a. Department of Radiology, First Hospital of China Medical University, Shenyang, Liaoning,110001 P. R. China.
Find articles by Xiangjun Hana. Department of Radiology, First Hospital of China Medical University, Shenyang, Liaoning,110001 P. R. China.
Find articles by Ke Xub. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon state University, Corvallis, Oregon 97331, USA
Find articles by Olena Taratulac. Charles T. Dotter Department of interventional Radiology, Oregon Health and Science University, Portland, Oregon 97239-3011, USA
Find articles by Khashayar Farsada. Department of Radiology, First Hospital of China Medical University, Shenyang, Liaoning,110001 P. R. China.
b. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon state University, Corvallis, Oregon 97331, USA
c. Charles T. Dotter Department of interventional Radiology, Oregon Health and Science University, Portland, Oregon 97239-3011, USA
The publisher's final edited version of this article is available at NanoscaleAn urgent need for early detection and diagnosis of diseases continuously pushes the advancements of imaging modalities and contrast agents. Current challenges remain for fast and detailed imaging of tissue microstructures and lesion characterization that could be achieved via development of nontoxic contrast agents with longer circulation time. Nanoparticle technology offers this possibility. Here, we review nanoparticle-based contrast agents employed in most common biomedical imaging modalities, including fluorescence imaging, MRI, CT, US, PET and SPECT, addressing their structure related features, advantages and limitations. Furthermore, their applications in each imaging modality are also reviewed using commonly studied examples. Future research will investigate multifunctional nanoplatforms to address safety, efficacy and theranostic capabilities. Nanoparticles as imaging contrast agents have promise to greatly benefit clinical practice.
Early detection and diagnosis of disease is a crucial part of clinical practice, especially for cancer. For example, the two-year survival rate of gastrointestinal cancer patients for those who benefited from early detection has been observed to be much higher than in those without early detection (92.3% VS 33.3%). 1 In addition, the ten-year mortality rate for breast cancer patients who benefited from early detection was reduced by 17–28%. 2 Medical imaging technology often plays the most important role in the early detection and therapeutic response assessment of various diseases. Imaging modalities in current use include X-ray radiography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), positron emission tomography (PET), single photon emission computed tomography (SPECT), and fluorescence imaging ( Fig. 1 ). 3 To improve lesion detection, very often more than one imaging modality is combined. 4, 5 To get more accurate anatomic and functional information, medical imaging contrast agents are used to distinguish between normal tissue and abnormal lesions. For traditional clinical imaging contrast agents, tumor detection is limited by the spatial resolution generated by the imaging hardware, such as the ability of contrast-enhanced CT to detect a hypervascular hepatoma as small as 3 mm. 6 Currently used medical imaging contrast agents are mostly small molecules that exhibit fast metabolism, and have non-specific distribution and potential undesirable toxicities. 7, 8
The primary imaging technologies in biomedical practice, including A: fluorescence image of tumor cells; B: CT diagnosis for artery stenosis; C: MRI image of lumber cancer metastasis; D: US detection of portal vein thrombosis; E: SPECT evaluation for 125 I seeds implantation; and F: PET detection of lung cancer tumor. All images were obtained from medical imaging research institute of China Medical University.
Recently, nanomaterials have stimulated efforts in improving biomedical detection and imaging due to unique passive, active and physical targeting properties. Due to their small size, nanoparticles exhibit enhanced permeability and retention (EPR) effects in tumors, with relative increases in local tumor concentrations of contrast agent. 9 Among all features of the nanoparticle, size plays a particularly important role for tumor imaging. Nanoparticle size significantly influences biodistribution, blood circulation half-life, cellular uptake, tumor penetration and targeting. 10 As the average renal filtration pore is 10 nm, 11 nanoparticles with sizes less than 10 nm are rapidly cleared by the renal excretion system. 12 By contrast, nanoparticles with sizes over than 100 nm are easily identified by macrophages and accumulate in organs with the mononuclear phagocyte system (MPS), such as lymph nodes, liver, spleen and lung. 13 Furthermore, several reviews summarized that nanoparticle sizes between 10 to 60 nm have consistently demonstrated enhanced cellular uptake. 10, 14
In addition to passive targeting strategies, nanoparticle surface labeling with various ligands to target receptors can increase imaging contrast agent localization through specific binding to target receptors in lesions. 15–17 For example, gold nanoparticles surface decorated with a prostate-specific membrane antigen RNA aptamer have been shown a higher CT density for prostate cancer cell imaging. 18 In addition, nano-sized superparamagnetic iron oxide (SPIO) agents surface decorated with a high-affinity anti-EGFR antibody have been shown to target lung tumors by MRI. 19
