Center for Imaging Research and Education

Eindhoven, Netherlands

Center for Imaging Research and Education

Eindhoven, Netherlands

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Motaal A.G.,TU Eindhoven | Motaal A.G.,Center for Imaging Research and Education | Noorman N.,TU Eindhoven | Noorman N.,Center for Imaging Research and Education | And 8 more authors.
International Journal of Cardiovascular Imaging | Year: 2014

Abstract: We introduce a fast protocol for ultra-short echo time (UTE) Cine magnetic resonance imaging (MRI) of the beating murine heart. The sequence involves a self-gated UTE with golden-angle radial acquisition and compressed sensing reconstruction. The self-gated acquisition is performed asynchronously with the heartbeat, resulting in a randomly undersampled kt-space that facilitates compressed sensing reconstruction. The sequence was tested in 4 healthy rats and 4 rats with chronic myocardial infarction, approximately 2 months after surgery. As a control, a non-accelerated self-gated multi-slice FLASH sequence with an echo time (TE) of 2.76 ms, 4.5 signal averages, a matrix of 192 × 192, and an acquisition time of 2 min 34 s per slice was used to obtain Cine MRI with 15 frames per heartbeat. Non-accelerated UTE MRI was performed with TE = 0.29 ms, a reconstruction matrix of 192 × 192, and an acquisition time of 3 min 47 s per slice for 3.5 averages. Accelerated imaging with 2×, 4× and 5× undersampled kt-space data was performed with 1 min, 30 and 15 s acquisitions, respectively. UTE Cine images up to 5× undersampled kt-space data could be successfully reconstructed using a compressed sensing algorithm. In contrast to the FLASH Cine images, flow artifacts in the UTE images were nearly absent due to the short echo time, simplifying segmentation of the left ventricular (LV) lumen. LV functional parameters derived from the control and the accelerated Cine movies were statistically identical. © 2014, Springer Science+Business Media Dordrecht.


Sanches P.G.,TU Eindhoven | Sanches P.G.,Center for Imaging Research and Education | Muhlmeister M.,Radboud University Nijmegen | Seip R.,Philips | And 8 more authors.
Journal of Controlled Release | Year: 2014

Localized gene delivery has many potential clinical applications. However, the nucleic acids (e.g. pDNA and siRNA) are incapable of passively crossing the endothelium, cell membranes and other biological barriers which must be crossed to reach their intracellular targets. A possible solution is the use of ultrasound to burst circulating microbubbles inducing transient permeabilization of surrounding tissues which mediates nucleic acid extravasation and cellular uptake. In this study we report on an optimization of the ultrasound gene delivery technique. Naked pDNA (200 μg) encoding luciferase and SonoVue® microbubbles were co-injected intravenously in mice. The hindlimb skeletal muscles were exposed to ultrasound from a non-focused transducer (1 MHz, 1.25 MPa, PRI 30 s) and injection protocols and total amounts as well as ultrasound parameters were systemically varied. Gene expression was quantified relative to a control using a bioluminescence camera system at day 7 after sonication. Bioluminescence ratios in sonicated/control muscles of up to 101 × were obtained. In conclusion, we were able to specifically deliver genetic material to the selected skeletal muscles and overall, the use of bolus injections and high microbubble numbers resulted in increased gene expression reflected by stronger bioluminescence signals. Based on our data, bolus injections seem to be required in order to achieve transient highly concentrated levels of nucleic acids and microbubbles at the tissue of interest which upon ultrasound exposure should lead to increased levels of gene delivery. Thus, ultrasound mediated gene delivery is a promising technique for the clinical translation of localized drug delivery. © 2014 Elsevier B.V. All rights reserved.


Yeo S.Y.,TU Eindhoven | Yeo S.Y.,Center for Imaging Research and Education | De Smet M.,TU Eindhoven | De Smet M.,Center for Imaging Research and Education | And 8 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2014

Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn 2 +) or [Gd(HPDO3A)(H2O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity (r1) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r1 will increase and hence, provides a means to monitor drug distribution in situ. Here, the effects of encapsulated CAs on the phospholipid bilayer and the resulting change in r1 were investigated using MR titration studies and 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. Our results show that Mn2 + interacted with the phospholipid bilayer of TSLs and consequently, reduced doxorubicin retention capability at 37 °C within the interior of the liposomes over time. Despite that, Mn2 +-phospholipid interaction resulted in higher r1 increase, from 5.1 ± 1.3 mM- 1 s- 1 before heating to 32.2 ± 3 mM - 1 s- 1 after heating at 60 MHz and 37 °C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2 ± 0.3 mM- 1 s- 1 and 4.4 ± 0.3 mM- 1 s- 1, respectively. Upon heating, Dox was released from TSL(Mn,Dox) and complexation of Mn2 + to Dox resulted in a similar Mn2 + release profile. From 25 to 38 °C, r1 of [Gd(HPDO3A)(H2O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38 °C, the release of [Gd(HPDO3A)(H2O)] and Dox was irreversible and the release profiles coincided. By understanding the non-covalent interactions between the MRI CAs and phospholipid bilayer, the properties of the paramagnetic TSLs can be tailored for MR guided drug delivery. © 2014 Published by Elsevier B.V.


Starmans L.W.E.,TU Eindhoven | Starmans L.W.E.,Center for Imaging Research and Education | Van Duijnhoven S.M.J.,TU Eindhoven | Van Duijnhoven S.M.J.,Center for Imaging Research and Education | And 11 more authors.
Molecular Pharmaceutics | Year: 2013

Fibrin targeting is an attractive strategy for nuclear imaging of thrombosis, atherosclerosis and cancer. Recently, FibPep, an 111In-labeled fibrin-binding peptide, was established as a tracer for fibrin SPECT imaging and was reported to allow sensitive detection of minute thrombi in mice using SPECT. In this study, we developed EPep, a novel 111In-labeled fibrin-binding peptide containing the fibrin-binding domain of the clinically verified EP-2104R peptide, and sought to compare the potential of EPep and FibPep as tracers for fibrin SPECT imaging. In vitro, both EPep and FibPep showed high stability in serum, but were less stable in liver and kidney homogenate assays. Both peptide probes displayed comparable affinities toward human and mouse derived fibrin (Kd ≈ 1 μM), and similarly to FibPep, EPep showed fast blood clearance, low nontarget uptake and high thrombus uptake (6.8 ± 1.2% ID g-1) in a mouse carotid artery thrombosis model. Furthermore, EPep showed a similar affinity toward rat derived fibrin (Kd ≈ 1 μM), displayed high thrombus uptake in a rat carotid artery thrombosis model (0.74 ± 0.39% ID g -1), and allowed sensitive detection of thrombosis in rats using SPECT. In contrast, FibPep displayed a significantly lower affinity toward rat derived fibrin (Kd ≈ 14 μM) and low uptake in rat thrombi (0.06 ± 0.02% ID g-1) and did not allow clear visualization of carotid artery thrombosis in rats using SPECT. These results were confirmed ex vivo by autoradiography, which showed a 7-fold higher ratio of activity in the thrombus over the contralateral carotid artery for EPep in comparison to FibPep. These findings suggest that the FibPep binding fibrin epitope is not fully homologous between humans and rats, and that preclinical rat models of disease should not be employed to gauge the clinical potential of FibPep. In conclusion, both peptides showed approximately similar metabolic stability and affinity toward human and mouse derived fibrin, and displayed high thrombus uptake in a mouse carotid artery thrombosis model. Therefore, both EPep and FibPep are promising fibrin targeted tracers for translation into clinical settings to serve as novel tools for molecular imaging of fibrin. © 2013 American Chemical Society.


Van Duijnhoven S.M.J.,TU Eindhoven | Van Duijnhoven S.M.J.,Center for Imaging Research and Education | Robillard M.S.,Center for Imaging Research and Education | Robillard M.S.,Philips | And 8 more authors.
Molecular Pharmaceutics | Year: 2014

The noninvasive imaging of matrix metalloproteinases (MMPs) activity in postischemic myocardial tissue holds great promise to predict cardiac function post-myocardial infarction. Consequently, development of MMP specific molecular imaging probes for noninvasive visualization and quantification of MMP activity is of great interest. A novel MMP imaging strategy is based on activatable cell-penetrating peptide probes (ACPP) that are sensitive to the proteolytic activity of MMP-2 and -9. The MMP-mediated activation of these ACPPs drives probe accumulation at the target site. The aim of this study was the development and characterization of radiolabeled MMP-2/9 sensitive ACPPs to assess MMP activity in myocardial remodeling in vivo. Specifically, a short and long-circulating MMP activatable cell-penetrating imaging probe (ACPP and Alb-ACPP, respectively; the latter is an ACPP modified with an albumin binding ligand that prolongs blood clearance) were successfully synthesized and radiolabeled. Subsequently, their biodistributions were determined in vivo in a Swiss mouse model of myocardial infarction. Both peptide probes showed a significantly higher uptake in infarcted myocardium compared to remote myocardium. The biodistribution for dual-isotope radiolabeled probes, which allowed us to discriminate between uncleaved ACPP and activated ACPP, showed increased retention of activated ACPP and activated Alb-ACPP in infarcted myocardium compared to remote myocardium. The enhanced retention correlated to gelatinase levels determined by gelatin zymography, whereas no correlation was found for the negative control: an MMP-2/9 insensitive non-ACPP. In conclusion, radiolabeled MMP sensitive ACPP probes enable to assess MMP activity in the course of remodeling post-myocardial infarction in vivo. Future research should evaluate the feasibility and the predictive value of the ACPP strategy for assessing MMP activity as a main player in postinfarction myocardial remodeling in vivo. © 2014 American Chemical Society.


