Dual-modal magnetic resonance and fluorescence imaging of atherosclerotic plaques in vivo using VCAM-1 targeted tobacco mosaic virus.
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SUBMITTER: Bruckman MA
PROVIDER: S-EPMC4169141 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeIntracranial atherosclerosis is one of the main causes of stroke, and high-resolution magnetic resonance imaging provides useful imaging biomarkers related to the risk of ischemic events. This study aims to evaluate differences in histogram features between culprit and nonculprit intracranial atherosclerosis using high-resolution magnetic resonance imaging.MethodsTwo hundred forty-seven patients with intracranial atherosclerosis who underwent high-resolution magnetic resonance imaging sequentially between January 2015 and December 2016 were recruited. Quantitative features, including stenosis, plaque burden, minimum luminal area, intraplaque hemorrhage, enhancement ratio, and dispersion of signal intensity (coefficient of variation), were analyzed based on T2-, T1-, and contrast-enhanced T1-weighted images. Step-wise regression analysis was used to identify key determinates differentiating culprit and nonculprit plaques and to calculate the odds ratios (ORs) with 95% CIs.ResultsIn total, 190 plaques were identified, of which 88 plaques (37 culprit and 51 nonculprit) were located in the middle cerebral artery and 102 (57 culprit and 45 nonculprit) in the basilar artery. Nearly 90% of culprit lesions had a degree of luminal stenosis of <70%. Multiple logistic regression analyses showed that intraplaque hemorrhage (OR, 16.294 [95% CI, 1.043-254.632]; P=0.047), minimum luminal area (OR, 1.468 [95% CI, 1.032-2.087]; P=0.033), and coefficient of variation (OR, 13.425 [95% CI, 3.987-45.204]; P<0.001) were 3 significant features in defining culprit plaques in middle cerebral artery. The enhancement ratio (OR, 9.476 [95% CI, 1.256-71.464]; P=0.029), intraplaque hemorrhage (OR, 2.847 [95% CI, 0.971-10.203]; P=0.046), and coefficient of variation (OR, 10.068 [95% CI, 2.820-21.343]; P<0.001) were significantly associated with plaque type in basilar artery. Coefficient of variation was a strong independent predictor in defining plaque type for both middle cerebral artery and basilar artery with sensitivity, specificity, and accuracy being 0.79, 0.80, and 0.80, respectively.ConclusionsFeatures characterized by high-resolution magnetic resonance imaging provided complementary values over luminal stenosis in defined lesion type for intracranial atherosclerosis; the dispersion of signal intensity in histogram analysis was a particularly effective predictive parameter.
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Project description:The increasing prevalence of ultra-high-field magnetic resonance imaging (UHFMRI) in biomedical research and clinical settings will improve the resolution and diagnostic accuracy of MRI scans. However, better contrast agents are needed to achieve a satisfactory signal-to-noise ratio. Here, we report the synthesis of a bimodal contrast agent prepared by loading the internal cavity of tobacco mosaic virus (TMV) nanoparticles with a dysprosium (Dy3+) complex and the near-infrared fluorescence (NIRF) dye Cy7.5. The external surface of TMV was conjugated with an Asp-Gly-Glu-Ala (DGEA) peptide via a polyethylene glycol linker to target integrin ?2?1. The resulting nanoparticle (Dy-Cy7.5-TMV-DGEA) was stable and achieved a high transverse relaxivity in ultra-high-strength magnetic fields (326 and 399 mM-1 s-1 at 7 and 9.4 T, respectively). The contrast agent was also biocompatible (low cytotoxicity) and targeted PC-3 prostate cancer cells and tumors in vitro and in vivo as confirmed by bimodal NIRF imaging and T2-mapping UHFMRI. Our results show that Dy-Cy7.5-TMV-DGEA is suitable for multiscale MRI scanning from the cellular level to the whole body, particularly in the context of UHFMRI applications.
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Project description:Despite the contribution of changes in pancreatic ?-cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic-resonance imaging (MRI) provides a potentially useful technique, targeting MRI-active probes to the ? cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual-modal probes based on transition-metal chelates capable of binding zinc. The first of these, Gd?1, binds Zn(II) directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from ?em =410 to 500?nm with an increase in relaxivity from r1 =4.2 up to 4.9?mM(-1) ?s(-1) . The probe is efficiently accumulated into secretory granules in ?-cell-derived lines and isolated islets, but more poorly by non-endocrine cells, and leads to a reduction in T1 in human islets. In vivo murine studies of Gd?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140?minutes.
