Review Article
Iron Oxide Nanoparticles as Contrast Agents in Molecular Magnetic Resonance Imaging Do They Open New Perspectives in Cardiovascular Imaging? Agapi G. Ploussi, MSc,* Maria Gazouli, PhD,† George Stathis, MD,* Nikolaos L. Kelekis, MD, PhD,* Efstathios P. Efstathopoulos, PhD*
Abstract: Molecular magnetic resonance imaging has recently emerged as a powerful tool for the detection and assessment of cardiovascular diseases. Contrast agents have an important role in this novel modality because molecular imaging requires highly sensitive, specific, and efficient imaging agents. Iron oxide nanoparticles (IONs) are a new class of contrast agents with unique properties that provide special opportunities in cardiovascular molecular imaging. IONs are captured by macrophages and can be successfully used in the detection and evaluation of atherosclerotic plaques, abdominal aortic aneurysms, and inflammations related to myocardial infarction. The purpose of this review is to provide a brief description of the basic characteristics of IONs, with a special focus on their role as molecular magnetic resonance imaging contrast agents and their cardiovascular applications. Key Words: molecular magnetic resonance imaging, cardiovascular imaging, iron oxide nanoparticles (Cardiology in Review 2015;23: 229–235)
(4) safety use in patients with chronic kidney disease (CKD), (5) the ability to change magnetic properties according to their size, shape, and structure, and (6) selective localization to the desired target in conjugation with specific ligands.4 In clinical practice, IONs were initially used in oncology for the diagnosis of lymph node metastases. Several studies have shown that IONs are captured by the reticuloendothelial system (RES) and offer higher diagnostic precision, sensitivity, and specificity for the detection of lymph-node metastases in relation to unenhanced MRI.5,6 In cardiovascular imaging, the role of ION-enhanced MRI has not yet been fully established but is gaining acceptance because of the expanded utility of molecular imaging.2 In this review, we provide an overview of the characteristics and the mechanism of IONs as MRI contrast agents and their potential role in cardiovascular molecular imaging. This review is based on an extensive literature review concerning the last decade and presents the most recent advances in the area of cardiovascular molecular MRI using IONs.
M
Characteristics and Properties
From the *Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; and †Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. Disclosure: The authors have no conflicts of interest to report. Correspondence: Efstathios P. Efstathopoulos, PhD, Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, 1, Rimini Str, 124 62 Haidari, Athens, Greece. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2305-229 DOI: 10.1097/CRD.0000000000000055
IONs are mainly used as T2 contrast agents due to their ability to shorten the T2 and T2* relaxation times of the tissues in which they accumulate. Reduction of T2 and T2* relaxation times provides a negative enhancement and consequently results in a hypointense signal that appears dark on T2/T2*-weighted images. With the appropriate composition, IONs can reduce both T1 and T2/T2* relaxation times. IONs consist of a magnetic iron oxide core (magnetite-Fe3O4 or/and maghemite-γ-Fe2O3) surrounded by a surface coating. The core is responsible for the signal enhancement, whereas the coating material is necessary to prevent nanoparticle destabilization and agglomeration, allow conjugation of targeted ligands, and achieve aqueous or biological media solubility. In addition, the surface coating reduces toxicity and increases the circulation time of IONs. The most commonly used surface coatings are polymers, such as dextran, carbodextran, and small molecular ligands, such as citrate and silica.7,8 The blood half-life of IONs is dependent on their size, their surface coating material, and the administered dose. At clinical doses (8–74 μmol Fe/kg depending on the contrast agent), the blood half-life of IONs ranges from 1 to 24–36 hours.9 For the same surface coating, smaller nanoparticles have a longer plasma half-life. IONs used for MRI do not exceed 200 nm, whereas the size of the core is usually 4–15 nm. According to their overall hydrodynamic size (core + coating), IONs are classified into supermagnetic iron oxide (SPIO) nanoparticles with a diameter greater than 50 nm and ultrasmall supermagnetic iron oxide (USPIO) nanoparticles with a diameter less than 50 nm. The physicochemical properties of IONs are influenced by the core material, the surface coating, the core and their overall hydrodynamic size, the surface charge, and the surface hydrophobicity.8,10
olecular imaging using magnetic resonance has expanded its role from a research tool into a clinical imaging modality for the diagnosis and management of cardiovascular diseases (CVDs). Molecular magnetic resonance imaging (MRI) focuses on the visualization and quantification of molecular and cellular targets that underlie changes in cardiovascular morphology, physiology, and function. Cardiovascular molecular MRI is now considered an effective technique for the assessment of a wide range of CVDs, such as atherosclerosis, vascular disease, inflammation, myocardial infarction (MI), and also for stem cell imaging.1–3 Contrast agents play a crucial role in MRI, and so far, gadolinium (Gd)-based contrast agents (GBCAs) are considered the standard agents for MRI. However, GBCAs are inadequate to detect molecular targets because of their low sensitivity (in the micromolar range), their extremely short circulation plasma time, and their rapid renal excretion.1,4 To overcome these limitations, a new generation of MRI contrast agents, magnetic iron oxide nanoparticles (IONs), has been developed. IONs have several advantages over the conventional contrast agents including (1) higher detection sensitivity, (2) better biocompatibility, and therefore low toxicity, (3) long retention time,
IONS AS MRI CONTRAST AGENTS
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Bayer Schering Pharma AG/Medicadoc Liver, spleen, bone marrow AMAG Pharmaceuticals/Guerbet Lymph nodes, MRA Bayer Schering Pharma AG Macrophage imaging AMAG Pharmaceuticals/Takeda Pharmaceutical Company Limited Lymph nodes, liver, spleen, MRA GE-Healthcare
Mechanisms and Route of Action Due to their small size, long circulation half-life, and insignificant migration into extravascular space, IONs act as intravascular contrast agents. IONs accumulate in the phagocytic cells of the mononuclear phagocyte system (MPS), also known as the RES. The MPS includes monocytes from bone marrow and blood and macrophages located in the liver (Kupffer cells), spleen, lymph node, bone, bone marrow, lung, connective tissue, pleura and peritoneum, and central nervous system. After administration, SPIOs are quickly taken up by the MPS and accumulate in the liver and spleen. In contrast, USPIOs, due to their smaller size, remain in the blood circulation for a longer time and mainly accumulate in the macrophages of the lymph nodes and bone marrow. USPIOs are transported to the lymph nodes via 2 mechanisms: by direct transcapillary passage of nanoparticles from venules into the medullary sinuses of lymph nodes or by nonselective endothelial transcytosis into the interstitial space.9 The USPIOs are taken up by macrophages present in normal lymph nodes, resulting in a reduction of signal intensity (SI) on T2 and T2*-weighted MRIs.12 USPIO imaging of the bone marrow is similar to USPIO imaging of the lymph nodes. The USPIO particles are phagocytosed only by normal bone marrow (which contains macrophages of the MPS) and cause SI loss.13 USPIOs are also localized in inflammatory cells. Macrophages play an important role in inflammation because during the initial inflammation process, these phagocytic cells become activated and have destructive effects.14 Hence, inflammatory areas appear dark while no alteration in SI is observed in noninflammatory tissues. The possible mechanisms that have been proposed for transporting USPIOs to macrophages include the following: (1) endocytosis by activated blood monocytes, which migrate into the pathological tissues; (2) transcytosis through the endothelium and their migration into the tissue, followed by progressive endocytosis of these USPIOs by in situ macrophages; and (3) transport of USPIOs into the pathological tissue, in some cases via the inflammatory neovasculature (vasa vasorum) irrigating the media and adventitia in atherosclerotic lesions.15
3–4 6
15/89
20
Carboxymethyl dextran Pegylated starch 30
10–14
9.7/189 10.7/38 Dextran Carboxydextran 80–180 21
2 6
10.1/120 2.4–3.6 Carboxydextran 60
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*For clinical doses. †1.5 T, 37°C, water or in plasma, mM−1 s−1. MRA indicates magnetic resonance angiography.