Hijnen N.,TU Eindhoven | Hijnen N.,Center for Imaging Research and Education | Langereis S.,Philips | Langereis S.,Center for Imaging Research and Education | And 3 more authors.
Advanced Drug Delivery Reviews | Year: 2014

Magnetic resonance guided high-intensity focused ultrasound (MR-HIFU) is a versatile technology platform for noninvasive thermal therapies in oncology. Since MR-HIFU allows heating of deep-seated tissue to well-defined temperatures under MR image guidance, this novel technology has great potential for local heat-mediated drug delivery from temperature-sensitive liposomes (TSLs). In particular, MR provides the ability for image guidance of the drug delivery when an MRI contrast agent is co-encapsulated with the drug in the aqueous lumen of the liposomes. Monitoring of the tumor drug coverage offers possibilities for a personalized thermal treatment in oncology. This review focuses on MR-HIFU as a noninvasive technology platform, temperature-sensitive liposomal formulations for drug delivery and image-guided drug delivery, and the effect of HIFU-induced hyperthermia on the TSL and drug distribution. Finally, the opportunities and challenges of localized MR-HIFU-mediated drug delivery from temperature-sensitive liposomes in oncology are discussed. © 2014 Elsevier B.V.


Hectors S.J.C.G.,TU Eindhoven | Hectors S.J.C.G.,Center for Imaging Research and Education | Jacobs I.,TU Eindhoven | Jacobs I.,Center for Imaging Research and Education | And 4 more authors.
Magnetic Resonance in Medicine | Year: 2014

Purpose: In this study, the suitability of amide proton transfer (APT) imaging as a biomarker for the characterization of high intensity focused ultrasound (HIFU)-treated tumor tissue was assessed. Methods: APT imaging was performed on tumor-bearing mice before (n=15), directly after (n=15) and at 3 days (n=8) after HIFU treatment. A control group (n=7) of nontreated animals was scanned at the same time points. Histogram analysis of the tumor APT-weighted signal distributions was performed to assess HIFU-induced changes in the tumor APT contrast. Results: Distinct regions of decreased APT-weighted signal were observed at both time points after HIFU treatment. Analysis of the tumor APT-weighted signal distribution showed a pronounced shift toward lower APT-weighted signal values after HIFU treatment. A significantly increased fraction of pixels with an APT-weighted signal value between-10 and-2% was observed both directly (0.37±0.16) and at 3 days (0.49±0.16) after HIFU treatment as compared to baseline (0.2260.16). Conclusion: The presented results show that APT imaging is sensitive to HIFU-induced changes in tumor tissue and may thus serve as a new biomarker for monitoring the response of tumor tissue to HIFU treatment. © 2013 Wiley Periodicals, Inc.


Hectors S.J.C.G.,TU Eindhoven | Hectors S.J.C.G.,Center for Imaging Research and Education | Moonen R.P.M.,TU Eindhoven | Moonen R.P.M.,Center for Imaging Research and Education | And 5 more authors.
Magnetic Resonance in Medicine | Year: 2015

Purpose This study was aimed to assess the effects of High Intensity Focused Ultrasound (HIFU) thermal ablation on tumor T1ρ. Methods In vivo T1ρ measurements of murine tumors at various spin-lock amplitudes (B1 = 0-2000 Hz) were performed before (n = 13), directly after (n = 13) and 3 days (n = 7) after HIFU treatment. T2 maps were obtained from the measurements at B1 = 0 Hz. Results Average tumor T1ρ distributions at the different experimental time points showed a shift toward lower T1ρ values after HIFU for all spin-lock amplitudes, which became larger with increasing spin-lock amplitude at 3 days after treatment. Statistical analysis confirmed a significant effect of spin-lock amplitude on the average change in T1ρ (ΔT1ρ) as compared to baseline at 3 days after HIFU. At 3 days after treatment, ΔT1ρ values at B1 above 100 Hz were significantly lower (more negative) than at B1 = 0 Hz (T2). Conclusion Significant changes in tumor T1ρ were observed after HIFU treatment. These T1ρ changes were distinctly more pronounced than HIFU-induced changes in T2. The results indicate that T1ρ imaging is sensitive to HIFU-induced tissue changes and may thus be a suitable MR method for the evaluation of HIFU treatment. © 2014 Wiley Periodicals, Inc.