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Project description:Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. Myeloperoxidase is a central inflammatory enzyme secreted by activated macrophages and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance agent can visualize myeloperoxidase activity in atherosclerotic plaques in a rabbit model.We performed magnetic resonance imaging of the thoracic aorta of New Zealand White rabbits fed a cholesterol (n=14) or normal (n=4) diet up to 2 hours after injection of the myeloperoxidase sensor bis-5HT-DTPA(Gd) [MPO(Gd)], the conventional agent DTPA(Gd), or an MPO(Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hours after injection) showed focal areas of increased contrast (>2-fold) in diseased wall but not in normal wall (P=0.84) compared with both DTPA(Gd) (n=11; P<0.001) and bis-tyr-DTPA(Gd) (n=3; P<0.05). Biochemical assays confirmed that diseased wall possessed 3-fold elevated myeloperoxidase activity compared with normal wall (P<0.01). Areas detected by MPO(Gd) imaging colocalized and correlated with myeloperoxidase-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, P<0.0001). Although macrophages were the main source of myeloperoxidase, not all macrophages secreted myeloperoxidase, which suggests that distinct subpopulations contribute differently to atherogenesis and supports our functional approach.The present study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme to noninvasively provide both anatomic and functional information in vivo.
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Project description:Nanoprobes that offer both fluorescence imaging (FI) and magnetic resonance imaging (MRI) can provide supplementary information and hold synergistic advantages. However, synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups, high stability, great biocompatibility and desired dual-modality imaging results remains challenging. In this study, we used an amphiphilic block polymer from (ethylene glycol) methyl ether methacrylate (OEGMA) and N-(2-hydroxypropyl) methacrylamide (HPMA) derivatives as a carrier to conjugate a MR contrast agent, Gd-DOTA, and a two-photon fluorophore with an aggregation-induced emission (AIE) effect, TPBP, to construct a MR/two-photon fluorescence dual-modality contrast agent, Gd-DOTA-TPBP. Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r 1 value for Gd-DOTA-TPBP, revealing a great MR imaging resolution. The contrast agent specifically accumulated in the tumor region, allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging. Meanwhile, coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity, but also significantly enhanced its imaging performance in an aqueous phase. Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI. Since high-resolution, complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP, it has great potential in the early phase of disease diagnosis.
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Project description:The development of an effective method for staging liver fibrosis has always been a hot topic of research in the field of liver fibrosis. In this paper, PEGylated ultrafine superparamagnetic iron oxide nanocrystals (SPIO@PEG) were developed for T1-T2 dual-modal contrast-enhanced magnetic resonance imaging (MRI) and combined with Matrix Laboratory (MATLAB)-based image fusion for staging liver fibrosis in the rat model. Firstly, SPIO@PEG was synthesized and characterized with physical and biological properties as a T1-T2 dual-mode MRI contrast agent. Secondly, in the subsequent MR imaging of liver fibrosis in rats in vivo, conventional T1 and T2-weighted imaging, and T1 and T2 mapping of the liver pre- and post-intravenous administration of SPIO@PEG were systematically collected and analyzed. Thirdly, by creative design, we fused the T1 and T2 mapping images by MATLAB and quantitively measured each rat's hepatic fibrosis positive pixel ratio (PPR). SPIO@PEG was proved to have an ultrafine core size (4.01 ± 0.16 nm), satisfactory biosafety and T1-T2 dual-mode contrast effects under a 3.0 T MR scanner (r2/r1 = 3.51). According to the image fusion results, the SPIO@PEG contrast-enhanced PPR shows significant differences among different stages of liver fibrosis (P < 0.05). The combination of T1-T2 dual-modal SPIO@PEG and MATLAB-based image fusion technology could be a promising method for diagnosing and staging liver fibrosis in the rat model. PPR could also be used as a non-invasive biomarker to diagnose and discriminate the stages of liver fibrosis.