Clariscan PEG-feron/NC 100150 Feruglose
Code 7228
Feraheme/Rienso Ferumoxytol
AMI-25 SHU 555 C
Feridex/Endorem Supravist
Ferucarbotran or Ferrixan Ferumoxide Ferucarbotran SHU 555A
15–40 Ferumoxtran-10
Resovist/Cliavist
24–36
9.9/65
Lymph nodes, liver, macrophage imaging Liver, spleen, bone marrow
Guerbet/AMAG Pharmaceuticals
Several IONs have been approved by the Food and Drug Administration for intravenous use as MRI contrast agents. Table 1 presents the characteristics of the most commonly used IONs that have been approved or are in different clinical phases for use in Europe and the United States.9,11 At the present time, only Ferumoxytol is commercially available in the US and European markets.
Safety
AMI-227
Agent
Generic Name
Sinerem/Combidex
Dextran
Plasma Half-Time* Relaxivities (hour) (r1/r2)† Surface Coating Hydrodynamic Size (nm) Trade Name
TABLE 1. IONs Approved for Clinical Application or Clinically Tested (Data from Corot et al9 and Ittrich et al11)
Indication
Developer
Ploussi et al
Toxicity is a major concern in the development of contrast agents. The toxicity of IONs depends on various parameters including particle size, surface coating, chemical composition, and dosage. Various studies have investigated the cytotoxic potential for several different types of USPIOs. All reports demonstrated that IONs are biocompatible and show low or no cytotoxicity.16 Human studies in malignancy patients using dextran-coated IONs suggested side effects, such as headache, back pain, and urticaria. Most of the symptoms were mild to moderate and of short duration, whereas none of them were clinically significant.17,18 It is known that the development of nephrogenic systematic fibrosis is associated with GBCA administration in patients with stage 4 or 5 CKD and acute kidney injury.19 GBCAs are eliminated almost entirely by the renal system, and in renal failure, the prolonged half-life of the free toxic Gd+3 ions affects tissues and leads to fibrosis.20 In contrast with GBCAs, IONs are rapidly removed from the RES and especially from the Kupffer cells within the liver. Neuwelt et al21 demonstrated that USPIO agents are safe for patients with kidney disease for both central nervous system MRI and magnetic resonance (MR) angiography and suggested USPIO © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Cardiology in Review • Volume 23, Number 5, September/October 2015
agents as a future alternative MR contrast agent for patients at risk for nephrogenic systematic fibrosis. In addition, it has been proven that USPIO nanoparticles are safe for patients undergoing hemodialysis.22,23 The potential to use IONs in patients with CKD is one of the strongest reasons to consider the use of nanoparticles in clinical practice.
IONS-ENHANCED MRI TECHNIQUES IN CARDIOVASCULAR IMAGING
where SIpost indicates SI in postcontrast scan; SIpre, SI in precontrast scan. Higher USPIO accumulation leads to lower negative values of ΔSI. In addition, a quantitative analysis of the concentration of nanoparticles is performed by calculating T2* relaxation times before and after the USPIO administration on a pixel-by-pixel basis to generate T2* maps for each segment. The T2* value is the decay constant for the exponential decay of SI with time [SI(t) = SI(0) exp − (t/T2*)]. In a T2* map, each pixel represents the T2* value.
CLINICAL APPLICATIONS IN CARDIOVASCULAR IMAGING
Acquisition Protocol Cardiovascular MRI with nanoparticles requires 2 scans: a precontrast scan and a postcontrast scan within 24–72 hours after administration of USPIOs. After the injection of iron oxide contrast agents, a T2 or T2*-weighted sequence is obtained for the evaluation of USPIO uptake. Both T2 and T2* images enable the quantification of USPIO accumulation and the generation of T2/T2* maps. Although T2 sequences are more specific and provide better contrast and signal-to-noise ratio, in most USPIO-enhanced cardiovascular MR acquisition protocols, a T2*-weighted gradient-echo sequence is chosen because of the greater sensitivity to iron deposition and the higher speed.24,25 Acquisition of T2 or T2* sequences is also necessary in the first scan to compare pre-USPIO and post-USPIO contrast images.
Image Analysis The most convenient method for the evaluation of USPIOs accumulation is based on differences in SI between precontrast and postcontrast MR images. The assessment can be qualitative or/and quantitative, usually on a segmental basis. For qualitative analysis, the SI changes (decrease, increase, or no change) in preinfusion and postinfusion T2*-weighted images and is evaluated by independent radiologists by consensus. In quantitative analysis, the precontrast and postcontrast T2*-weighted images are registered using fixed reference markers, and subsequent regions of interests are subdivided into radial segments. For each segment, the mean SI is measured using an appropriate software tool, and the percentage difference in SI is calculated as follows: ∆SI% =
SIpost − SIpre × 100 (1) SIpre
Iron Oxide Nanoparticles in Molecular MRI
The literature search indicated that USPIOs have been used to image atherosclerotic plaque, infarcted myocardium, and inflammations involved in the development of abdominal aortic aneurysms (AAAs). An overview of the literature articles is presented in Table 2.26–42
Atherosclerotic Plaque Imaging Atherosclerosis is a chronic inflammatory disease affecting large-sized and medium-sized arteries.43,44 Because inflammation is accompanied by macrophage activity, USPIOs are accumulated in the macrophages present in atherosclerotic plaques and cause a strong signal reduction in T2/T2*-weighted sequences. Schmitz et al26 incidentally observed USPIO uptake in the aortic and arterial wall in patients who had initially received USPIO contrast agent for staging lymph node metastases. This was the first observation, which proved that USPIO can accumulate in human atherosclerotic plaques. Kooi et al27 performed pre-USPIO and post-USPIO MRI in symptomatic patients scheduled for carotid endarterectomy. All patients were administered Ferumoxtran-10 at a dose of 2.6 mg Fe/kg. The results showed a 24% decrease in SI on T2* gradient-echo images acquired 24 hours after USPIO administration, indicating USPIO accumulation in macrophages of atherosclerotic plaques. USPIO uptake was also verified by histology analysis in 75% of ruptured and rupture-prone lesions and by electron microscopy analyses of the plaques. A 24% average signal loss on T2*W post-USPIO images was also observed later by Trivedi et al29 in symptomatic patients with carotid stenosis. The same group28 studied patients with internal carotid artery stenosis who underwent MRI before and after Sinerem administration
TABLE 2. Overview of Literature Articles Study Schmitz et al26 Kooi et al27 Trivedi et al28 Trivedi et al29 Tang et al30 Tang et al31 Tang et al32 Tang et al33 Tang et al34 Howarth et al35 Degnan et al36 Metz et al37 Richard et al38 Sadat et al24 Yilmaz et al39 Alam et al40 Yilmaz et al41 Yilmaz et al42
Clinical Application
No. of Patients
USPIO Contrast Agent
Atherosclerotic plaques Atherosclerotic plaques Carotid atheroma Carotid plaque Carotid stenosis Carotid atheroma Carotid atheroma Carotid plaque Carotid plaque Carotid plaque Carotid atherosclerosis Carotid plaques Abdominal aortic aneurysm Abdominal aortic aneurysm Acute myocardial infarction Acute myocardial infarction Acute myocardial infarction Acute myocardial infarction
20 11 8 30 20 40 20 6 47 20 62 12 29 14 20 16 Case report 14
Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferucarbotran (SHU 555C) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferucarbotran (Resovist) Ferumoxytol Ferumoxytol Ferumoxytol
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Administered Dose (mg Fe/kg) 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.2 (40 μmol Fe/kg) 2.6 2.6 0.65 4 510 mg Fe 5.4 (median dose)
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using a standard cardiovascular MRI protocol. The findings demonstrated that USPIO particles were captured by cells of MPS within the carotid atheroma, and therefore, can be used to identify inflamed plaques. Histology and electron microscopy confirmed the areas of USPIO accumulation. The maximum postcontrast reduction in mean SI was observed on T2*-weighted spiral sequence at 24 and 36 hours, whereas the minimal reduction was at 72 hours. This observation is very useful because it defined an optimal-time window for postUSPIO infusion imaging. In a similar carotid atheromatous plaque study,33 the imaging window to detect maximum signal changes in T1W, T2*W, and quantitative T2* post-USPIO images was determined between 36 and 48 hours after Sinerem administration (Fig. 1). The contralateral sides of symptomatic patients with carotid stenosis in an USPIO-based study were also evaluated by Tang et al.30 The results revealed that all symptomatic carotid stenosis had inflammation, while 95% of the patients showed bilateral USPIO uptake, suggesting additional inflammatory activity in the contralateral side. Patients with contralateral symptomatic disease exhibited more inflammatory activity in relation to the completely asymptomatic cohort.31 Symptomatic patients showed more USPIO uptake than do asymptomatic patients, indicating that their plaques had large inflammatory infiltrate.35 In addition, Tang et al32 found that asymptomatic patients waiting for coronary artery bypass grafting had more inflammatory activity in their atheroma than the asymptomatic group with no coronary artery disease. These studies support the assumption that inflammatory atheroma is a systematic disease, and that one symptomatic inflammatory vessel is more likely to increase the probability of another vessel to be or become inflammatory.31,32 In this way, an inflammatory area may constitute a prognostic risk factor for inflammation in another territory. In the atorvastatin therapy: effects on reduction of macrophage activity trial,34 USPIO-enhanced MRI was successfully used as an imaging tool to evaluate the response of low-dose (10 mg) and high-dose (80 mg) statin therapy for 12 weeks in patients with carotid plaque inflammation. The investigators found a significant reduction of plaque inflammation as seen on USPIOenhanced MRI at both 6 and 12 weeks after 80 mg atorvastatin treatment. In a recent study, Metz et al,37 using Ferucarbotran (SHU 555C) contrast agent in patients with severe carotid stenosis, demonstrated that Ferucarbotran-enhanced MRI can be used to characterize atherosclerotic carotid plaques by assessing vascularity and plaque
inflammation. Degnan et al,36 in an USPIO-enhanced MRI study of carotid atherosclerosis, failed to investigate a statistically significant correlation between maximum SI reduction after USPIO infusion and cerebrovascular or cardiovascular morbidity and mortality.
