Review pubs.acs.org/CR
Nanomaterials for In Vivo Imaging Bryan Ronain Smith*,† and Sanjiv Sam Gambhir*,‡ †
Stanford University, 3155 Porter Drive, #1214, Palo Alto, California 94304-5483, United States The James H. Clark Center, 318 Campus Drive, First Floor, E-150A, Stanford, California 94305-5427, United States
‡
ABSTRACT: In vivo imaging, which enables us to peer deeply within living subjects, is producing tremendous opportunities both for clinical diagnostics and as a research tool. Contrast material is often required to clearly visualize the functional architecture of physiological structures. Recent advances in nanomaterials are becoming pivotal to generate the high-resolution, high-contrast images needed for accurate, precision diagnostics. Nanomaterials are playing major roles in imaging by delivering large imaging payloads, yielding improved sensitivity, multiplexing capacity, and modularity of design. Indeed, for several imaging modalities, nanomaterials are now not simply ancillary contrast entities, but are instead the original and sole source of image signal that make possible the modality’s existence. We address the physicochemical makeup/ design of nanomaterials through the lens of the physical properties that produce contrast signal for the cognate imaging modalitywe stratify nanomaterials on the basis of their (i) magnetic, (ii) optical, (iii) acoustic, and/or (iv) nuclear properties. We evaluate them for their ability to provide relevant information under preclinical and clinical circumstances, their in vivo safety profiles (which are being incorporated into their chemical design), their modularity in being fused to create multimodal nanomaterials (spanning multiple different physical imaging modalities and therapeutic/theranostic capabilities), their key properties, and critically their likelihood to be clinically translated.
CONTENTS 1. Introduction 1.1. Background 1.1.1. Passive Targeting of Nanomaterials 1.1.2. Active Targeting of Nanomaterials 1.2. Why Nanomaterials In Vivo? 2. Imageable Nanomaterials 2.1. Key Nanomaterial Properties 2.2. Nanomaterial Limitations 2.3. Magnetic Nanomaterials 2.3.1. Magnetic Resonance Imaging 2.3.2. Magnetic Particle Imaging 2.3.3. Magneto-motive Imaging 2.3.4. Electrical Impedance Imaging 2.4. Optical Nanomaterials 2.4.1. Luminescence 2.4.2. Resonance Energy Transfer 2.4.3. Raman 2.4.4. Optical Coherence Tomography 2.4.5. Photoacoustics 2.5. Acoustic Nanomaterials 2.6. Nuclear Nanomaterials 2.6.1. Radioactive Nanomaterials 2.6.2. Nanomaterials for Computed Tomography 2.7. Adaptable Nanomaterials 2.7.1. Lipid Nanomaterials 2.7.2. Polymeric Nanomaterials 2.7.3. Silicon-Based Nanomaterials 2.7.4. Natural Nanomaterials 3. Multifunctional Nanomaterials © 2017 American Chemical Society
3.1. Multimodality Nanomaterials 3.2. Theranostic Nanomaterials 3.2.1. Smart Theranostic Nanomaterials 4. Clinical Nanomaterials 5. Conclusions and Outlook Associated Content Special Issue Paper Author Information Corresponding Authors Notes Biographies Acknowledgments References
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1. INTRODUCTION The explosive growth in novel in vivo imaging modalities has led to a dizzying array of new nanomaterials over the past 5−10 years. These nanomaterials are spurring completely new imaging applications in living subjects, such as exploiting the ability of nanoscale metallic particles to scatter light for added contrast in optical coherence tomography (OCT) applications. Chemists working closely with imaging scientists have played a key role in the development of these novel materials to tackle some of the critical issues confronting diagnostic imaging. At minimum, imaging with nanomaterials rather than conventional approaches can afford intelligent control over delivery and greatly increased diagnostic sensitivity and specificity not
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Received: January 28, 2016 Published: January 3, 2017 901
DOI: 10.1021/acs.chemrev.6b00073 Chem. Rev. 2017, 117, 901−986
Chemical Reviews
Review
Figure 1. Nanomaterials for in vivo imaging. The Review follows the framework displayed, describing magnetic, optical, nuclear, acoustic, and adaptable nanomaterials for injection into living subjects. The focus is on how the chemistry of these nanomaterials allows them to be imageable by the respective imaging modalities. While the focus of the Review is on preclinical (animal) imaging, we highlight the translation of nanomaterials for in vivo human imaging where applicable. “Polymeric” nanomaterial image created by Digizyme Inc. MRI/PI image from “Animal Imaging” is reprinted with permission from ref 578. Copyright 2015 Creative Commons Open-Access. Clinical translation (right) image reprinted with permission from ref 435. Copyright 2014 AAAS. From Phillips, E., et al., clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe.
