Molecular imaging in oncology: Current impact and future directions

Introduction

On its website, the Society of Nuclear Medicine and Molecular Imaging defines molecular imaging as a type of medical imaging that provides detailed pictures at the molecular and cellular levels of what is occurring inside the body.1 This accurate, but staid, definition belies the immense progress researchers and clinicians have made over the past 2 decades in applying the principles of molecular imaging across several fields, from basic and translational science through state-of-the-art patient diagnosis and therapy. Fundamentally, molecular imaging allows for the visualization of biochemical processes and patterns of target localization that are invisible at the anatomic imaging level.

Although endogenous image contrast can be leveraged or induced within tissues,2, 3 much of molecular imaging requires administration of an imaging agent, usually intravenously, which interacts with a targeted environment to uncover biological pathways. Because a hallmark of molecular imaging is lack of perturbation of the cell, environment, or process under study, the imaging agents often serve as tracers, with no effect on the entity they are designed to measure. Tracers can be molecules or analogs of molecules that participate in metabolic pathways or they can be targeted to serve as substrates for or bind to specific enzymes, receptors, antigens, or transporters. In many scenarios, the tracer will be radiolabeled, ie, with a radionuclide, although, as discussed below, this is not always the case. A second component necessary for molecular imaging is appropriate hardware—a sensor or scanner that can detect the tracer and translate that detection into spatial information. Optimized molecular imaging approaches will have a high-affinity tracer for a pathway or target that is near-uniquely present in the process of interest, as well as a scanner with high sensitivity and high spatial, contrast, and temporal resolution.

In the current review, we focus on selected, common imaging modalities and examples that highlight molecular imaging in oncology. Specifically, we detail techniques in optical and near-infrared (NIR) imaging, magnetic resonance imaging (MRI), and nuclear medicine techniques, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) (Table 1).4-119 We also provide specific examples from translational science and cancer clinical care of the utilization of molecular imaging, with a particular focus on the use of these methods to guide and improve patient management. Finally, we delineate the challenges faced by the field and the potential benefits of overcoming them.