Abdominal Aortic Aneurysm Imaging AAA is characterized by inflammation, neovascularization, and extracellular matrix degradation. The inflammation is predominantly localized to the media and adventitia and contributes to the weakening of the vessel wall.45 As IONs accumulate at sites of cellular inflammations (monocytes/macrophages), imaging inflammatory activity within aneurysms using USPIO-enhanced MRI is potentially feasible. Recently, Richards et al38 evaluated the use of USPIOs in patients with AAAs. Patients with asymptomatic AAA underwent cardiac MRI before and after the administration of Ferumoxtran-10. USPIO accumulation resulted in a significant signal reduction on T2*-weighted images within the wall of AAA. The presence of nanoparticles in the AAA wall was confirmed by histology analysis. In addition, the investigators examined the correlation between USPIO uptake and the rate of AAA expansion. It was shown that patients with distinct mural uptake of USPIO had a threefold higher growth rate in comparison with patients with no or diffuse USPIO uptake. Fig. 2a shows maps of patients with (a) no, (b) diffuse, and (c) distinct USPIO uptake within the aortic wall, alongside the corresponding T2W anatomic image (d–f). The study demonstrated that MRI combined with USPIO can detect and quantify inflammation in AAA, and the associated USPIO uptake with the AAA expansion.38 This last observation is an interesting clinical finding because the growth rate in AAA is a predictor of the potential risk of rupture, and therefore, sets the indications for surgical repair. Sadat et al24 evaluated patients with infrarenal AAA. T2 and T2* MRI was acquired before and 36 hours after intravenous administration of USPIO. Image analysis resulted in a 36% and 46% signal reduction on T2 and T2* postcontrast images, respectively. Furthermore, a significant correlation between T2* and T2 post-USPIO infusion values was observed. The study demonstrated the feasibility of using USPIO as an imaging biomarker in the detection of inflammatory AAA and provided a quantitative method for the evaluation of USPIO uptake by the aortic wall.
FIGURE 1. T2*-weighted images through the same level of the internal carotid artery of a patient before infusion, at 36, 48, 56, 72, and 96 hours after infusion of Sinerem. Maximal signal loss (arrow) occurs around 36 hours post-USPIO infusion. Reproduced from Tang et al33 with permission. 232 | www.cardiologyinreview.com
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Iron Oxide Nanoparticles in Molecular MRI
FIGURE 2. A, Abdominal aortic aneurysm: Maps (a–c) and the corresponding T2W anatomic images (d–f) in 3 patients with AAA. (a) USPIO uptake in periluminal area, (b) diffuse USPIO uptake throughout the thrombus, and (c) discrete focal area of USPIO uptake involving the wall of the AAA. The blue color indicates minimal change whereas red color shows maximum change in T2* value. Reproduced from Richards et al.38 with permission from Wolters Kluwer Health, LWW. B, Myocardial infarction: Comparison of R2* maps in a patient with MI at (a) baseline and (b) 24 hours after the infusion of USPIO. (c) R2* values rise in the liver, the remote and the infarct myocardium. Reproduced from Alam et al.40 with permission.
Myocardial Infarction Imaging MI is characterized by a loss of cardiomyocytes (necrosis) caused by prolonged ischemia. Myocardial necrosis evokes an inflammation reaction, typically within 1–3 days after an MI. The inflammation process is followed by a wave of macrophages that remove necrotic cells and allow remodeling of the infarcted region, representing an important mechanism for infarct wound healing and scar formation. However, an excessive or chronic postinfarction inflammation response results in adverse myocardial remodeling and infarct expansion.46,47 Cardiac MRI with GBCA provides clinically significant information for the characterization of MI by identifying myocardial edema, viability of infarcted tissue, microvascular obstruction, and ventricular volumes and functions. A good contrast between the blood and MI enables the evaluation of the extent of the infarction, and therefore, quantification of the infarcted area.48,49 Recent studies have tested T2*-weighted imaging in combination with USPIO contrast agents for the detection of postinflammation in MI. Yilmaz et al39 sought to evaluate the diagnostic value of IONs for in vivo imaging of macrophages in the MI zone. Patients who had an acute ST-elevation or non–ST-elevation MI © 2015 Wolters Kluwer Health, Inc. All rights reserved.
underwent a standard pre-SPIO and post-SPIO cardiac MR scan. The post-SPIO scan was performed 4–12 hours after the first scan. All patients received a maximum of 0.65 mg Fe/kg of Ferucarbotran (SHU 555A) SPIO. Results showed that T2*-weighted imaging after SPIO administration did not allow improved delineation of the infracted area or the area at risk in patients with ischemic myocardial injury. Therefore, the recommended dose of the specific SPIO does not add any additional information in comparison with the Gdenhanced MRI of necrosis. In a case report study, the same research group41 investigated the role of USPIO imaging in MI pathology, utilizing a different USPIO contrast agent. A cardiac MR scan was performed in a 50-year-old man with ST-elevation MI before and after the administration of Ferumoxytol. The results of this study were more encouraging and demonstrated that MRI in combination with USPIO allows an accurate visualization and detection of both the infarcted and the peri-infarcted zones. The study expanded 1 year later in a larger cohort of patients with acute ST-elevation MI.42 Cardiac MRI was obtained before and after the intravenous administration of Ferumoxytol contrast medium at a median dose of 5.4 mg Fe/kg. It is worth noting that this amount of administered dose of iron is almost 13-fold than the dose used in the first study www.cardiologyinreview.com | 233
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(510 mg Fe in Ferumoxytol compared with only 39 mg Fe in Ferucarbotran).39 The results showed a 64% and 44% reduction in T2* values in the infarct and peri-infarct zones, respectively, confirming the accumulation of USPIO in the inflammed areas. The study raised additional significant clinical findings. The hypoenhancement on T2/T2*-weighted images reached its maximum value 48 hours after Ferumoxytol administration, thereby determining an optimal time window for USPIO-enhanced MRI after MI. The investigators observed hyperenhancement in cine-cardiac MRI 48 hours after infusion of Ferumoxytol in the region of the MI, which was not present in pre-USPIO images. Although the reasons of this observation are not totally clear, the authors attribute it to a predominant T1 effect and almost exclusively to the Ferumoxytol infusion itself. In addition to the T2* signal drop within the infarcted and peri-infarcted tissues, a considerable reduction (44%) was observed in the noninfarcted remote myocardium. This observation suggests that macrophages extend beyond the area at risk, which is in accordance with findings from a previous similar clinical study,40 which demonstrated an increase of R2* (=1/T2*) value not only in the infarcted tissue but also in the myocardium remote from the site of infarction, after administration of Ferumoxytol. As expected, R2* values were increased in organs of RES (liver and spleen). In control patients who did not receive USPIO, no changes in R2* values occurred. Figure 2b illustrates an R2* color map and changes in R2* value in patients who received USPIO.
