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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.

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.

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.

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.

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.

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