Shelton D Caruthers

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (120)481.96 Total impact

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    ABSTRACT: Due to their small size, lower cost, short reproduction cycle, and genetic manipulation, rodents have been widely used to test the safety and efficacy for pharmaceutical development in human disease. In this report, MRI cholangiography demonstrated an unexpected rapid (<5min) biliary elimination of gadolinium-perfluorocarbon nanoparticles (approximately 250nm diameter) into the common bile duct and small intestine of rats, which is notably different from nanoparticle clearance patterns in larger animals and humans. Unawareness of this dissimilarity in nanoparticle clearance mechanisms between small animals and humans may lead to fundamental errors in predicting nanoparticle efficacy, pharmacokinetics, biodistribution, bioelimination, and toxicity.
    Nanomedicine: nanotechnology, biology, and medicine 05/2014; · 6.93 Impact Factor
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    ABSTRACT: In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol(®) or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane(®) given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.
    Theranostics 01/2014; 4(6):565-78. · 7.81 Impact Factor
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    ABSTRACT: MR cholangiography shows unexpected, rapid excretion of 250 nm-sized paramagnetic perfluorocarbon nanoparticles into the rat bile duct and small intestine in less than 5 minutes.
    Nanomedicine: Nanotechnology, Biology and Medicine. 01/2014;
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    ABSTRACT: We sought to develop a unique sensor-reporter approach for functional kidney imaging that employs circulating perfluorocarbon nanoparticles and multinuclear (1) H/(19) F MRI. (19) F spin density weighted and T1 weighted images were used to generate quantitative functional mappings of both healthy and ischemia-reperfusion (acute kidney injury) injured mouse kidneys. (1) H blood-oxygenation-level-dependent (BOLD) MRI was also employed as a supplementary approach to facilitate the comprehensive analysis of renal circulation and its pathological changes in acute kidney injury. Heterogeneous blood volume distributions and intrarenal oxygenation gradients were confirmed in healthy kidneys by (19) F MRI. In a mouse model of acute kidney injury, (19) F MRI, in conjunction with blood-oxygenation-level-dependent MRI, sensitively delineated renal vascular damage and recovery. In the cortico-medullary junction region, we observed 25% lower (19) F signal (P < 0.05) and 70% longer (1) H T2* (P < 0.01) in injured kidneys compared with contralateral kidneys at 24 h after initial ischemia-reperfusion injury. We also detected 71% higher (19) F signal (P < 0.01) and 40% lower (1) H T2* (P < 0.05) in the renal medulla region of injured kidneys compared with contralateral uninjured kidneys. Integrated (1) H/(19) F MRI using perfluorocarbon nanoparticles provides a multiparametric readout of regional perfusion defects in acutely injured kidneys. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 08/2013; · 3.27 Impact Factor
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    ABSTRACT: Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which has been unappreciated until recently. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat left pulmonary artery ligation (LPAL) model, which was employed to create pulmonary ischemia and induce angiogenesis. In rats 3 days after LPAL, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following αvβ3-targeted perfluorocarbon nanoparticles [(19)F signal (normalized to background) = 0.80 ± 0.2] that was greater (p = 0.007) than the non-targeted (0.30 ± 0.04) and the sham-operated (0.07 ± 0.09) control groups. Almost no (19)F signal was found in control right lung with any treatment. Competitive blockade of the integrin-targeted particles greatly decreased the (19)F signal (p = 0.002) and was equivalent to the non-targeted control group. Fluorescent and light microscopy illustrated heavy decorating of vessel walls in and around large bronchi and large pulmonary vessels. Focal segmental regions of neovessel expansion were also noted in the lung periphery. Our results demonstrate that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung.
    Angiogenesis 08/2013; · 3.97 Impact Factor
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    ABSTRACT: Purpose:To assess the dependence of neovascular molecular magnetic resonance (MR) imaging on relaxivity (r1) of αvβ3-targeted paramagnetic perfluorocarbon (PFC) nanoparticles and to delineate the temporal-spatial consistency of angiogenesis assessments for individual animals.Materials and Methods:Animal protocols were approved by the Washington University Animal Studies Committee. Proton longitudinal and transverse relaxation rates of αvβ3-targeted and nontargeted PFC nanoparticles incorporating gadolinium diethylenetrianime pentaacedic acid (Gd-DTPA) bisoleate (BOA) or gadolinium tetraazacyclododecane tetraacetic acid (Gd-DOTA) phosphatidylethanolamine (PE) into the surfactant were measured at 3.0 T. These paramagnetic nanoparticles were compared in 30 New Zealand White rabbits (four to six rabbits per group) 14 days after implantation of a Vx2 tumor. Subsequently, serial MR (3.0 T) neovascular maps were developed 8, 14, and 16 days after