DISCUSSION Molecular MRI offers the potential for early detection and characterization of CVDs and for monitoring the response to therapy. Inflammation, associated with increased macrophage activity, is now considered an important contributing factor in the pathogenesis of CVDs. A very recent study shows that heart macrophages are actively involved in wound healing, regeneration, and tissue remodeling, and they have a central role in cancer, infection, rheumatoid arthritis, diabetes, obesity, atherosclerosis, and stroke.50 It is now well known that inflammation plays an important role in the formation and progression of atherosclerosis and is considered a risk factor for plaque rupture and arterial thrombosis.44,51 Histological examinations of AAAs have demonstrated extensive transmural infiltration by macrophages and lymphocytes, especially in the aneurysm aortic wall.45 In addition, macrophages seem to be protagonists in infarcted inflammation and healing after an MI.46 Other noninvasive modalities that are used for inflammation imaging are positron emission tomography (PET) and ultrasound. Compared to USPIO-enhanced MRI, PET is more sensitive but has poor spatial resolution.52 Due to this reason, PET requires computed tomography coregistration. Studies have shown that PET/computed tomography can successfully be used for the detection of inflammation in CVDs53 but delivers a high radiation dose to patients. In recent years, ultrasound has also been used in molecular imaging with the use of microbubbles contrast agents. The contrast ultrasound molecular imaging seems to be a promising tool in the evaluation of inflammatory disease but has several limitations. Although the technique is superior to MRI and PET in terms of temporal resolution, it is less sensitive than PET and of lower spatial resolution than MRI, while the specificity remains a challenge.54 Therefore, the evaluation of macrophage activity, and consequently the evaluation of the inflammatory process through molecular MRI, seems to be of exceptional importance in the detection and management of several CVDs. IONs, due to their particular intravascular characteristics and their uptake by macrophages, offer special opportunities for molecular macrophage imaging. USPIOs are more suitable for molecular imaging than SPIOs due to their longer circulation time. The prolonged blood pool circulation time of USPIOs 234 | www.cardiologyinreview.com
increases the probability for macrophages in inflammation areas to capture and phagocytose the nanoparticles.9 USPIOs have proved to be safe, well tolerated, and can be used even in patients with renal failure, in contrast to conventional GBCA. In conclusion, USPIOs provide new opportunities in molecular imaging and may potentially provide improved CVD characterization and evaluation of response to therapy. However, the establishment of an USPIO-enhanced MRI technique in clinical practice would require ongoing trials. REFERENCES 1. Sosnovik DE, Nahrendorf M, Weissleder R. Molecular magnetic resonance imaging in cardiovascular medicine. Circulation. 2007;115:2076–2086. 2. Sosnovik DE, Nahrendorf M, Weissleder R. Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol. 2008;103:122–130. 3. Jaffer FA, Libby P, Weissleder R. Molecular imaging of cardiovascular disease. Circulation. 2007;116:1052–1061. 4. Zhu D, Liu F, Ma L, et al. Nanoparticle-based systems for T1-weighted magnetic resonance imaging contrast agents. Int J Mol Sci. 2013;14:10591–10607. 5. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticleenhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol. 2006;7:52–60. 6. Feldman AS, McDougal WS, Harisinghani MG. The potential of nanoparticleenhanced imaging. Urol Oncol. 2008;26:65–73. 7. Lodhia J, Mandarano G, Ferris Nj, et al. Development and use of iron oxide nanoparticles (part 1): synthesis of iron oxide nanoparticles for MRI. Biomed Imaging Interv J. 2010;6:e12. 8. Mandarano G, Lodhia J, Eu P, et al. Development and use of iron oxide nanoparticles (part 2): the application of iron oxide contrast agents in MRI. Biomed Imaging Interv J. 2010;6:e13. 9. Corot C, Robert P, Idée JM, et al. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev. 2006;58:1471–1504. 10. Na HB, Song IC, Hyeon T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 2009;21:2133–2148. 11. Ittrich H, Peldschus K, Raabe N, et al. Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy. Rofo. 2013;185:1149–1166. 12. Russell M, Anzai Y. Ultrasmall supermagnetic iron oxide enhanced MR imaging for lymph node metastases. Radiography. 2007;13:e73–e84. 13. Storey P, Arbini AA. Bone marrow uptake of ferumoxytol: a preliminary study in healthy human subjects. J Magn Reson Imaging. 2014;39:1401–1410. 14. Valledor AF, Comalada M, Santamaría-Babi LF, et al. Macrophage proinflammatory activation and deactivation: a question of balance. Adv Immunol. 2010;108:1–20. 15. Corot C, Petry KG, Trivedi R, et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol. 2004;39:619–625. 16. Singh N, Jenkins GJS, Asadi R, et al. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010;1:5358. 17. Anzai Y, Piccoli CW, Outwater EK, et al; Group. Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology. 2003;228:777–788. 18. Bernd H, Kerviler E, Gaillard S, et al. Safety and tolerability of ultrasmall supermagnetic iron oxide contrast agents. Invest Radiol. 2009;44:336–342. 19. Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int. 2007;72:260–264. 20. Chopra T, Kandukurti K, Shah S, et al. Understanding nephrogenic systemic fibrosis. Int J Nephrol. 2012;2012:912189. 21. Neuwelt EA, Hamilton BE, Varallyay CG, et al. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009;75:465–474. 22. Besarab A, Coyne D, Bolton WK, et al. Ferumoxytol as an intravenous iron replacement therapy: safety results from two phase III studies in subject with chronic kidney diseases (CKD). American Society of Nephrology 40th Annual Meeting and Scientific Exposition. San Francisco; 2007:SUPO805. 23. Schiller B, Bhat P, Sharma A. Safety and effectiveness of ferumoxytol in hemodialysis patients at 3 dialysis chains in the United States over a 12-month period. Clin Ther. 2014;36:70–83.
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Cardiology in Review • Volume 23, Number 5, September/October 2015
24. Sadat U, Taviani V, Patterson AJ, et al. Ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging of abdominal aortic aneurysms—a feasibility study. Eur J Vasc Endovasc Surg. 2011;41:167–174. 25. Tang MY, Chen TW, Zhang XM, et al. GRE T2*-weighted MRI: principles and clinical applications. BioMed Res Int. 2014; 2014:312142. 26. Schmitz SA, Taupitz M, Wagner S, et al. Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles. J Magn Reson Imaging. 2001;14:355–361. 27. Kooi ME, Cappendijk VC, Cleutjens KB, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation. 2003;107:2453–2458. 28. Trivedi RA, U-King-Im JM, Graves MJ, et al. In vivo detection of macrophages in human carotid atheroma: temporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI. Stroke. 2004;35:1631–1635. 29. Trivedi RA, Mallawarachi C, U-King-Im JM, et al. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol. 2006;26:1601–1606. 30. Tang T, Howarth SP, Miller SR, et al. Assessment of inflammatory burden contralateral to the symptomatic carotid stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke. 2006;37:2266–2270. 31. Tang TY, Howarth SP, Miller SR, et al. Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques contralateral to symptomatic carotid stenosis: an ultra small superparamagnetic iron oxide enhanced magnetic resonance study. J Neurol Neurosurg Psychiatry. 2007;78:1337–1343. 32. Tang TY, Howarth SP, Miller SR, et al. Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: an ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study. Eur J Vasc Endovasc Surg. 2008;35:392–398. 33. Tang TY, Patterson AJ, Miller SR, et al. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques. Neuroradiology. 2009;51:457–465. 34. Tang TY, Howarth SP, Miller SR, et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol. 2009;53:2039–2050. 35. Howarth SP, Tang TY, Trivedi R, et al. Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous cap: a comparison of symptomatic and asymptomatic individuals. Eur J Radiol. 2009;70:555–560. 36. Degnan AJ, Patterson AJ, Tang TY, et al. Evaluation of ultrasmall superparamagnetic iron oxide-enhanced MRI of carotid atherosclerosis to assess risk of cerebrovascular and cardiovascular events: follow-up of the ATHEROMA trial. Cerebrovasc Dis. 2012;34:169–173. 37. Metz S, Ambros J, Beer AJ, et al. Characterization of carotid artery plaques with USPIOenhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability. Int J Cardiovasc Imaging. 2011;27:901–912.