TABLE 1. Selected Modalities for Molecular Imaging in Oncology and Relative Advantages and Disadvantages MODALITY USES IN ONCOLOGY ADVANTAGES/DISADVANTAGES (AVAILABILITY) SELECTED REFERENCES Optical Fluorescence Surgical guidance Nonionizing radiation; photodynamic and photoimmunotherapy/moderate penetration depth (research, translational) Serkova 2021,4 Rowe &Mapp 2008,5 Rabut & Ellenberg 2004,6 Gao 2010,7 Shaner 2004,8 Hernot 2019,9 Hyun 2016,10 Vahrmeijer 2013,11 Lu 2018,12 Ishizawa 2009,13 Xu 2020,14 Asanuma 2015,15 Hernot 201916 Photoacoustic Tissue characterization; surgical guidance Nonionizing radiation; high optical specificity; real-time/moderate penetration depth (research) Attia 2019,17 Mitsunaga 201118 Ultrasound Targeted drug delivery; blood-brain barrier disruption; tumor characterization Nonionizing radiation; readily available scanners; low cost (translational, clinical) Xu 2020,14 Endo-Takahashi 2020,19 Airan 2017,20 Hult 2020,21 Farhadi 201922 Magnetic resonance Spectroscopy Brain tumors, prostate cancer Endogenous contrast; widely available/low sensitivity; limited metabolites (translational, clinical) Koutcher & Burt 1984,23 Pillai 2009,24 Barker 2009,25 Negendank 1996,26 Brindle 2017,27 Brat 2015,28 Choi 2012,29 Li 2015,30 Chan 2019,31 Edden 2007,32 Ma 2013,33 Claudino 2007,34 Qi 201935 CEST Brain tumors, obstructive uropathy Endogenous contrast; new chemical signatures/technically complex; sensitivity unknown (translational) Wu 2016,36 Ward 2000,37 Xu 201538, 39 USPIO Cell tracking; phagocyte detection; lymph node metastases Endogenous contrast; new chemical signatures/technically complex; sensitivity unknown (translational) Zimmer 1995,40 Wu 2019,41 Ngen 2021,42 Glover 2020,43 Mathiasen 2019,44 Schilham 2021,45 Toth 2017,46 Barajas 201947 Hyperpolarization Characterization of tumor metabolism High signal; potential to investigate a wide array of metabolic pathways; expensive; pathways under study may be perturbed by high concentration of hyperpolarized agents (research) van Zijl 2021,48 Wang 2019,49 Woitek 202050 Radionucleotide SPECT Bone scans; brain tumors; sentinel node mapping; radiation dosimetry for theranostics Widely available/low sensitivity; low resolution; diminishing use in oncology (clinical) Anger 1952,51 Kelly 2020,52 Rowe 2015,53 Gorin 2016,54 Rowe 2017,55 Wilson 202056 PET Specific molecular targets; metabolism (glucose/glutamine) High sensitivity and potential for high specificity/complex infrastructure; costly agents (translational, clinical) Wahl 2008,57 Sanchez-Crespo 2013,58 Verhagen 2021,59 Cherry 201760 and 2018,61 Zhang 2020,62 Sanli 2017,63 Wahl 1994,64 Newman 1994,65 Lu 2012,66 Shreve 1999,67 Cheson 2014,68 Hicks 2021,69 Johnson 2016,70 Hope 2019,71 Jadvar 2016,72 Fanti 2016,73 Savir-Baruch 2017,74 Rowe 2019,75 Barratto 2018,76 Eiber 2017,77 Werner 2020,78 Perera 2020,79 Kiess 2015,80 Maurer 2016,81, 82 Gorin 2018,83 Pienta 2021,84 van Leeuwen 2019,85 Cookson 2007,86 Roach 2006,87 Fendler 2019,88 Markowski 2020,89 Morris 2021,90 Joice 2017,91 Phillips 2020,92 Sharma 2021,93 Rohrich 2021,94 Serfling 2021,95 Giesel 2021,96 Lindner 2021,97 Kessler 2021,98 Wu 2021,99 Friedman 2020,100 Van Acker 2001,101 Stumpe 2004,102 Familiari 2011,103 Kagna 2012,104 Cho 2020,105 Mutch 2018,106 Ordonez 2021,107 Foss 2018,108 Petrik 2012109 and 2014,110 Davies 2017111 Theranostic Thyroid cancer, neuroendocrine tumors, prostate cancer High specificity through image guidance/complex infrastructure; costly agents (translational, clinical) van der Heil 2003,112 Strosberg 2017,113 Buatti 2021,114 Burkett 2021,115 Yadav 2019,116 Hofman 2018117 and 2021,118 Novartis AG 2021119 Abbreviations: CEST, chemical exchange saturation transfer; PET, positron emission tomography; SPECT, single-photon emission computed tomography; USPIO, ultrasmall superparamagnetic iron oxide nanoparticles. Modalities

A comprehensive description of all molecular imaging modalities is beyond the scope of this review, with several valuable reviews having recently appeared.120-122 Accordingly, we endeavored to highlight a subset of the most commonly used modalities and their relative advantages and disadvantages. Key aspects of these modalities are listed in Table 1.

Optical Techniques

Optical imaging is primarily a preclinical tool, although its extensive use in molecular imaging in small animal models of cancer merits discussion here. In many modern early phase clinical trials, aspects of the biological justifications for many of the agents being investigated have been preclinically evaluated with optical imaging techniques. Optical imaging subsumes multiple submodalities, including bioluminescence imaging (BLI), fluorescence, and chemiluminescence.4 BLI, first reported by Contag and colleagues, enabled the ability to follow cellular activity, including gene expression, in living animals.123 BLI makes use of the reaction between luciferase enzymes and their substrates, eg, firefly luciferase and luciferin, which produces light.4 Clever applications of chemical techniques have allowed bioluminescence to be used to understand several fundamental mechanistic aspects of cancer biology,124 and it is routinely used to monitor the effects of cancer therapy.125, 126

