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WIREs Nanomed Nanobiotechnol
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Imaging of apoptosis in the heart with nanoparticle technology

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Abstract Apoptosis plays an important role in the loss of cardiomyocytes in both ischemic injury and heart failure. Pioneering work with single photon emission computed tomography imaging of 99Tc‐annexin showed that cell death in the heart could be imaged in vivo. Over the last 5 years a significant amount of experience with annexin‐labeled magnetic nanoparticles, principally AnxCLIO‐Cy5.5, has also been gained. Here, we review the experience with AnxCLIO‐Cy5.5 in the heart and compare this experience to that of earlier studies with 99Tc‐annexin. The imaging of apoptosis with AnxCLIO‐Cy5.5 provides valuable insights not only into molecular imaging in the heart but, more broadly, into the use of nanoparticle technology for molecular imaging in general. WIREs Nanomed Nanobiotechnol 2011 3 86–99 DOI: 10.1002/wnan.115 This article is categorized under: Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease

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Molecular imaging of cell death in the heart with 99Tc‐annexin. (a, b) Patients with acute coronary syndromes showed uptake of 99Tc‐annexin in areas of the myocardium that subsequently showed corresponding perfusion defects. The white arrows point to (a) a perfusion defect produced by the acute coronary syndrome and (b) to the area of myocardium with acute uptake of 99Tc‐annexin during the event. L = liver (Reprinted with permission from Ref 7. Copyright 2000 Elsevier). (c, d) Diffuse uptake of 99Tc‐annexin in a patient with cardiac transplant rejection. Long and short axis views of the heart are shown (Reprinted with permission from Ref 8. Copyright 2001 Nature Publishing Group).

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Simultaneous molecular imaging of cardiomyocyte (CM) apoptosis and necrosis with a nanoparticle‐based approach in acute ischemia reperfusion injury.15 Images at three slice locations, proceeding from the midventricular level to the apex, are shown. Areas of myocardium with apoptotic and/or necrotic CMs accumulate AnxCLIO‐Cy5.5 (left column), producing signal hypointensity in the injured myocardium. However, only areas of necrosis also show delayed enhancement with Gd‐DTPA‐NBD (red arrows, middle column). The spatial resolution of molecular MRI allows the transmural extent of CM apoptosis and necrosis to be accurately determined. Immunohistochemistry for NBD (right column) confirms that Gd‐DTPA‐NBD accumulates only in necrotic myocardium, where cell rupture has resulted in the expansion of the extracellular space (Reprinted with permission from Ref 15. Copyright 2009 the American Heart Association).

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Strategy for simultaneous molecular MRI of AnxCLIO‐Cy5.5 and delayed gadolinium enhancement.15 The contrast produced by AnxCLIO‐Cy5.5 is strongly modulated by the echo time (TE) used: At a TE of 1 ms at 9.4 T (a) the r1 and r2* effects of AnxCLIO‐Cy5.5 balance each other, and the injured and uninjured areas of the myocardium are isointense. As the TE is increased to 2.5 ms (b) and 4 ms (c) signal hypointensity due to the accumulation of AnxCLIO‐Cy5.5 in the injured myocardium becomes clearly visible (yellow arrows). A TE of 1 ms at 9.4 T thus produces a proton density‐weighted image in the vicinity of AnxCLIO‐Cy5.5, allowing delayed gadolinium enhancement to be detected (Reprinted with permission from Ref 15. Copyright 2009 the American Heart Association).

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Molecular MRI of cardiomyocyte (CM) apoptosis [echo time (TE) 4 ms] within 4–6 h of ischemia–reperfusion in mice with severe and extensive injury.15 (a, b) Mouse injected with AnxCLIO‐Cy5.5; (c, d) mouse injected with the control probe Inact_CLIO‐Cy5.5. Robust accumulation of AnxCLIO‐Cy5.5 is seen throughout the injured myocardium (yellow arrows). In contrast, only small foci of hypointensity from the persistence of Inact_CLIO‐Cy5.5 are seen. (e) Fluorescence microscopy (magnification 100×) of AnxCLIO‐Cy5.5 uptake correlates well with the in vivo MR images [panel (a, b)]. (The endocardial boundary in panel (e) has been manually traced to aid visualization, white arrow = epicardium). (f) Fluorescence microscopy (400×) showing AnxCLIO‐Cy5.5 bound to the cell surface of morphologically intact CMs. The use of AnxCLIO‐Cy5.5 allows the uptake of the agent to be correlated with regional cardiac function and to be characterized ex vivo at the cellular level with fluorescence microscopy (Reprinted with permission from Ref 15. Copyright 2009 the American Heart Association).

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Sensitivity of AnxCLIO‐Cy5.5 for cardiomyocyte (CM) apoptosis.16 Postpartum Gaq‐overexpressing mice with heart failure have been used. These mice develop a postpartum cardiomyopathy with very low levels of apoptosis (1–2%), minimal inflammation and necrosis, and normal capillary membrane permeability. AnxCLIO‐Cy5.5, however, is able to penetrate the interstitial space and detect the very sparsely expressed apoptotic CMs. Mice injected with the active probe are shown in (a, d) and those injected with the control probe in (b, e). T2* maps are shown in (a, b) and T2*‐weighted images in (d, e). T2* is significantly reduced in the animals injected with AnxCLIO‐Cy5.5 and numerous discrete foci of probe uptake (signal hypointensity, white arrows) are seen. (f) Fluorescence microscopy of a mouse injected with AnxCLIO‐Cy5.5 shows the uptake of the agent by an apoptotic CM with characteristic membrane blebbing (yellow arrows) (Reprinted with permission from Ref 16. Copyright 2009 the American Heart Association).

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Gadolinium‐based constructs for molecular imaging of apoptosis. The uptake of these agents can be detected by measuring a reduction in T1. An annexin‐labeled nanoparticle consisting of a quantum dot and gadolinium‐loaded micelles [panel (a)] has been used to image apoptotic cells in vitro. A5 = annexin (Reprinted with permission from Ref 27. Copyright 2006 American Chemical Society). (b) An annexin‐labeled gadolinium‐containing liposome was able to image apoptosis (arrows) in isolated perfused hearts ex vivo (Reprinted with permission from Ref 26. Copyright 2006 BC Decker Inc.). (c, d) Imaging of chemotherapy‐induced apoptosis in implanted tumors (white arrows) with a gadolinium–synaptotagmin construct.28 (c) A significant reduction in T1 is seen in a treated tumor. (d) No uptake of the agent or reduction in T1 is seen in a control mouse with an identical tumor. A test tube (labeled ‘R’) was placed next to the mice and used as a reference signal (Reprinted with permission from Ref 28. Copyright 2008 RSNA). While this experience is encouraging, the potential of gadolinium‐based constructs to image apoptosis in the heart in vivo remains unknown and will require further study.

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Schematic of magnetic particles for medical applications. Agents marked with ** have been used extensively clinically (clinically approved or completed phase 3 trials) and have an extensive safety record (Reprinted with permission from Ref 19. Copyright 2008 Springer Science+Business Media).

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