Antibodies and antibody fragments are the most common and efficient active targeting ligands. Antibodies have a high specific affinity to the corresponding antigens which can increase nanoparticle concentration to a specific location. 20 Another ligand used for targeting is an aptamer, which is also named as a chemical antibody. It is a single DNA or RNA sequence that folds into a secondary structure with a high targeting affinity to cell surface receptors. Compared with antibodies, aptamers are small, easy to synthesize and confer lower immunogenicity. 21 However, aptamers are rapidly cleared by the renal system and degraded by nucleases, preventing the desired blood circulation time for effective tumor localization. 22, 23 Peptides represent an additional ligand targeting moiety, with benefits including chemical stability, ease of synthesis and reduced immunogenicity. 24 The arginine-glycine-aspartic acid (RGD) peptide is the principal integrin-binding doman and can bind to multiple integrin species, 25 it is very common in nanoparticle application. 26 Other proteins and molecules with active targeting roles include transferrin, folic acid and biotin. 27
In addition to active and passive targeting strategies, various stimuli also play a targeting role in nanoparticle imaging applications, In these physical targeting strategies, external sources or fields guide nanoparticles to the target site and control the release process, as seen in photothermal and magnetic hyperthermia therapy. 28 An acidic pH/reduction dual-stimuli responsive nanoprobe for enhanced CT imaging of tumor is another example. 29 For all targeting types, drug release can be triggered by a change in pH, temperature, or a combination of both. The pH, temperature, enzyme activity and redox gradient belong to endogenous stimuli, and light, magnetic and ultrasound belong to external stimuli. 30
Compared to traditional contrast agents, prolonged blood circulation time of nanoparticle-based contrast agents plays a key role for their enhanced contrast signal. Nanoparticle modification to promote circulation time is thus a critical factor in imaging performance. The most common modification method is encapsulation of hydrophobic nanomaterials in a polyethylene glycol (PEG) shell, 31 which greatly increases solubility and prolongs blood circulation time. Due to the hydrophilic backbone of PEG, nanoparticle binding to opsonins and recognition by macrophages is decreased, reducing nanoparticle clearance by the reticuloendothelial system (RES). 32, 33 Dextrose and polysaccharide, such as chitosan, hyaluronic acid and fucoidan, play a similar role in prolonging nanoparticle circulation. 34, 35 Zwitterionic modification endows nanoparticles with surface properties resistant to aggregation, binding plasma proteins and macrophage uptake, significantly prolonging circulation time. 36, 37 Additionally, albumin surface modification of nanoparticles increases blood circulation time while maintaining biological activity and decreasing immunogenicity. 38
Due to improved targeting strategies and a long circulation life in blood, nanoparticles have been studied for early tumor detection and diagnosis. 39 Nanoparticles have been used for early detection in three major ways. The most common use has been employing nano-contrast agents with existing imaging modalities. For instance, gold nanocages conjugated with α-melanocyte-stimulating hormone (α-MSH) peptide and 64 Cu radiolabeled melanocortin 1 receptor-(MC1R) have been used for melanoma detection by PET in a mouse model. 40 Nanoparticles can also act as specific delivery platforms loaded with other imaging elements to identify cancers. An example includes the liposome encapsulated gold nanoclusters functionalized with Her2 antibody to detect human breast cancer cells in serum and tissue by colorimetry. 41 Additionally, nanoparticles can be employed for selective tumor biomarker detection. 42, 43 Early detection of certain cancer biomarkers can be very challenging, and nanoparticles have been used to magnify the signal. For example, a nano-genosensor was found to significantly amplify the signal from the known breast cancer biomarker, miRNA-21, in clinical samples. 44 Nano-immunosensor was employed to ultrasensitively detect cancer antigen 15–3 for breast cancer in human plasma samples. 45 Other uses of nanoparticle detection have included identification of circulating tumor cells (CTCs). 46
In contrast to traditional contrast agents, nano-imaging agents demonstrate a high surface area to volume ratio enabling surface labeling with specific molecules and ligands to improve the toxicity profile and imaging properties. 47, 48 Additional benefits of imaging nanoparticle include functional visualization and monitoring of biological processes, such as macrophage detection in atherosclerotic lesions using CT, 49 and molecular imaging of angiogenesis by MRI. 50 Furthermore, the prolonged plasma circulation time of nanoparticles improves biodistribution with a greater lesion to background contrast signal. 51 Additionally, the shape and size of the nanoparticles can be manipulated to optimize the loading of imaging compounds, and their intrinsic physical properties can also be changed to meet specific clinical needs. 52, 53
Considering the limits of current imaging contrast agents and the potential advantages of nanoparticles for early diagnosis and microstructure visualization, interest in nanotechnology for biomedical imaging is rapidly increasing. A search for the term “nanoparticle and imaging” on PubMed shows a significant recent increase in the number of relevant publications, highlighting the intense efforts being placed in this domain ( Fig. 2 ). Synthesis and decoration of nanoparticles, with features related to therapeutic use, pharmacokinetics and toxicity have been reported. 54, 55 In this review, we summarize the application of nanoparticles with different imaging modalities, including fluorescence imaging, MRI, CT, US, PET, and SPECT. We mainly focus on structural properties of nanoparticles and pertinent biomedical imaging applications, including for cancer imaging and other diseases. Commonly studied examples for each imaging modality are discussed.
The number of publications searching for “nanoparticle and imaging” in Pubmed is rapidly increasing each year. Fluorescence and MRI imaging modalities represent the greatest areas of activity.
