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      Hybrid, metal oxide-peptide amphiphile micelles for molecular magnetic resonance imaging of atherosclerosis

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          Atherosclerosis, a major source of cardiovascular disease, is asymptomatic for decades until the activation of thrombosis and the rupture of enlarged plaques, resulting in acute coronary syndromes and sudden cardiac arrest. Magnetic resonance imaging (MRI) is a noninvasive nuclear imaging technique to assess the degree of atherosclerotic plaque with high spatial resolution and excellent soft tissue contrast. However, MRI lacks sensitivity for preventive medicine, which limits the ability to observe the onset of vulnerable plaques. In this study, we engineered hybrid metal oxide-peptide amphiphile micelles (HMO-Ms) that combine an inorganic, magnetic iron oxide or manganese oxide inner core with organic, fibrin-targeting peptide amphiphiles, consisting of the sequence CREKA, for potential MRI imaging of thrombosis on atherosclerotic plaques.


          Hybrid metal oxide-peptide amphiphile micelles, consisting of an iron oxide (Fe-Ms) or manganese oxide (Mn-Ms) core with CREKA peptides, were self-assembled into 20–30 nm spherical nanoparticles, as confirmed by dynamic light scattering and transmission electron microscopy. These hybrid nanoparticles were found to be biocompatible with human aortic endothelial cells in vitro, and HMO-Ms bound to human clots three to five times more efficiently than its non-targeted counterparts. Relaxivity studies showed ultra-high r 2 value of 457 mM −1 s −1 and r 1 value of 0.48 mM −1 s −1 for Fe-Ms and Mn-Ms, respectively. In vitro, MR imaging studies demonstrated the targeting capability of CREKA-functionalized hybrid nanoparticles with twofold enhancement of MR signals.


          This novel hybrid class of MR agents has potential as a non-invasive imaging method that specifically detects thrombosis during the pathogenesis of atherosclerosis.

          Electronic supplementary material

          The online version of this article (10.1186/s12951-018-0420-8) contains supplementary material, which is available to authorized users.

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          Most cited references 46

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          Gold nanocages covered by smart polymers for controlled release with near-infrared light

          Photosensitive caged compounds have enhanced our ability to address the complexity of biological systems by generating effectors with remarkable spatial/temporal resolutions1-3. The caging effect is typically removed by photolysis with ultraviolet light to liberate the bioactive species. Although this technique has been successfully applied to many biological problems, it suffers from a number of intrinsic drawbacks. For example, it requires dedicated efforts to design and synthesize a precursor compound to the effector. The ultraviolet light may cause damage to biological samples and is only suitable for in vitro studies because of its quick attenuation in tissue4. Here we address these issues by developing a platform based on the photothermal effect of gold nanocages. Gold nanocages represent a class of nanostructures with hollow interiors and porous walls5. They can have strong absorption (for the photothermal effect) in the near-infrared (NIR) while maintaining a compact size. When the surface of a gold nanocage is covered with a smart polymer, the pre-loaded effector can be released in a controllable fashion using a NIR laser. This system works well with various effectors without involving sophiscated syntheses, and is well-suited for in vivo studies due to the high transparency of soft tissue in NIR6.
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            Pathogenesis of atherosclerosis.

             Erling Falk (2006)
            Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease of medium-sized and large arteries fuelled by lipids. Endothelial cells, leukocytes, and intimal smooth muscle cells are the major players in the development of this disease. The most devastating consequences of atherosclerosis, such as heart attack and stroke, are caused by superimposed thrombosis. Therefore, the vital question is not why atherosclerosis develops but rather why atherosclerosis, after years of indolent growth, suddenly becomes complicated with luminal thrombosis. If thrombosis-prone plaques could be detected and thrombosis averted, atherosclerosis would be a much more benign disease. Approximately 76% of all fatal coronary thrombi are precipitated by plaque rupture. Plaque rupture is a more frequent cause of coronary thrombosis in men (approximately 80%) than in women (approximately 60%). Ruptured plaques are characterized by a large lipid-rich core, a thin fibrous cap that contains few smooth muscle cells and many macrophages, angiogenesis, adventitial inflammation, and outward remodeling. Plaque rupture is the most common cause of coronary thrombosis. Ruptured plaques and, by inference, rupture-prone plaques have characteristic pathoanatomical features that might be useful for their detection in vivo by imaging. This article describes the pathogenesis of atherosclerosis, how it begets thrombosis, and the possibility to detect thrombosis-prone plaques and prevent heart attack.
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              Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery.

              Highly versatile nanocomposite nanoparticles were synthesized by decorating the surface of mesoporous dye-doped silica nanoparticles with multiple magnetite nanocrystals. The superparamagnetic property of the magnetite nanocrystals enabled the nanoparticles to be used as a contrast agent in magnetic resonance (MR) imaging, and the dye molecule in the silica framework imparted optical imaging modality. Integrating a multitude of magnetite nanocrystals on the silica surface resulted in remarkable enhancement of MR signal due to the synergistic magnetism. An anticancer drug, doxorubicin (DOX), could be loaded in the pores and induced efficient cell death. In vivo passive targeting and accumulation of the nanoparticles at the tumor sites was confirmed by both T2 MR and fluorescence imaging. Furthermore, apoptotic morphology was clearly detected in tumor tissues of mice treated with DOX loaded nanocomposite nanoparticles, demonstrating that DOX was successfully delivered to the tumor sites and its anticancer activity was retained.

                Author and article information

                +1-213-740-2825 ,
                J Nanobiotechnology
                J Nanobiotechnology
                Journal of Nanobiotechnology
                BioMed Central (London )
                15 November 2018
                15 November 2018
                : 16
                [1 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Biomedical Engineering, , University of Southern California, ; 1042 Downey Way, Los Angeles, CA 90089 USA
                [2 ]ISNI 0000 0004 0521 6935, GRID grid.420330.6, Advanced (Magnetic) Theranostic Nanostructures Lab, Department of Life Sciences, , International Iberian Nanotechnology Laboratory, ; Avenida Mestre José Veiga, Braga, Portugal
                [3 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Materials Science and Chemical Engineering, , University of Southern California, ; 925 Bloom Walk, Los Angeles, CA 90089 USA
                [4 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                [5 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                [6 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Norris Comprehensive Cancer Center, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef, National Heart, Lung, and Blood Institute;
                Award ID: R00HL124279
                Award Recipient :
                Funded by: FundRef, Eli and Edythe Broad Foundation;
                Funded by: FundRef, L. K. Whittier Foundation;
                Funded by: North Portugal Regional Operational Programme
                Funded by: FundRef, European Regional Development Fund;
                Funded by: H2020 European Union's Research and Innovation
                Award ID: Nº686009
                Award Recipient :
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                © The Author(s) 2018


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