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Iron Oxide Nanoparticles in Molecular MRI
38. Richards JM, Semple SI, MacGillivray TJ, et al. Abdominal aortic aneurysm growth predicted by uptake of ultrasmall superparamagnetic particles of iron oxide: a pilot study. Circ Cardiovasc Imaging. 2011;4:274–281. 39. Yilmaz A, Rösch S, Klingel K, et al. Magnetic resonance imaging (MRI) of inflamed myocardium using iron oxide nanoparticles in patients with acute myocardial infarction—preliminary results. Int J Cardiol. 2013;163:175–182. 40. Alam SR, Shah AS, Richards J, et al. Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience. Circ Cardiovasc Imaging. 2012;5:559–565. 41. Yilmaz A, Rösch S, Yildiz H, et al. First multiparametric cardiovascular magnetic resonance study using ultrasmall superparamagnetic iron oxide nanoparticles in a patient with acute myocardial infarction: new vistas for the clinical application of ultrasmall superparamagnetic iron oxide. Circulation. 2012;126:1932–1934. 42. Yilmaz A, Dengler MA, van der Kuip H, et al. Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach. Eur Heart J. 2013;34:462–475. 43. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–126. 44. Hansson JK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–1695. 45. Ailawadi G, Eliason JL, Upchurch GR Jr. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg. 2003;38:584–588. 46. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010;121:2437–2445. 47. Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012;110:159–173. 48. Marra MP, Lima ACJ, Iliceto S: MRI in acute myocardial infarction. Eur Heart J. 2011;32: 284–293. 49. Bandettini WP, Kellman P, Mancini C, et al. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson. 2012;14:83. 50. Frantz S, Nahrendorf M. Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res. 2014;102:240–248. 51. Libby P, Ridker PM, Hansson GK; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–2138. 52. Chatterjee K, Anderson M, Heistad D, et al. Cardiology. An Illustrated Textbook, Volume 1. 1st ed. New Delhi: Jaypee Brother Medical Publishers; 2012. 53. James OG, Christensen JD, Wong TZ, et al. Utility of FDG PET/CT in inflammatory cardiovascular disease. Radiographics. 2011;31:1271–1286. 54. Linder G. Contrast ultrasound molecular imaging of inflammation in cardiovascular disease. Cardiovasc Res. 2009;84:182–189.
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Iron Oxide Nanoparticles as Contrast Agents in Molecular Magnetic Resonance Imaging Do They Open New Perspectives in Cardiovascular Imaging? Agapi G. Ploussi, MSc,* Maria Gazouli, PhD,† George Stathis, MD,* Nikolaos L. Kelekis, MD, PhD,* Efstathios P. Efstathopoulos, PhD*
Abstract: Molecular magnetic resonance imaging has recently emerged as a powerful tool for the detection and assessment of cardiovascular diseases. Contrast agents have an important role in this novel modality because molecular imaging requires highly sensitive, specific, and efficient imaging agents. Iron oxide nanoparticles (IONs) are a new class of contrast agents with unique properties that provide special opportunities in cardiovascular molecular imaging. IONs are captured by macrophages and can be successfully used in the detection and evaluation of atherosclerotic plaques, abdominal aortic aneurysms, and inflammations related to myocardial infarction. The purpose of this review is to provide a brief description of the basic characteristics of IONs, with a special focus on their role as molecular magnetic resonance imaging contrast agents and their cardiovascular applications. Key Words: molecular magnetic resonance imaging, cardiovascular imaging, iron oxide nanoparticles (Cardiology in Review 2015;23: 229–235)
(4) safety use in patients with chronic kidney disease (CKD), (5) the ability to change magnetic properties according to their size, shape, and structure, and (6) selective localization to the desired target in conjugation with specific ligands.4 In clinical practice, IONs were initially used in oncology for the diagnosis of lymph node metastases. Several studies have shown that IONs are captured by the reticuloendothelial system (RES) and offer higher diagnostic precision, sensitivity, and specificity for the detection of lymph-node metastases in relation to unenhanced MRI.5,6 In cardiovascular imaging, the role of ION-enhanced MRI has not yet been fully established but is gaining acceptance because of the expanded utility of molecular imaging.2 In this review, we provide an overview of the characteristics and the mechanism of IONs as MRI contrast agents and their potential role in cardiovascular molecular imaging. This review is based on an extensive literature review concerning the last decade and presents the most recent advances in the area of cardiovascular molecular MRI using IONs.
M
Characteristics and Properties
From the *Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; and †Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. Disclosure: The authors have no conflicts of interest to report. Correspondence: Efstathios P. Efstathopoulos, PhD, Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, 1, Rimini Str, 124 62 Haidari, Athens, Greece. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2305-229 DOI: 10.1097/CRD.0000000000000055
IONs are mainly used as T2 contrast agents due to their ability to shorten the T2 and T2* relaxation times of the tissues in which they accumulate. Reduction of T2 and T2* relaxation times provides a negative enhancement and consequently results in a hypointense signal that appears dark on T2/T2*-weighted images. With the appropriate composition, IONs can reduce both T1 and T2/T2* relaxation times. IONs consist of a magnetic iron oxide core (magnetite-Fe3O4 or/and maghemite-γ-Fe2O3) surrounded by a surface coating. The core is responsible for the signal enhancement, whereas the coating material is necessary to prevent nanoparticle destabilization and agglomeration, allow conjugation of targeted ligands, and achieve aqueous or biological media solubility. In addition, the surface coating reduces toxicity and increases the circulation time of IONs. The most commonly used surface coatings are polymers, such as dextran, carbodextran, and small molecular ligands, such as citrate and silica.7,8 The blood half-life of IONs is dependent on their size, their surface coating material, and the administered dose. At clinical doses (8–74 μmol Fe/kg depending on the contrast agent), the blood half-life of IONs ranges from 1 to 24–36 hours.9 For the same surface coating, smaller nanoparticles have a longer plasma half-life. IONs used for MRI do not exceed 200 nm, whereas the size of the core is usually 4–15 nm. According to their overall hydrodynamic size (core + coating), IONs are classified into supermagnetic iron oxide (SPIO) nanoparticles with a diameter greater than 50 nm and ultrasmall supermagnetic iron oxide (USPIO) nanoparticles with a diameter less than 50 nm. The physicochemical properties of IONs are influenced by the core material, the surface coating, the core and their overall hydrodynamic size, the surface charge, and the surface hydrophobicity.8,10
olecular imaging using magnetic resonance has expanded its role from a research tool into a clinical imaging modality for the diagnosis and management of cardiovascular diseases (CVDs). Molecular magnetic resonance imaging (MRI) focuses on the visualization and quantification of molecular and cellular targets that underlie changes in cardiovascular morphology, physiology, and function. Cardiovascular molecular MRI is now considered an effective technique for the assessment of a wide range of CVDs, such as atherosclerosis, vascular disease, inflammation, myocardial infarction (MI), and also for stem cell imaging.1–3 Contrast agents play a crucial role in MRI, and so far, gadolinium (Gd)-based contrast agents (GBCAs) are considered the standard agents for MRI. However, GBCAs are inadequate to detect molecular targets because of their low sensitivity (in the micromolar range), their extremely short circulation plasma time, and their rapid renal excretion.1,4 To overcome these limitations, a new generation of MRI contrast agents, magnetic iron oxide nanoparticles (IONs), has been developed. IONs have several advantages over the conventional contrast agents including (1) higher detection sensitivity, (2) better biocompatibility, and therefore low toxicity, (3) long retention time,
IONS AS MRI CONTRAST AGENTS
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Cardiology in Review • Volume 23, Number 5, September/October 2015
Bayer Schering Pharma AG/Medicadoc Liver, spleen, bone marrow AMAG Pharmaceuticals/Guerbet Lymph nodes, MRA Bayer Schering Pharma AG Macrophage imaging AMAG Pharmaceuticals/Takeda Pharmaceutical Company Limited Lymph nodes, liver, spleen, MRA GE-Healthcare
Mechanisms and Route of Action Due to their small size, long circulation half-life, and insignificant migration into extravascular space, IONs act as intravascular contrast agents. IONs accumulate in the phagocytic cells of the mononuclear phagocyte system (MPS), also known as the RES. The MPS includes monocytes from bone marrow and blood and macrophages located in the liver (Kupffer cells), spleen, lymph node, bone, bone marrow, lung, connective tissue, pleura and peritoneum, and central nervous system. After administration, SPIOs are quickly taken up by the MPS and accumulate in the liver and spleen. In contrast, USPIOs, due to their smaller size, remain in the blood circulation for a longer time and mainly accumulate in the macrophages of the lymph nodes and bone marrow. USPIOs are transported to the lymph nodes via 2 mechanisms: by direct transcapillary passage of nanoparticles from venules into the medullary sinuses of lymph nodes or by nonselective endothelial transcytosis into the interstitial space.9 The USPIOs are taken up by macrophages present in normal lymph nodes, resulting in a reduction of signal intensity (SI) on T2 and T2*-weighted MRIs.12 USPIO imaging of the bone marrow is similar to USPIO imaging of the lymph nodes. The USPIO particles are phagocytosed only by normal bone marrow (which contains macrophages of the MPS) and cause SI loss.13 USPIOs are also localized in inflammatory cells. Macrophages play an important role in inflammation because during the initial inflammation process, these phagocytic cells become activated and have destructive effects.14 Hence, inflammatory areas appear dark while no alteration in SI is observed in noninflammatory tissues. The possible mechanisms that have been proposed for transporting USPIOs to macrophages include the following: (1) endocytosis by activated blood monocytes, which migrate into the pathological tissues; (2) transcytosis through the endothelium and their migration into the tissue, followed by progressive endocytosis of these USPIOs by in situ macrophages; and (3) transport of USPIOs into the pathological tissue, in some cases via the inflammatory neovasculature (vasa vasorum) irrigating the media and adventitia in atherosclerotic lesions.15
3–4 6
15/89
20
Carboxymethyl dextran Pegylated starch 30
10–14
9.7/189 10.7/38 Dextran Carboxydextran 80–180 21
2 6
10.1/120 2.4–3.6 Carboxydextran 60
230 | www.cardiologyinreview.com
*For clinical doses. †1.5 T, 37°C, water or in plasma, mM−1 s−1. MRA indicates magnetic resonance angiography.
