to treatment in prostate cancer with images. The readers can find the progress of advanced MRI and PET techniques and novel radiotracers being eloquently described in the rest of the article. “Noninvasive in vivo spectroscopic nanorod-contrast photoacoustic mapping of sentinel lymph nodes” by Drs. Lihong Wang and Kwanghyun Song can be considered as the next step in clinics for sentinel lymph node detection. The technique can be used before surgery and has the advantage of being non-invasive and also lacks radioactivity. To overcome the poor spatial resolution of the pure optical imaging methods, hybrid imaging modalities such as photoacoustic (PA) imaging is used which is capable of detecting ultrasound instead of light. The ultrasonic waves are created by the thermo-elastic expansion of the tissue which absorbs the optical energy from the short pulsed laser. The technique and the features of the equipment are fully described with the experiment performed on a rat model. In their article, Drs. Rutman and Kuo are trying to decrease the gap between the genomic and radiologic imaging characteristics of tissues and ease the need interventions for histopathological examinations. After a detailed explanation of high throughput methods and their new roles in molecular biology, the authors are concentrating on novel methods of associating gene expression patterns obtained with high throughput methods such as microarray analysis with radiographic imaging phenotypes. A promising local treatment strategy utilizes ultrasound especially high intensity focused ultrasound (HIFU) which can precisely focus the thermal energy to a small volume. The resulting local hyperthermia causes cell death via coagulative necrosis. Ultrasound energy can also be used non-destructively for increasing the efficacy for delivery of drugs and genetic material; both with heat and pressure activated particles. Both techniques integrate imaging with therapy. Microbubbles and their extended use in targeted imaging as well as formation of pores in cell membranes (sonoporation) and methods of drug and genetic material incorporation into those microbubbles is also extensively discussed by Böhmer et al. in their article. Clinical perspectives in cardiologic and oncologic applications are also provided. The paper from Dr. Anna Moore summarizes recent progress of in vivo beta-cell imaging from two aspects. One is multimodality imaging techniques (MRI, PET, and optical) in molecular imaging application while the other is different approaches in identifying specific imaginable beta-cell markers; an important measure for tracking the effectiveness of pancreatic beta-cell transplantation in treating Type-1 diabetes in particular. The paper provides important information of principal, limitation, and expectation on the frontier of this specific field. MR imaging techniques are also actively developed to improve the sensitivity and specificity to detect the small number of labeled cells in in vivo pathology. The review article by Drs. Wei Liu and Joseph Frank provide a concise and excellent summary of the development and practice issues of cellular MRI and different cell labeling methods, including superparamagnetic iron oxide (SPIO) nanoparticles, paramagnetic contrast agent (gadolinium) or perfluorocarbons to track and quantitate single or clusters of labeled cells within target tissues. They consider that quantitative image analysis methods to reveal the presence and migration of labeled cells in host system is required in addition to the qualitative assessment of cellular MRI alone. The article by Dr. Mukherjee et al. list and discuss several oncogenes and their roles in the genetic diagnosis of certain cancers. The basic properties of in vivo gene imaging agents, with a special focus on antisense agents are presented with an outline of the role of molecular imaging in in vivo oncogene expression. In their article Dr. Pan et al. comment on nanomedicine and its role in ligand-directed molecular imaging. They describe a number of advanced molecular imaging methods and targeted nano-sized contrast agents for ultrasound, MRI, and CT imaging modalities for detection and treatment of cardiovascular and related diseases. Targeted molecular imaging using different modalities is introduced with a special emphasis on perfluorocarbon nanoemulsion. The article also contains basic information about the conjugation strategies. The treatment approach and options of available cancer therapeutic agents have significantly changed from cytotoxic agents towards more selective and local treatments relying on targets. In their article, Alves et al. are introducing major considerations in antibody directed enzyme prodrug therapy (ADEPT). The major issue in ADEPT is discovering tumor-specific antibodies, so that we can obtain high retention within the tumor and fast clearance from the circulation. In addition, the near infrared frequency (NIRF) imaging can be used to assess the binding kinetics of such antibodies, flat-panel volume computed tomography (fpVCT) can be used to analyse the anatomical structures, and the fusion of them gives us clear visualization of both functional and structural effects. This approach will give us insights about the efficacy of novel agents in pre-clinical studies. The paper from Dr. Chen et al. addresses heat shock proteins and their role in cancer treatment via Hsp70 (heat shock protein 70) promoter-driven gene therapy and inhibition of Hsp90 (heat shock protein 90) activity with small molecule inhibitors. In this review, most recent information related to heat shock proteins is described. The article provides a balanced summary of a broad spectrum of applications using molecular imaging approaches that have been applied to understand Hsp70 and Hsp90 in the past two decades. It is not possible to think of a special issue on the subject of molecular imaging without a discussion on vascular targeting. In their article Drs. Lyubomir Zagorchev and Mary J. Mulligan-Kehoe provide an overview on the general characteristics of complexity of angiogenesis mechanisms in cellular level. After that, they focus on the use of microCT, ultrasound, microPET, and confocal microscopy for imaging of angiogenesis and molecular vascular targets in a mouse tumor model of angiogenesis.