nanomaterials to contribute centrally to the future of imaging in living subjects. While nanomaterials reviews have typically divided their sections based on the nanomaterial type (e.g., nanotubes, quantum dots, liposomes, etc.), in this Review we instead divide the information with respect to the particular physicochemical properties enabling the nanomaterial to be advantageous for a relevant imaging modality. Thus, some nanomaterials will be in multiple sections because their fundamental properties lend themselves to detection with multiple imaging modalities, and they are self-contained within each section. For instance, carbon nanotubes are included in both the optical nanomaterials sections (e.g., fluorescence, Raman, and photoacoustic activity) and the acoustic nanomaterials section (ultrasound signal), as their use in each imaging modality arises from disparate properties. This concept-driven approach allows us to organize our Review around the fundamental physicochemical nature of the nanomaterial that results in its ability to provide contrast for a particular imaging modality (see Figure 1 and Table 1).
otherwise possible; in other cases, the use of nanomaterials actually enables the use of contrast agents for imaging modalities that historically did not have contrast agents available, making nanomaterials a driver for molecular imaging capabilities for imaging modalities in which no other contrast agents are yet possible. In even other cases, nanomaterials are required simply to make imaging possiblefor example, magnetic particle imaging (MPI) and magneto-motive imaging require magnetization to image that cannot be found in small molecules but rather require nanoscale magnetic nanomaterials such as superparamagnetic iron oxide nanoparticles for them to produce images. Recent reviews have discussed the advantages of nanomaterials for applications using more than one imaging modality at a time (i.e., multimodal imaging),1,2 while other reviews have focused on subcategories such as disease-specific applications (e.g., cancer diagnostic imaging), modality-specific applications (e.g., optical imaging), cell-specific applications (e.g., macrophage imaging), or nanomaterial-specific applications (e.g., quantum dots).3−6 In our Review, we (i) focus on nanomaterials for in vivo imaging (see Figure 1); (ii) describe how specific chemical and physical properties of nanomaterials drive in vivo imaging applications and potential diagnostic value; and (iii) review only nanomaterials that have actually been used for in vivo imaging (i.e., have actually been injected into living subjects), even though many novel nanomaterials are currently being developed with the eventual intention to be injected in vivo.7−9 We define nanomaterials as materials that are specifically engineered and between 1 and 100 nm in at least one dimension that is critical to its application.10,11 Our Review focuses on the recent literature (past 5 years) involving nanomaterials that have been used to enhance image contrast and their roles in diagnostic imaging in living subjects including humans. We review nanomaterials for in vivo imaging without special regard to the particular disease process for which they are being used to provide contrast, but instead focus on the connection between the nanomaterial and its relevance for in vivo imaging. Most of all, we aim to describe the key underlying chemical and physical properties that will likely enable
1.1. Background
A fundamental goal of contemporary noninvasive imaging is to measure and localize specific molecular targets, pathways, and physiology, often in the context of a disease state. In contrast agent-based imaging, diseases are generally identified by the accumulation of an agent at the disease site. These agents must produce a signal recognized by an imaging modality. Traditionally, the agents are injected systemically and are small molecules or, more recently, may be connected to peptides, proteins, oligonucleotides (aptamers), or antibodies. These small imaging agents are designed to accumulate at disease sites on the basis of a difference in the fundamental biology of the disease in contrast to the biology of normal tissues, e.g., a distinctive physiological/biochemical hallmark. For instance, positron emission tomography (PET) can be performed to locate many cancers because cells in those cancers proliferate so rapidly that they require and metabolize sugars such as glucose more than cells in most other human tissues. Small-molecule 902
DOI: 10.1021/acs.chemrev.6b00073 Chem. Rev. 2017, 117, 901−986
radio frequency magnetic pulse
ultraviolet to nearinfrared light ultraviolet to nearinfrared light ultraviolet to nearinfrared light light light light
sound waves
magnetic particle imaging magneto-motive approaches
fluorescence (macroscopic)
Raman optical coherence tomography
photoacoustics
ultrasound
903
single photon emission computed tomography computed tomography
positron emission tomography
γ-imaging
resonance energy transfer
radionuclide (γ-rays detected) radionuclide (positrons) radionuclide (γ-rays detected) X-rays
radio frequency
magnetic resonance imaging
intravital microscopy
input signal type
imaging modality
temporal resolution penetration depth
0.5−2 mm (preclinical), 8−10 mm (clinical) 25−200 μm (preclinical), 0.5−1 mm (clinical)
unlimited unlimited unlimited
min s−min
s−min