Clariscan PEG-feron/NC 100150 Feruglose
Code 7228
Feraheme/Rienso Ferumoxytol
AMI-25 SHU 555 C
Feridex/Endorem Supravist
Ferucarbotran or Ferrixan Ferumoxide Ferucarbotran SHU 555A
15–40 Ferumoxtran-10
Resovist/Cliavist
24–36
9.9/65
Lymph nodes, liver, macrophage imaging Liver, spleen, bone marrow
Guerbet/AMAG Pharmaceuticals
Several IONs have been approved by the Food and Drug Administration for intravenous use as MRI contrast agents. Table 1 presents the characteristics of the most commonly used IONs that have been approved or are in different clinical phases for use in Europe and the United States.9,11 At the present time, only Ferumoxytol is commercially available in the US and European markets.
Safety
AMI-227
Agent
Generic Name
Sinerem/Combidex
Dextran
Plasma Half-Time* Relaxivities (hour) (r1/r2)† Surface Coating Hydrodynamic Size (nm) Trade Name
TABLE 1. IONs Approved for Clinical Application or Clinically Tested (Data from Corot et al9 and Ittrich et al11)
Indication
Developer
Ploussi et al
Toxicity is a major concern in the development of contrast agents. The toxicity of IONs depends on various parameters including particle size, surface coating, chemical composition, and dosage. Various studies have investigated the cytotoxic potential for several different types of USPIOs. All reports demonstrated that IONs are biocompatible and show low or no cytotoxicity.16 Human studies in malignancy patients using dextran-coated IONs suggested side effects, such as headache, back pain, and urticaria. Most of the symptoms were mild to moderate and of short duration, whereas none of them were clinically significant.17,18 It is known that the development of nephrogenic systematic fibrosis is associated with GBCA administration in patients with stage 4 or 5 CKD and acute kidney injury.19 GBCAs are eliminated almost entirely by the renal system, and in renal failure, the prolonged half-life of the free toxic Gd+3 ions affects tissues and leads to fibrosis.20 In contrast with GBCAs, IONs are rapidly removed from the RES and especially from the Kupffer cells within the liver. Neuwelt et al21 demonstrated that USPIO agents are safe for patients with kidney disease for both central nervous system MRI and magnetic resonance (MR) angiography and suggested USPIO © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Cardiology in Review • Volume 23, Number 5, September/October 2015
agents as a future alternative MR contrast agent for patients at risk for nephrogenic systematic fibrosis. In addition, it has been proven that USPIO nanoparticles are safe for patients undergoing hemodialysis.22,23 The potential to use IONs in patients with CKD is one of the strongest reasons to consider the use of nanoparticles in clinical practice.
IONS-ENHANCED MRI TECHNIQUES IN CARDIOVASCULAR IMAGING
where SIpost indicates SI in postcontrast scan; SIpre, SI in precontrast scan. Higher USPIO accumulation leads to lower negative values of ΔSI. In addition, a quantitative analysis of the concentration of nanoparticles is performed by calculating T2* relaxation times before and after the USPIO administration on a pixel-by-pixel basis to generate T2* maps for each segment. The T2* value is the decay constant for the exponential decay of SI with time [SI(t) = SI(0) exp − (t/T2*)]. In a T2* map, each pixel represents the T2* value.
CLINICAL APPLICATIONS IN CARDIOVASCULAR IMAGING
Acquisition Protocol Cardiovascular MRI with nanoparticles requires 2 scans: a precontrast scan and a postcontrast scan within 24–72 hours after administration of USPIOs. After the injection of iron oxide contrast agents, a T2 or T2*-weighted sequence is obtained for the evaluation of USPIO uptake. Both T2 and T2* images enable the quantification of USPIO accumulation and the generation of T2/T2* maps. Although T2 sequences are more specific and provide better contrast and signal-to-noise ratio, in most USPIO-enhanced cardiovascular MR acquisition protocols, a T2*-weighted gradient-echo sequence is chosen because of the greater sensitivity to iron deposition and the higher speed.24,25 Acquisition of T2 or T2* sequences is also necessary in the first scan to compare pre-USPIO and post-USPIO contrast images.