tumor implantation by using αvβ3-targeted Gd-DOTA-PE nanoparticles (n = 4) or nontargeted Gd-DOTA-PE nanoparticles (n = 4). Data were analyzed with analysis of variance and nonparametric statistics.Results:At 3.0 T, Gd-DTPA-BOA nanoparticles had an ionic r1 of 10.3 L · mmol(-1) · sec(-1) and a particulate r1 of 927 000 L · mmol(-1) · sec(-1). Gd-DOTA-PE nanoparticles had an ionic r1 of 13.3 L · mmol(-1) · sec(-1) and a particulate r1 of 1 197 000 L · mmol(-1) · sec(-1). Neovascular contrast enhancement in Vx2 tumors (at 14 days) was 5.4% ± 1.06 of the surface volume with αvβ3-targeted Gd-DOTA-PE nanoparticles and 3.0% ± 0.3 with αvβ3-targeted Gd-DTPA-BOA nanoparticles (P = .03). MR neovascular contrast maps of tumors 8, 14, and 16 days after implantation revealed temporally consistent and progressive surface enhancement (1.0% ± 0.3, 4.5% ± 0.9, and 9.3% ± 1.4, respectively; P = .0008), with similar time-dependent changes observed among individual animals.Conclusion:Temporal-spatial patterns of angiogenesis for individual animals were followed to monitor longitudinal tumor progression. Neovasculature enhancement was dependent on the relaxivity of the targeted agent.© RSNA, 2013Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13120789/-/DC1.
    Radiology 06/2013; · 6.34 Impact Factor
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    ABSTRACT: PURPOSE: To evaluate the feasibility of prospectively guiding 4-dimensional (4D) magnetic resonance imaging (MRI) image acquisition using triggers at preselected respiratory amplitudes to achieve T(2) weighting for abdominal motion tracking. METHODS AND MATERIALS: A respiratory amplitude-based triggering system was developed and integrated into a commercial turbo spin echo MRI sequence. Initial feasibility tests were performed on healthy human study participants. Four respiratory states, the middle and the end of inhalation and exhalation, were used to trigger 4D MRI image acquisition of the liver. To achieve T(2) weighting, the echo time and repetition time were set to 75 milliseconds and 4108 milliseconds, respectively. Single-shot acquisition, together with parallel imaging and partial k-space imaging techniques, was used to improve image acquisition efficiency. 4D MRI image sets composed of axial or sagittal slices were acquired. RESULTS: Respiratory data measured and logged by the MRI scanner showed that the triggers occurred at the appropriate respiratory levels. Liver motion could be easily observed on both 4D MRI image datasets by sensing either the change of liver in size and shape (axial) or diaphragm motion (sagittal). Both 4D MRI image datasets were T(2)-weighted as expected. CONCLUSIONS: This study demonstrated the feasibility of achieving T(2)-weighted 4D MRI images using amplitude-based respiratory triggers. With the aid of the respiratory amplitude-based triggering system, the proposed method is compatible with most MRI sequences and therefore has the potential to improve tumor-tissue contrast in abdominal tumor motion imaging.
    International journal of radiation oncology, biology, physics 02/2013; · 4.59 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). · 4.44 Impact Factor
  • Expert Review of Cardiovascular Therapy 12/2012; 10(12):1459-61.
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    ABSTRACT: Rationale: Cardiomyocyte organization is a critical determinant of coordinated cardiac contractile function. Because of the acute opening of the pulmonary circulation, the relative workload of the left ventricle (LV) and right ventricle (RV) changes substantially immediately after birth. We hypothesized that three dimensional cardiomyocyte architecture might be required to adapt rapidly to accommodate programmed perinatal changes of cardiac function. Materials and Methods: Isolated fixed hearts from pig fetuses or pigs at mid-gestation, pre-born, postnatal day 1 (P1), P5, P14, and adulthood were acquired for diffusion-weighted magnetic resonance imaging (DTMRI). Cardiomyocyte architecture was visualized by 3D fiber tracking and was quantitatively evaluated by the measured helix angle (α(h)). Upon the completion of MRI, hearts were sectioned and stained with hematoxylin/eosin to evaluate cardiomyocyte alignment; with picrosirius red to evaluate collagen content; and with anti-Ki67 to evaluate postnatal cell proliferation. Results: The helical architecture of cardiomyocyte was observed as early as the mid-gestational period. Post-natal changes of cardiomyocyte architecture were observed from P1 to P14, which primary occurred in the septum and RV free wall (RVFW). In the septum, the volume ratio of LV- vs. RV-associated cardiomyocytes rapidly changed from RV-LV balanced pattern at birth to LV dominant pattern by P14. In the RVFW, subendocardial α(h) decreased by approximately 30° from P1 to P14. Conclusions: The helical architecture of cardiomyocyte is developed as early as the mid-gestation period. Substantial and rapid adaptive changes in cardiac microarchitecture suggested considerable developmental plasticity of cardiomyocyte form and function in the postnatal period.
    AJP Heart and Circulatory Physiology 11/2012; · 3.63 Impact Factor