Fluorescence, the process of light emission after excitation of a fluorophore with a different wavelength of light, relies on genetically encoded fluorescent proteins or on synthetic or naturally fluorescent molecules, which may be targeted to a cell or protein of interest.4 Preclinically, it has found application in the study of protein-protein interactions, cell tracking, and tumor targeting in vivo.5-7 The rapidly growing areas of photoacoustic imaging, photodynamic therapy, and photoimmunotherapy all leverage an aspect of fluorescence by detecting sound generated by the thermoelastic expansion of tissues induced by fluorescent light (photoacoustic imaging) or by creating an environment conducive to tumor cell kill (photodynamic therapy and photoimmunotherapy).17, 18 A significant disadvantage of fluorescence imaging is the intrinsic fluorescence present in normal proteins within tissues, leading to a decrease in signal-to-noise, although this can be addressed through the design of red-shifted fluorescent proteins.8 Fluorescent agents that emit in the NIR region (see below) enable sufficient depth of light penetration to allow for real-time surgical guidance, including in clinical trials.9

NIR has multiple advantages for intraoperative imaging, including low absorption in blood and other tissues, low scatter, and invisibility to the human eye without the aid of instrumentation.10 NIR-guided surgery offers opportunities for better discrimination of diseased tissue from normal tissue, decreased margin positivity rates, and minimization of anesthesia times.11 For these reasons, NIR has been extensively explored for guiding cancer surgeries (Fig. 1),127 and a specific example is discussed below.

image The Use of Indocyanine Green for Surgical Guidance During a Lung Segmentectomy. (A) The intersegmental plane was difficult to identify with traditional techniques but (B) was visualized much more clearly with the use of indocyanine green (red arrows in B). Reproduced from: Liu Z, Yang R, Cao H. Near-infrared intraoperative imaging with indocyanine green is beneficial in video-assisted thoracoscopic segmentectomy for patients with chronic lung diseases: a retrospective single-center propensity-score matched analysis. J Cardiothorac Surg. 2020;15:303.127

Surface-enhanced Raman scattering (SERS) is another type of optical imaging with high sensitivity and specificity for the delineation of surgical margins. This technique may be an important part of surgical guidance in the future. Jermyn and colleagues studied SERS for intraoperative brain cancer detection.128 Those authors reported a sensitivity of 93% and specificity of 91% for the differentiation of normal brain from dense cancer and adjacent brain invaded by cancer cells,128 suggesting utility in a class of tumors that is often extensively infiltrative. Li et al used a high-affinity, small-molecule Raman probe targeted against the prostate-specific membrane antigen (PSMA) to selectively identify prostate cancer (PCa) cells,129 an important step toward the use of SERS in intraoperative guidance for PCa.

Although optical techniques remain largely in the preclinical domain, advancements in tracer development for other molecular imaging modalities may help to drive the translation of NIR probes into human clinical practice.9 Challenges to implementing NIR probes in clinical routine include the need for optimized tracers that have rapid uptake in the tissue of interest but clear quickly from background tissues as well as the intrinsic need for development of highly sensitive instruments and bright fluorescent dyes.9 As with many molecular imaging modalities that depend on exogenously administered agents, there are significant barriers to clinical translation, such as expensive biodistribution and toxicology studies that need to be carried out for any new composition of matter.

Magnetic Resonance Imaging

Often classified as an anatomic imaging modality, recent advances with MRI demonstrate the ability of this modality to image molecular processes. All MRI techniques are based on the principle that some atomic nuclei are able to align like small magnets within a magnetic field because of their spin properties.23 Fundamentally, MRI involves a high magnetic field and the generation of images through the selective application of radiofrequency pulses, which lead to different patterns of signal in different tissues based on tissue composition, ie, based on the nature and concentration of the nuclei present in those tissues. Traditionally, MRI has been used to create high-resolution anatomic images of soft tissue structures, such as the brain and musculoskeletal system, for which computed tomography (CT) has lacked the contrast resolution to provide useful diagnostic information.

However, MRI uses the same principles as nuclear magnetic resonance spectroscopy (MRS), meaning that it can identify the individual resonances of protons (and other paramagnetic atomic nuclei) and specific compounds if those entities are present in sufficient concentrations. As such, many clinical and investigational MRI techniques fall under the aegis of molecular imaging. For example, MRS can detect compounds that are present at high (millimolar) concentrations and that have a proton signal resolvable from water. As suggested above, MRS uses the same principles of signal acquisition as other MRI techniques. However, the data are analyzed in a different way so that, instead of anatomic images being created, the concentrations of different paramagnetic atoms are displayed as a function of their chemical shift resonances.24 As with other MRI techniques, the massive amount of hydrogen present in biological molecules makes it the paramagnetic atom of choice for MRS, although examining hydrogen atoms in metabolites requires suppression of the signal from hydrogen atoms in surrounding bulk water.