Image Analysis The most convenient method for the evaluation of USPIOs accumulation is based on differences in SI between precontrast and postcontrast MR images. The assessment can be qualitative or/and quantitative, usually on a segmental basis. For qualitative analysis, the SI changes (decrease, increase, or no change) in preinfusion and postinfusion T2*-weighted images and is evaluated by independent radiologists by consensus. In quantitative analysis, the precontrast and postcontrast T2*-weighted images are registered using fixed reference markers, and subsequent regions of interests are subdivided into radial segments. For each segment, the mean SI is measured using an appropriate software tool, and the percentage difference in SI is calculated as follows: ∆SI% =
SIpost − SIpre × 100 (1) SIpre
Iron Oxide Nanoparticles in Molecular MRI
The literature search indicated that USPIOs have been used to image atherosclerotic plaque, infarcted myocardium, and inflammations involved in the development of abdominal aortic aneurysms (AAAs). An overview of the literature articles is presented in Table 2.26–42
Atherosclerotic Plaque Imaging Atherosclerosis is a chronic inflammatory disease affecting large-sized and medium-sized arteries.43,44 Because inflammation is accompanied by macrophage activity, USPIOs are accumulated in the macrophages present in atherosclerotic plaques and cause a strong signal reduction in T2/T2*-weighted sequences. Schmitz et al26 incidentally observed USPIO uptake in the aortic and arterial wall in patients who had initially received USPIO contrast agent for staging lymph node metastases. This was the first observation, which proved that USPIO can accumulate in human atherosclerotic plaques. Kooi et al27 performed pre-USPIO and post-USPIO MRI in symptomatic patients scheduled for carotid endarterectomy. All patients were administered Ferumoxtran-10 at a dose of 2.6 mg Fe/kg. The results showed a 24% decrease in SI on T2* gradient-echo images acquired 24 hours after USPIO administration, indicating USPIO accumulation in macrophages of atherosclerotic plaques. USPIO uptake was also verified by histology analysis in 75% of ruptured and rupture-prone lesions and by electron microscopy analyses of the plaques. A 24% average signal loss on T2*W post-USPIO images was also observed later by Trivedi et al29 in symptomatic patients with carotid stenosis. The same group28 studied patients with internal carotid artery stenosis who underwent MRI before and after Sinerem administration
TABLE 2. Overview of Literature Articles Study Schmitz et al26 Kooi et al27 Trivedi et al28 Trivedi et al29 Tang et al30 Tang et al31 Tang et al32 Tang et al33 Tang et al34 Howarth et al35 Degnan et al36 Metz et al37 Richard et al38 Sadat et al24 Yilmaz et al39 Alam et al40 Yilmaz et al41 Yilmaz et al42
Clinical Application
No. of Patients
USPIO Contrast Agent
Atherosclerotic plaques Atherosclerotic plaques Carotid atheroma Carotid plaque Carotid stenosis Carotid atheroma Carotid atheroma Carotid plaque Carotid plaque Carotid plaque Carotid atherosclerosis Carotid plaques Abdominal aortic aneurysm Abdominal aortic aneurysm Acute myocardial infarction Acute myocardial infarction Acute myocardial infarction Acute myocardial infarction
20 11 8 30 20 40 20 6 47 20 62 12 29 14 20 16 Case report 14
Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferucarbotran (SHU 555C) Ferumoxtran-10 (Sinerem) Ferumoxtran-10 (Sinerem) Ferucarbotran (Resovist) Ferumoxytol Ferumoxytol Ferumoxytol
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Administered Dose (mg Fe/kg) 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.2 (40 μmol Fe/kg) 2.6 2.6 0.65 4 510 mg Fe 5.4 (median dose)
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Ploussi et al
using a standard cardiovascular MRI protocol. The findings demonstrated that USPIO particles were captured by cells of MPS within the carotid atheroma, and therefore, can be used to identify inflamed plaques. Histology and electron microscopy confirmed the areas of USPIO accumulation. The maximum postcontrast reduction in mean SI was observed on T2*-weighted spiral sequence at 24 and 36 hours, whereas the minimal reduction was at 72 hours. This observation is very useful because it defined an optimal-time window for postUSPIO infusion imaging. In a similar carotid atheromatous plaque study,33 the imaging window to detect maximum signal changes in T1W, T2*W, and quantitative T2* post-USPIO images was determined between 36 and 48 hours after Sinerem administration (Fig. 1). The contralateral sides of symptomatic patients with carotid stenosis in an USPIO-based study were also evaluated by Tang et al.30 The results revealed that all symptomatic carotid stenosis had inflammation, while 95% of the patients showed bilateral USPIO uptake, suggesting additional inflammatory activity in the contralateral side. Patients with contralateral symptomatic disease exhibited more inflammatory activity in relation to the completely asymptomatic cohort.31 Symptomatic patients showed more USPIO uptake than do asymptomatic patients, indicating that their plaques had large inflammatory infiltrate.35 In addition, Tang et al32 found that asymptomatic patients waiting for coronary artery bypass grafting had more inflammatory activity in their atheroma than the asymptomatic group with no coronary artery disease. These studies support the assumption that inflammatory atheroma is a systematic disease, and that one symptomatic inflammatory vessel is more likely to increase the probability of another vessel to be or become inflammatory.31,32 In this way, an inflammatory area may constitute a prognostic risk factor for inflammation in another territory. In the atorvastatin therapy: effects on reduction of macrophage activity trial,34 USPIO-enhanced MRI was successfully used as an imaging tool to evaluate the response of low-dose (10 mg) and high-dose (80 mg) statin therapy for 12 weeks in patients with carotid plaque inflammation. The investigators found a significant reduction of plaque inflammation as seen on USPIOenhanced MRI at both 6 and 12 weeks after 80 mg atorvastatin treatment. In a recent study, Metz et al,37 using Ferucarbotran (SHU 555C) contrast agent in patients with severe carotid stenosis, demonstrated that Ferucarbotran-enhanced MRI can be used to characterize atherosclerotic carotid plaques by assessing vascularity and plaque
inflammation. Degnan et al,36 in an USPIO-enhanced MRI study of carotid atherosclerosis, failed to investigate a statistically significant correlation between maximum SI reduction after USPIO infusion and cerebrovascular or cardiovascular morbidity and mortality.
Abdominal Aortic Aneurysm Imaging AAA is characterized by inflammation, neovascularization, and extracellular matrix degradation. The inflammation is predominantly localized to the media and adventitia and contributes to the weakening of the vessel wall.45 As IONs accumulate at sites of cellular inflammations (monocytes/macrophages), imaging inflammatory activity within aneurysms using USPIO-enhanced MRI is potentially feasible. Recently, Richards et al38 evaluated the use of USPIOs in patients with AAAs. Patients with asymptomatic AAA underwent cardiac MRI before and after the administration of Ferumoxtran-10. USPIO accumulation resulted in a significant signal reduction on T2*-weighted images within the wall of AAA. The presence of nanoparticles in the AAA wall was confirmed by histology analysis. In addition, the investigators examined the correlation between USPIO uptake and the rate of AAA expansion. It was shown that patients with distinct mural uptake of USPIO had a threefold higher growth rate in comparison with patients with no or diffuse USPIO uptake. Fig. 2a shows maps of patients with (a) no, (b) diffuse, and (c) distinct USPIO uptake within the aortic wall, alongside the corresponding T2W anatomic image (d–f). The study demonstrated that MRI combined with USPIO can detect and quantify inflammation in AAA, and the associated USPIO uptake with the AAA expansion.38 This last observation is an interesting clinical finding because the growth rate in AAA is a predictor of the potential risk of rupture, and therefore, sets the indications for surgical repair. Sadat et al24 evaluated patients with infrarenal AAA. T2 and T2* MRI was acquired before and 36 hours after intravenous administration of USPIO. Image analysis resulted in a 36% and 46% signal reduction on T2 and T2* postcontrast images, respectively. Furthermore, a significant correlation between T2* and T2 post-USPIO infusion values was observed. The study demonstrated the feasibility of using USPIO as an imaging biomarker in the detection of inflammatory AAA and provided a quantitative method for the evaluation of USPIO uptake by the aortic wall.
FIGURE 1. T2*-weighted images through the same level of the internal carotid artery of a patient before infusion, at 36, 48, 56, 72, and 96 hours after infusion of Sinerem. Maximal signal loss (arrow) occurs around 36 hours post-USPIO infusion. Reproduced from Tang et al33 with permission. 232 | www.cardiologyinreview.com
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FIGURE 2. A, Abdominal aortic aneurysm: Maps (a–c) and the corresponding T2W anatomic images (d–f) in 3 patients with AAA. (a) USPIO uptake in periluminal area, (b) diffuse USPIO uptake throughout the thrombus, and (c) discrete focal area of USPIO uptake involving the wall of the AAA. The blue color indicates minimal change whereas red color shows maximum change in T2* value. Reproduced from Richards et al.38 with permission from Wolters Kluwer Health, LWW. B, Myocardial infarction: Comparison of R2* maps in a patient with MI at (a) baseline and (b) 24 hours after the infusion of USPIO. (c) R2* values rise in the liver, the remote and the infarct myocardium. Reproduced from Alam et al.40 with permission.
Myocardial Infarction Imaging MI is characterized by a loss of cardiomyocytes (necrosis) caused by prolonged ischemia. Myocardial necrosis evokes an inflammation reaction, typically within 1–3 days after an MI. The inflammation process is followed by a wave of macrophages that remove necrotic cells and allow remodeling of the infarcted region, representing an important mechanism for infarct wound healing and scar formation. However, an excessive or chronic postinfarction inflammation response results in adverse myocardial remodeling and infarct expansion.46,47 Cardiac MRI with GBCA provides clinically significant information for the characterization of MI by identifying myocardial edema, viability of infarcted tissue, microvascular obstruction, and ventricular volumes and functions. A good contrast between the blood and MI enables the evaluation of the extent of the infarction, and therefore, quantification of the infarcted area.48,49 Recent studies have tested T2*-weighted imaging in combination with USPIO contrast agents for the detection of postinflammation in MI. Yilmaz et al39 sought to evaluate the diagnostic value of IONs for in vivo imaging of macrophages in the MI zone. Patients who had an acute ST-elevation or non–ST-elevation MI © 2015 Wolters Kluwer Health, Inc. All rights reserved.