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Project description:ObjectiveIn vivo visualization of intracranial atherosclerotic plaque has been performed only with high-resolution magnetic resonance imaging (HRMR). We investigated whether atherosclerotic plaque of the basilar artery (BA) can be identified in conventional magnetic resonance imaging (MRI).MethodsPatients with acute ischemic stroke who had BA stenosis ("symptomatic BAA") were retrospectively recruited using the prospective stroke registry. In the HRMR databank, subjects without BA stenosis were recruited and classified as those with silent plaque ("silent BAA") and without any plaque ("normal controls"). Outer diameter of the BA and T2 plaque sign (an eccentric or complete obscuration of normal flow-void) within the BA were assessed by two blinded raters using conventional T2 MRI.ResultsSeventy-five patients with symptomatic BAA, 40 with asymptomatic BAA, and 36 normal controls were included in the study. Maximal BA diameter was significantly larger in symptomatic BAA patients with <30%, 30-50%, 50-70%, and >70% stenosis (all p<0.01 in each subgroup) and silent BAA subjects (p = 0.018) than controls. T2 plaque signs were present in 46 (61.3%) patients with symptomatic BAA and 6 (14.6%) subjects with asymptomatic BAA, while none in normal controls (p <0.001 and 0.057, respectively). Detection rates were increased with an increase in stenosis degree (25.0% in <30% stenosis, 57.9% in 30-50% stenosis, 38.5% in 50-70% stenosis, 92.3% in 70-99% stenosis, and 100.0% in occlusion).ConclusionsOur data suggest that BA atherosclerosis can be detected by conventional MRI. When the use of HRMR is limited, conventional MR imaging may give additive information to clinicians.
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Project description:Atherosclerosis is an inflammatory disease of arterial walls and the rupturing of atherosclerotic plaques is a major cause of heart attack and stroke. Imaging techniques that can enable the detection of atherosclerotic plaques before clinical manifestation are urgently needed. Magnetic resonance imaging (MRI) is a powerful technique to image the morphology of atherosclerotic plaques. In order to better analyze molecular processes in plaques, contrast agents that can selectively bind to plaque receptors will prove invaluable. CD44 is a cell surface protein overexpressed in plaque tissues, the level of which can be correlated with the risks of plaque rupture. Thus, targeting CD44 is an attractive strategy for detection of atherosclerotic plaques. Herein, we report the synthesis of hyaluronan-conjugated iron oxide nanoworms (HA-NWs). A new purification and gel electrophoresis protocol was developed to ensure the complete removal of free HA from HA-NWs. Compared to the more traditional spherical HA-bearing nanoparticles, HA-NWs had an elongated shape, which interacted much stronger with CD44-expressing cells in CD44- and HA-dependent manners. Furthermore, the HA-NWs did not induce much inflammatory response compared to the spherical HA nanoparticles. When assessed in vivo, HA-NWs enabled successful imaging of atherosclerotic plaques in a clinically relevant model of ApoE knockout transgenic mice for noninvasive plaque detection by MRI. Thus, nanoprobe shape engineering can be a useful strategy to significantly enhance their desired biological properties.
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Project description:Nanotheranostic reagents that integrate magnetic resonance imaging (MRI) and photothermal therapy (PTT) offer a promising strategy for the treatment of human disease. However, classic gadolinium (Gd)-based T1-MRI contrast agents are limited by their low relaxivity. To address this, we produced Gd-loaded Tobacco mosaic virus (TMV) particles coated with the mussel-inspired biopolymer polydopamine (PDA). Such biocompatible nanotheranostic reagents can be used to facilitate PTT, guided by multimodal magnetic resonance/photoacoustic imaging. The r1-relaxivity of the Gd-TMV-PDA particles at 60 MHz was ?80 mM-1 s-1, compared to 13.63 mM-1 s-1 for the uncoated Gd-TMV particles. The Gd-TMV-PDA particles also promoted strong near-infrared absorption with high photothermal conversion efficiency (28.9%) and demonstrated excellent photoacoustic contrast. Multimodal imaging and PTT resulted in the effective killing of PC-3 prostate cancer cells. Gd-TMV-PDA nanoparticles therefore offer a promising theranostic approach that can now be tested in vivo in cancer models.
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