For compounds at lower (micromolar) concentrations, chemical exchange saturation transfer (CEST) can be used, provided the compound of interest has a proton that can be exchanged with surrounding water protons.36 CEST agents were first introduced in 2000 and offer an alternative to traditional MRI contrast materials that increase signal by enhancing water proton relaxivity.37 Although it is able to visualize the presence of substrates at lower concentrations than MRS, CEST still lacks the sensitivity of PET and also can suffer from some of the same specificity issues, including hyperemic effects that may lead to higher signal from exogenously administered agents in inflammation and other conditions. Examples of the uses of MRS and CEST in molecular imaging of cancer are presented below.

An early, preclinical molecular imaging technique that is finding its way into the clinic is the use of ultrasmall iron oxide nanoparticles and other metallic nanoparticles to image phagocytic cells by MRI and, by extension, tumors and metastases with which they become associated.40 A further advance of this technology has been the recent development of instrumentation specifically for magnetic particle imaging.41 Targeted magnetic nanoparticles can serve as a platform to define the depth of penetration of nanoparticles within solid tumors using MRI.42 Leveraging the high signal generated from metallic susceptibility, a key indication for this technology is for cell tracking, including the tracking of transplanted cardiac and other stem cells.43, 44 In a technique referred to as magnetic resonance (MR) lymphography, ferumoxytol and its analogs have been used to detect lymph nodes involved in PCa, in one clinical instance rivaling PSMA-targeted PET in sensitivity.45 Ultrasmall iron oxide nanoparticles have also found substantial application to neuroinflammation46 and in tracking pseudoprogression of glioblastoma.47

Lastly among the techniques that we will discuss in this section is hyperpolarized MRI, which makes use of a complex process to align the nuclei of 13C-labeled agents to massively increase the signal that is available.48, 49 Hyperpolarized MRI can be used to investigate a variety of physiologic and pathologic processes, including metabolic pathways in cancer.48 A recent example from Woitek et al showed that a reduction in the 13C-labeled lactate–to–13C-labeled pyruvate ratio was predictive of response to therapy in patients with breast cancer undergoing neoadjuvant chemotherapy.50

As with many imaging agents, placing them within a specific environment or changing the isotope if radioactive (see below) can convert them to therapeutics. An imaging agent that, with minimal alteration, can also effect therapy is referred to as a theranostic.130 For example, placing metallic nanoparticles within an alternating magnetic field creates a heating effect that has proved therapeutic in cancer.131

Single-Photon Emission Computed Tomography

Although other modalities can provide higher spatial resolution, SPECT remains an important methodology across the gamut of imaging-evaluable pathology. SPECT, like MRI but unlike PET, is clinically ubiquitous. SPECT relies on radiotracers that emit single photons from nuclear decay processes followed by the detection of these photons with a gamma camera. Traditionally, gamma cameras have been composed of a scintillation crystal that converts the emitted photons into visible light,51 a series of backing photomultiplier tubes that increase the signal from the visible light, and a collimator between the patient and the scintillation crystal that allows the emitted photons to be spatially localized. Gamma cameras can be used for planar imaging; however, in many modern molecular imaging applications, they are spun around the patient to create tomographic images, ie, SPECT.

The limited spatial resolution of SPECT is still adequate for many clinical applications. The fundamental strengths of SPECT derive from the large number of single-photon–emitting radionuclides that are readily available, including technetium-99m (99mTc), iodine-123 (123I), and indium-111 (111I). These radionuclides produce emitted photons of different energies, which can be distinguished by the gamma camera, permitting the simultaneous acquisition of multiple radiotracers. Furthermore, the availability of radionuclides with a long physical half-life (T1/2), eg, 111In (T1/2 = 67 hours), allows for both delayed imaging for diagnostic purposes and the determination of dosimetry for selected therapeutic radiopharmaceuticals.52

Although single-photon–emitting radiotracers lack the high spatial resolution and routine quantifiability of PET radiotracers, the intrinsic advantages of having radionuclides that decay with different energies and the wide array of radiotracers that are available will keep SPECT relevant for routine clinical applications for the foreseeable future.