underwent a standard pre-SPIO and post-SPIO cardiac MR scan. The post-SPIO scan was performed 4–12 hours after the first scan. All patients received a maximum of 0.65 mg Fe/kg of Ferucarbotran (SHU 555A) SPIO. Results showed that T2*-weighted imaging after SPIO administration did not allow improved delineation of the infracted area or the area at risk in patients with ischemic myocardial injury. Therefore, the recommended dose of the specific SPIO does not add any additional information in comparison with the Gdenhanced MRI of necrosis. In a case report study, the same research group41 investigated the role of USPIO imaging in MI pathology, utilizing a different USPIO contrast agent. A cardiac MR scan was performed in a 50-year-old man with ST-elevation MI before and after the administration of Ferumoxytol. The results of this study were more encouraging and demonstrated that MRI in combination with USPIO allows an accurate visualization and detection of both the infarcted and the peri-infarcted zones. The study expanded 1 year later in a larger cohort of patients with acute ST-elevation MI.42 Cardiac MRI was obtained before and after the intravenous administration of Ferumoxytol contrast medium at a median dose of 5.4 mg Fe/kg. It is worth noting that this amount of administered dose of iron is almost 13-fold than the dose used in the first study www.cardiologyinreview.com | 233
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(510 mg Fe in Ferumoxytol compared with only 39 mg Fe in Ferucarbotran).39 The results showed a 64% and 44% reduction in T2* values in the infarct and peri-infarct zones, respectively, confirming the accumulation of USPIO in the inflammed areas. The study raised additional significant clinical findings. The hypoenhancement on T2/T2*-weighted images reached its maximum value 48 hours after Ferumoxytol administration, thereby determining an optimal time window for USPIO-enhanced MRI after MI. The investigators observed hyperenhancement in cine-cardiac MRI 48 hours after infusion of Ferumoxytol in the region of the MI, which was not present in pre-USPIO images. Although the reasons of this observation are not totally clear, the authors attribute it to a predominant T1 effect and almost exclusively to the Ferumoxytol infusion itself. In addition to the T2* signal drop within the infarcted and peri-infarcted tissues, a considerable reduction (44%) was observed in the noninfarcted remote myocardium. This observation suggests that macrophages extend beyond the area at risk, which is in accordance with findings from a previous similar clinical study,40 which demonstrated an increase of R2* (=1/T2*) value not only in the infarcted tissue but also in the myocardium remote from the site of infarction, after administration of Ferumoxytol. As expected, R2* values were increased in organs of RES (liver and spleen). In control patients who did not receive USPIO, no changes in R2* values occurred. Figure 2b illustrates an R2* color map and changes in R2* value in patients who received USPIO.
DISCUSSION Molecular MRI offers the potential for early detection and characterization of CVDs and for monitoring the response to therapy. Inflammation, associated with increased macrophage activity, is now considered an important contributing factor in the pathogenesis of CVDs. A very recent study shows that heart macrophages are actively involved in wound healing, regeneration, and tissue remodeling, and they have a central role in cancer, infection, rheumatoid arthritis, diabetes, obesity, atherosclerosis, and stroke.50 It is now well known that inflammation plays an important role in the formation and progression of atherosclerosis and is considered a risk factor for plaque rupture and arterial thrombosis.44,51 Histological examinations of AAAs have demonstrated extensive transmural infiltration by macrophages and lymphocytes, especially in the aneurysm aortic wall.45 In addition, macrophages seem to be protagonists in infarcted inflammation and healing after an MI.46 Other noninvasive modalities that are used for inflammation imaging are positron emission tomography (PET) and ultrasound. Compared to USPIO-enhanced MRI, PET is more sensitive but has poor spatial resolution.52 Due to this reason, PET requires computed tomography coregistration. Studies have shown that PET/computed tomography can successfully be used for the detection of inflammation in CVDs53 but delivers a high radiation dose to patients. In recent years, ultrasound has also been used in molecular imaging with the use of microbubbles contrast agents. The contrast ultrasound molecular imaging seems to be a promising tool in the evaluation of inflammatory disease but has several limitations. Although the technique is superior to MRI and PET in terms of temporal resolution, it is less sensitive than PET and of lower spatial resolution than MRI, while the specificity remains a challenge.54 Therefore, the evaluation of macrophage activity, and consequently the evaluation of the inflammatory process through molecular MRI, seems to be of exceptional importance in the detection and management of several CVDs. IONs, due to their particular intravascular characteristics and their uptake by macrophages, offer special opportunities for molecular macrophage imaging. USPIOs are more suitable for molecular imaging than SPIOs due to their longer circulation time. The prolonged blood pool circulation time of USPIOs 234 | www.cardiologyinreview.com
increases the probability for macrophages in inflammation areas to capture and phagocytose the nanoparticles.9 USPIOs have proved to be safe, well tolerated, and can be used even in patients with renal failure, in contrast to conventional GBCA. In conclusion, USPIOs provide new opportunities in molecular imaging and may potentially provide improved CVD characterization and evaluation of response to therapy. However, the establishment of an USPIO-enhanced MRI technique in clinical practice would require ongoing trials. REFERENCES 1. Sosnovik DE, Nahrendorf M, Weissleder R. Molecular magnetic resonance imaging in cardiovascular medicine. Circulation. 2007;115:2076–2086. 2. Sosnovik DE, Nahrendorf M, Weissleder R. Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol. 2008;103:122–130. 3. Jaffer FA, Libby P, Weissleder R. Molecular imaging of cardiovascular disease. Circulation. 2007;116:1052–1061. 4. Zhu D, Liu F, Ma L, et al. Nanoparticle-based systems for T1-weighted magnetic resonance imaging contrast agents. Int J Mol Sci. 2013;14:10591–10607. 5. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticleenhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol. 2006;7:52–60. 6. Feldman AS, McDougal WS, Harisinghani MG. The potential of nanoparticleenhanced imaging. Urol Oncol. 2008;26:65–73. 7. Lodhia J, Mandarano G, Ferris Nj, et al. Development and use of iron oxide nanoparticles (part 1): synthesis of iron oxide nanoparticles for MRI. Biomed Imaging Interv J. 2010;6:e12. 8. Mandarano G, Lodhia J, Eu P, et al. Development and use of iron oxide nanoparticles (part 2): the application of iron oxide contrast agents in MRI. Biomed Imaging Interv J. 2010;6:e13. 9. Corot C, Robert P, Idée JM, et al. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev. 2006;58:1471–1504. 10. Na HB, Song IC, Hyeon T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 2009;21:2133–2148. 11. Ittrich H, Peldschus K, Raabe N, et al. Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy. Rofo. 2013;185:1149–1166. 12. Russell M, Anzai Y. Ultrasmall supermagnetic iron oxide enhanced MR imaging for lymph node metastases. Radiography. 2007;13:e73–e84. 13. Storey P, Arbini AA. Bone marrow uptake of ferumoxytol: a preliminary study in healthy human subjects. J Magn Reson Imaging. 2014;39:1401–1410. 14. Valledor AF, Comalada M, Santamaría-Babi LF, et al. Macrophage proinflammatory activation and deactivation: a question of balance. Adv Immunol. 2010;108:1–20. 15. Corot C, Petry KG, Trivedi R, et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol. 2004;39:619–625. 16. Singh N, Jenkins GJS, Asadi R, et al. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010;1:5358. 17. Anzai Y, Piccoli CW, Outwater EK, et al; Group. Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology. 2003;228:777–788. 18. Bernd H, Kerviler E, Gaillard S, et al. Safety and tolerability of ultrasmall supermagnetic iron oxide contrast agents. Invest Radiol. 2009;44:336–342. 19. Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int. 2007;72:260–264. 20. Chopra T, Kandukurti K, Shah S, et al. Understanding nephrogenic systemic fibrosis. Int J Nephrol. 2012;2012:912189. 21. Neuwelt EA, Hamilton BE, Varallyay CG, et al. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009;75:465–474. 22. Besarab A, Coyne D, Bolton WK, et al. Ferumoxytol as an intravenous iron replacement therapy: safety results from two phase III studies in subject with chronic kidney diseases (CKD). American Society of Nephrology 40th Annual Meeting and Scientific Exposition. San Francisco; 2007:SUPO805. 23. Schiller B, Bhat P, Sharma A. Safety and effectiveness of ferumoxytol in hemodialysis patients at 3 dialysis chains in the United States over a 12-month period. Clin Ther. 2014;36:70–83.
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Iron Oxide Nanoparticles in Molecular MRI
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