Elsevier

Clinical Radiology

Volume 65, Issue 7, July 2010, Pages 500-516
Clinical Radiology

Molecular imaging: current status and emerging strategies

https://doi.org/10.1016/j.crad.2010.03.011Get rights and content

In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use positron-emission tomography (PET) or single photon-emission computed tomography (SPECT)-based techniques. In ongoing preclinical research, novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multi-modality molecular imaging. Contrast-enhanced molecular ultrasound (US) with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and US imaging with molecularly-targeted microbubbles are attractive strategies as they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and US techniques involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with US. Current preclinical findings and advances in instrumentation, such as endoscopes and microcatheters, suggest that these molecular imaging methods have numerous potential clinical applications and will be translated into clinical use in the near future.

Introduction

Molecular imaging is defined as the ability to visualize and quantitatively measure the function of biological and cellular processes in vivo.1, 2, 3, 4 While anatomical imaging plays a major role in medical imaging for diagnosis, surgical guidance/follow-up, and treatment monitoring, the rapidly evolving field of molecular imaging promises improvements in specificity and quantitation for screening and early diagnosis, focused and personalized therapy, and earlier treatment follow-up. The main advantage of in vivo molecular imaging is its ability to characterize diseased tissues without invasive biopsies or surgical procedures, and with this information in hand, a more personalized treatment planning regimen can be applied. For example, recent strategies for treatment of breast cancer involve combinations of several chemotherapeutic drugs that target epidermal growth factor receptor types I and 2 (EGFR and HER2/neu), mammalian target of rapamycin (mTor), oestrogen receptor, and/or histone deacetylase, among others; however, the most effective strategy is dependent on the molecular profile of the tumour (e.g., HER2/neu-targeted therapy is only effective in HER2-positive breast cancers).5In vivo molecular imaging can be used to identify and quantify the molecular marker profile (e.g., EGFR, HER2) of the tumour without the invasiveness of a surgical biopsy and time associated with pathological characterization. The personalized medicine approach is especially important for determining the best care for patients with advanced stage cancers and poor prognosis. In this case, the risk of exposure to unwanted side-effects of therapy may outweigh the quality of remaining life.

Recent preclinical advances in molecular imaging contrast agents have demonstrated the ability to multiplex nano- and/or microparticles with several entities (Fig. 1): (1) a molecule for targeting to a specific tissue/disease marker (binding ligand); (2) a molecule that enables detection of the agent with different imaging modalities; and (3) a direct attachment or system (e.g., Doxel is a liposome encapsulation of doxirubicin, a cytotoxic drug which inhibits DNA replication), for targeted delivery of a therapeutic drug at the site of interest. For example, Blanco et al.6 describe the direct attachment of the chemotherapy drug, Doxirubicin, to a superparamagnetic iron oxide (SPIO) nanoparticle, which is then encapsulated in liposomes coated with RGD-peptides; thus, these particles specifically attach to tumour angiogenic vessels expressing high levels of αVβ3-integrins (protein receptors which bind RGD peptides), and the localization of these magnetic particles can be visualized using magnetic resonance imaging (MRI).

In addition, molecular imaging can be used to measure the response to therapy. Current practices in measuring tumour response to chemotherapy are governed primarily by the Response Evaluation Criteria in Solid Tumours (RECIST) approach, which uses anatomical imaging methods such as computed tomography (CT) or magnetic resonance imaging (MRI) to measure changes in tumour size; however, measurable effects of therapy on tumour volume may take considerable time (weeks to months), indicating that tumour volumetric changes are not an accurate reflection of therapeutic efficacy in all cases.7 Molecular imaging has the potential to improve therapeutic monitoring by, for example, measuring the direct effect of a drug at an earlier time point before overt morphological–anatomical changes become visible on imaging. Most chemotherapeutic/anti-cancer drugs are either directed at specific molecular targets such as epidermal growth factor receptor (EGFR; drugs include erlotinib, cetuximab, and gefitnib), VEGFR (drugs include bevacizumab, sunitinib, axitinib, and vatalanib), oestrogen receptor (such as tamoxifen), and EGFR type 2 (also known as ErbB2 or HER2/neu; drug such as trastuzamab), or they are cytotoxic (drugs include paclitaxel/taxol, fluoruracil, or gemcitabine, among others) to promote tumour cell death. Molecular imaging agents have been designed and tested preclinically in rodent models to image all of the aforementioned molecular targets, as well as cellular events such as metabolic activity or apoptosis8 and, therefore, may be used in the future to monitor treatment effect at the molecular level at earlier time points after treatment initiation than with current imaging strategies.

This article reviews current clinical practices of molecular imaging and highlights promising strategies using optical and acoustic techniques that may be translated into clinical applications in the near future.

Section snippets

Current clinical molecular imaging strategies

Various imaging methods are used for medical imaging, including positron emission tomography (PET), single photon emission CT (SPECT), MRI, magnetic resonance spectroscopy (MRS), ultrasound (US), and CT (Table 1). The majority of molecular imaging in the clinic is currently performed only with PET, SPECT, and MRS imaging. Several PET (Table 2) and SPECT (Table 3) radiotracers are used for medical imaging applications, including oncology, cardiology, and neurology. MRS is a MRI technique that

Preclinical developments in molecular imaging and potential clinical applications

Preclinical molecular imaging in small animals is an invaluable part of evaluating new molecular targets and contrast agents, as well as developing drugs prior to clinical translation.34, 35Fig. 2 shows the time intensive and expensive preclinical steps involved in molecular target identification, validation, chemical synthesis, and characterization (in vitro and in vivo testing for activity, specificity, biodistribution, pharmacokinetics, off-target effects, toxicity, etc) for new molecular

Conclusions

Molecular imaging can be applied to all avenues of medical imaging: early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up. The current status of clinical molecular imaging is limited, with most current applications using PET and SPECT imaging, and a small number of highly specific applications for MRI/MRS, optical, and US. Current demands and trends are calling for new strategies to focus on early disease detection through improved imaging and screening

Acknowledgements

This work has been supported by the RSNA Seed grant RSD0809 (JKW), the Howard S. Stern Research Grant of the Society of Gastrointestinal Radiologists (JKW), NIH R21 CA139279 (JKW), the National Pancreas Foundation(JKW), the Canary Foundation (JKW), and the Stanford Molecular Imaging Scholars Program NIH/NCI R25 CA11868 (MAP).

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