Positron Emission Tomography

PET is the gold standard for sensitivity in clinical molecular imaging. The basic principle of PET is that proton-rich radionuclides decay by emitting positrons (β+), which subsequently travel a short distance and annihilate with an electron (β−) to create two 511-kiloelectron volt photons that arise almost exactly 180 degrees apart.57 Rings of detectors can be used to take advantage of coincidence detection to identify the locations of the annihilation events. Common radionuclides used for PET imaging include organic/organic-like isotopes (eg, carbon-11 [11C], nitrogen-13, and fluorine-18 [18F]) and radiometals (eg, gallium-68 [68Ga], copper-64 [64Cu], and zirconium-89 [89Zr]). For many clinical and research applications, 18F provides an ideal combination of medicinal chemistry properties, radionuclide half-life (T1/2 = 110 minutes), positron yield and energy.58

As noted above, radionuclide-based imaging techniques such as PET play important roles in theranostics, namely, in selecting patients for the corresponding therapy. An advantage of radionuclide-based theranostic pairs is that, by merely changing the radionuclide within the chelator, (eg, 68Ga to 177Lu) or changing the isotope of the halogen (eg, 123I to I24I), one may move from an imaging to a therapeutic agent within the same molecular scaffold.

Intrinsic advantages of PET include high-contrast resolution and quantifiable imaging parameters. In modern practice, coregistered CT is used to create attenuation maps that allow highly accurate attenuation correction. With advanced techniques, such as resolution recovery, motion correction, and point-spread function reconstruction, PET is continuing to evolve as a cornerstone of modern clinical molecular imaging. Furthermore, PET is increasingly being combined with MRI (ie, PET/MR), potentially allowing for powerful combinations of the molecular imaging features of each of the individual modalities while also saving radiation dose to patients.59 Along those lines, the sensitivity of total-body PET allows for the administration of radiopharmaceutical doses at a fraction of the dose of current clinical studies.60-62 That enables expanded use of PET in pediatric populations or for patients who require frequent studies in whom radiation dosimetry must be carefully taken into account.

Ultrasound

The advantages of ultrasound imaging include real-time dynamic imaging, small physical footprint of the (portable) scanning device, lack of radioactivity, and relatively low cost. Although primarily used clinically for anatomic delineation and for studying flow-based phenomena (Doppler), ultrasound molecular imaging with microbubbles for the targeted delivery of drugs, including genetic material, is proliferating.19 It is also used for focal disruption of the blood-brain barrier to enable access to the brain for hydrophilic diagnostic and therapeutic agents.20 Photoacoustic imaging may provide highly specific cancer signatures not available from other techniques.21 Through modification of what was originally a bacterial gene, Shapiro and coworkers have used ultrasound and an acoustic reporter to image gene expression in mammalian cells.22 The delivery of sound pulses to tissue is now being studied and implemented in analogy to using MR pulse sequences.12 As more is learned in this area, ultrasound may increase in versatility for biomedical research and medicine through further extension into the molecular realm.

Examples of Molecular Imaging Utilization

The breadth of the impact of modern molecular imaging on medicine and the biomedical sciences is difficult to encapsulate in any brief review. As opposed to a comprehensive listing of current applications of molecular imaging, we present a series of examples that demonstrate how the principles of molecular imaging can affect the care of patients with cancer.

Near-Infrared Imaging for Surgical Guidance

The major limitation of applying optical imaging techniques to human subjects is the limited depth of penetration achievable with the detectors for optical probes. However, this limitation is nearly moot in the context of intraoperative imaging, in which there is exposure of the tissues under study. As such, optical imaging techniques have been studied extensively for the purposes of surgical guidance. NIR probes have been suggested to improve clinical workflow and to have advantages in speed, patient outcomes, and cost relative to traditional, unguided surgical methods.11

The first application of NIR agents to intraoperative guidance made use of indocyanine green, a dye that is approved by the US Food and Drug Administration.20 In an initial study, Ishizawa and coworkers found that hepatobiliary excretion of indocyanine green allowed for the clear delineation of superficial colorectal liver metastases and primary hepatocellular carcinomas.13 The tumors were demarcated by surrounding rims of fluorescence, with little background uptake in the normal liver.

Since that first study, the number of available NIR probes has rapidly expanded to include specific tumor-targeting small molecules, peptides, antibodies, and aptamers.

留言 (0)

沒有登入
gif