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    ABSTRACT: We present a novel blood flow-enhanced-saturation-recovery (BESR) sequence, which allows rapid in vivo T(1) measurement of blood for both (1) H and (19) F nuclei. BESR sequence is achieved by combining homogeneous spin preparation and time-of-flight image acquisition and therefore preserves high time efficiency and signal-to-noise ratio for (19) F imaging of circulating perfluorocarbon nanoparticles comprising a perfluoro-15-crown-5-ether core and a lipid monolayer (nominal size = 250 nm). The consistency and accuracy of the BESR sequence for measuring T(1) of blood was validated experimentally. With a confirmed linear response feature of (19) F R(1) with oxygen tension in both salt solution and blood sample, we demonstrated the feasibility of the BESR sequence to quantitatively determine the oxygen tension within mouse left and right ventricles under both normoxia and hyperoxia conditions. Thus, (19) F BESR MRI of circulating perfluorocarbon nanoparticles represents a new approach to noninvasively evaluate intravascular oxygen tension. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 08/2012; · 3.27 Impact Factor
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    ABSTRACT: Cardiac dysfunction is a primary cause of patient mortality in Duchenne muscular dystrophy, potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between calcium mishandling and myocardial fiber/sheet function as a manifestation of dystrophin-deficient (mdx) cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx (N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate calcium concentrations. Optical mapping of calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular calcium reuptake, reflected by a 25% increase of decay times (T(50)) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with calcium mishandling, ultimately culminating in increased fibrosis. The preservation of relatively normal calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic calcium, points to the significance of regional mechanical factors in the progression of the disease.
    AJP Heart and Circulatory Physiology 07/2012; 303(5):H559-68. · 3.63 Impact Factor
  • Y Hu, S Caruthers, D Low, P Parikh, S Mutic
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    ABSTRACT: Purpose: To develop a practical triggering system based on pre-selected respiratory amplitudes to guide prospectively the image acquisition of 4DMRI to track abdominal tumor motion for radiotherapy treatment planning. Methods: The proposed triggering scheme consists of a preparation stage and an acquisition stage. Immediately prior to MRI acquisition, the preparation stage monitors the respiration via an external respiratory belt. Based on the respiratory amplitude and status (i.e., inhalation↑ or exhalation↓), the respiration cycle is equally divided into N respiratory states. For example, in the 4-state case, the 4 respiratory states are 5%↓", 50%↑, 95%↑ and 50%↓. The 5%↓ and 95%↑ are used instead of 0% and 100% to improve the robustness of the triggering system. Each state is associated with a trigger which starts image acquisition for one and only one slice. A complete 4DMRI imageset requires N dynamic scans. In each dynamic scan, all slices are acquired once and each is in a specific respiratory state. In different dynamic scans, each slice is associated with different respiratory states to form a 4D dataset. For proof-of-principle, the triggering system was integrated into a T2-weighted turbo spin echo sequence (TE=100ms, TR=7122ms) on a clinical 1.5T MRI (Philips Achieva) scanner. The 4-state case was tested on a healthy subject. Results: Plots of the physiology data recorded and exported from the scanner clearly verified that triggers occurred at the expected locations. Four T2-weighted images from a representative slice recorded the liver motion corresponding to the 4 respiratory states. Conclusions: Our results confirmed that the newly-developed system could trigger prospectively to guide 4DMRI image acquisition to achieve T2 weighting, which has a better tumor-tissue contrast than those offered by previous 4DMRI techniques with T1 or T2/T1 weighting. This is a first report of a pure T2-weighted 4DMRI to track respiration induced abdominal motion.
    Medical Physics 06/2012; 39(6):3971. · 2.91 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:M8. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:P136. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:O11. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:O41. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:O31. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:O42. · 4.44 Impact Factor

Publication Stats

3k Citations
481.96 Total Impact Points

Institutions

  • 2003–2014
    • Washington University in St. Louis
      • • Department of Medicine
      • • Division of Cardiovascular Division
      • • Department of Biomedical Engineering
      San Luis, Missouri, United States
  • 2003–2012
    • University of Washington Seattle
      • • Division of Cardiology
      • • Department of Medicine
      Seattle, WA, United States
  • 2008–2011
    • Philips
      Eindhoven, North Brabant, Netherlands
  • 2010
    • University of Toronto
      • Department of Medical Imaging
      Toronto, Ontario, Canada
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
  • 2009
    • Washington & Lee University
      Lexington, Virginia, United States
  • 2007
    • Northwestern University
      Evanston, Illinois, United States
  • 2005
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 2003–2005
    • Barnes Jewish Hospital
      San Luis, Missouri, United States