van Duijnhoven S.M.J.,TU Eindhoven | van Duijnhoven S.M.J.,Center for Imaging Research and Education | Robillard M.S.,Center for Imaging Research and Education | Robillard M.S.,Philips | And 5 more authors.
Contrast Media and Molecular Imaging | Year: 2015

Matrix metalloproteinases (MMPs) play a pivotal role in cancer progression and present therefore an interesting biomarker for early diagnosis, staging and therapy evaluation. Consequently, MMP-specific molecular imaging probes have been proposed for noninvasive visualization and quantification of MMP activity. An interesting approach is MMP-2/9 activatable cell-penetrating peptides (ACPP) that accumulate in the tumor tissue after activation. However, a recent study revealed that probe activation occurred already in the vasculature followed by nonspecific tumor targeting. In the latter study, biodistribution was determined 6 and 24h post-ACPP injection. An alternative explanation could still be that the kinetics of tumor-specific activation is faster than that of blood activation plus subsequent nonspecific uptake in tumor. The aim of this study was to assess if tumor-specific ACPP activation occurs in mice with MMP-2/9 positive subcutaneous HT-1080 tumors at 3h post-injection. As control, we studied the MMP-2/9 sensitive ACPP in mice bearing subcutaneous BT-20 tumors with low MMP-2/9 expression to test if probe cleavage correlates with tumoral MMP expression. Ex vivo biodistribution showed no improved tumoral ACPP activation in HT-1080 tumor-bearing mice at 3h post-injection compared with previous reported data collected at 24h post-injection. Furthermore, tumoral uptake and relative tumoral activation for ACPP were similar in both BT-20 and HT-1080 tumor-bearing mice. In conclusion, this study suggests that tumoral ACPP uptake in these tumor models originates from probe activation in the vasculature instead of tumor-specific MMP activation. Novel ACPPs that target tissue-specific proteases without nonspecific activation may unleash the full potential of the elegant ACPP concept. © 2014 John Wiley & Sons, Ltd.


Hectors S.J.C.G.,TU Eindhoven | Hectors S.J.C.G.,Center for Imaging Research and Education | Jacobs I.,TU Eindhoven | Jacobs I.,Center for Imaging Research and Education | And 5 more authors.
PLoS ONE | Year: 2014

Purpose: In this study endogenous magnetic resonance imaging (MRI) biomarkers for accurate segmentation of High Intensity Focused Ultrasound (HIFU)-treated tumor tissue and residual or recurring non-treated tumor tissue were identified. Methods: Multiparametric MRI, consisting of quantitative T 1, T2, Apparent Diffusion Coefficient (ADC) and Magnetization Transfer Ratio (MTR) mapping, was performed in tumor-bearing mice before (n = 14), 1 h after (n = 14) and 72 h (n = 7) after HIFU treatment. A non-treated control group was included (n = 7). Cluster analysis using the Iterative Self Organizing Data Analysis (ISODATA) technique was performed on subsets of MRI parameters (feature vectors). The clusters resulting from the ISODATA segmentation were divided into a viable and non-viable class based on the fraction of pixels assigned to the clusters at the different experimental time points. ISODATA-derived non-viable tumor fractions were quantitatively compared to histology-derived non-viable tumor volume fractions. Results: The highest agreement between the ISODATA-derived and histology-derived non-viable tumor fractions was observed for feature vector {T1, T2, ADC}. R1 (1/T1), R2 (1/T2), ADC and MTR each were significantly increased in the ISODATA-defined non-viable tumor tissue at 1 h after HIFU treatment compared to viable, non-treated tumor tissue. R1, ADC and MTR were also significantly increased at 72 h after HIFU. Conclusions: This study demonstrates that non-viable, HIFU-treated tumor tissue can be distinguished from viable, non-treated tumor tissue using multiparametric MRI analysis. Clinical application of the presented methodology may allow for automated, accurate and objective evaluation of HIFU treatment. © 2014 Hectors et al.

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