Perfluorocarbon nanodroplets stabilized by fluorinated surfactants: characterization and potentiality as theranostic agents.

We aim to produce emulsions that can act as contrast agents and drug carriers for cancer imaging and therapy. To increase tumor detection and decrease drug side effects, it is desirable to take advantage of the enhanced permeability and retention effect that allows nanoparticles to accumulate in tumor tissues. To do so, the emulsion droplets need to be small enough and stable over time in addition to enhancing image contrast and carrying a drug payload. In the present study, we have investigated the properties and potentiality as theranostic agents of perfluorocarbon emulsions stabilized by a biocompatible fluorinated surfactant called FTAC. To obtain better control of our system, the synthesis of those surfactants was studied and their physico-chemical properties were explored in different configurations such as micelles, in the perfluorocarbon droplet shell and at water/air and water/perfluorocarbon interfaces. The originality of this work lies in the determination of numerous characteristics of emulsions and fluorinated surfactants including surface tension, interfacial tension, critical micelle concentration, adiabatic compressibility, density, size distribution (aging studies), and ultrasonic echogenicity. These characterization studies were conducted using different types of FTAC and several perfluorocarbons (perfluoropentane, perfluorohexane, and perfluorooctyl bromide). We have also shown that a hydrophobic drug could be encapsulated in the FTAC-stabilized perfluorocarbon droplets thanks to triacetin addition. Finally, the perfluorocarbon emulsions were detectable in vitro by a clinical 3 T MRI scanner, equipped with a double frequency 19F/1H transmit-receive coil.

Management of respiratory motion in extracorporeal high-intensity focused ultrasound treatment in upper abdominal organs: current status and perspectives.

Extracorporeal high-intensity focused ultrasound (HIFU) is a minimally invasive therapy considered with increased interest for the ablation of small tumors in deeply located organs while sparing surrounding critical tissues. A multitude of preclinical and clinical studies have showed the feasibility of the method; however, concurrently they showed several obstacles, among which the management of respiratory motion of abdominal organs is at the forefront. The aim of this review is to describe the different methods that have been proposed for managing respiratory motion and to identify their advantages and weaknesses. First, we specify the characteristics of respiratory motion for the liver, kidneys, and pancreas and the problems it causes during HIFU planning, treatment, and monitoring. Second, we make an inventory of the preclinical and clinical approaches used to overcome the problem of organ motion. Third, we analyze their respective benefits and drawbacks to identify the remaining physical, technological, and clinical challenges. We thereby consider the outlook of motion compensation techniques and those that would be the most suitable for clinical use, particularly under magnetic resonance thermometry monitoring.

Keep breathing! Common motion helps multi-modal mapping.

We propose an unconventional approach for transferring of information between multi-modal images. It exploits the temporal commonality of multi-modal images acquired from the same organ during free-breathing. Strikingly there is no need for capturing the same region by the modalities. The method is based on extracting a low-dimensional description of the image sequences, selecting the common cause signal (breathing) for both modalities and finding the most similar sub-sequences for predicting image feature location. The approach was evaluated for 3 volunteers on sequences of 2D MRI and 2D US images of the liver acquired at different locations. Simultaneous acquisition of these images allowed for quantitative evaluation (predicted versus ground truth MRI feature locations). The best performance was achieved with signal extraction by slow feature analysis resulting in an average error of 2.6 mm (4.2 mm) for sequences acquired at the same (a different) time.

Morphological analysis of the interstitial ultrasonic ablation in porcine liver in vivo.

BACKGROUND: The shape of the induced thermal ablation area is as important as its dimension. The aim of this study was to analyze the size reproducibility and the aspect of the interstitial ultrasonic ablation obtained by a planar transducer in porcine liver in vivo. METHODS: Five pigs were used. Two complete ultrasonic lesions were made in each animal under pedicle clamping. All the lesions underwent MR examination on day 7 and then a histological analysis. RESULTS: The tested probe has the advantage of providing a step-by-step and highly directional treatment in the target zone. The ultrasonic lesions presented as well-defined and homogenous areas of tissue coagulation. The lesion volumes ranged from 8.1 to 92.3 cm3 with an averaged lesion length of 56 mm at gross examination. Three-dimensional reconstruction of the lesions from the MR images showed cylindrical and conical shapes. Large intrahepatic vessels distorted the lesion shape, and the vicinity of the application to the liver surface increased significantly the volume of the ultrasonic necrosis. Histological examination showed complete necrosis in the area of damage. CONCLUSION: The ultrasonic ablation has a regular shape, always with sharply defined borders. However, it showed some variability in the size of the induced lesions.

[Ultrasound interstitial mini invasive probes for thermal ablation in liver: feasibility study in vivo]. / Sondes ultrasonores interstitielles mini-invasives pour l'ablation thermique dans le foie: étude de faisabilité in vivo.

High intensity ultrasounds are routinely used for thermal ablation of some cancers. However, for treating hepatic tumours with physical agents, RF applicators and cryoprobes are still preferred. The goal of the present study was to demonstrate the feasibility of using interstitial ultrasound probes in liver following two approaches: percutaneous and intra-tissular or endo vascular. In vivo trials on a porcine model demonstrated the minimally invasive nature of both procedures. Homogeneous and reproducible thermal lesions, up to 20 mm deep, were obtained. The work on these two original approaches deserves to be completed with more extended prospective studies. The association with an imaging method will have to be studied before proceeding to clinical trials.

Interstitial devices for minimally invasive thermal ablation by high-intensity ultrasound.

Interstitial ultrasound applicators have been proposed for treating deep-seated tumours that cannot be reached with extra-corporeal high-intensity focused ultrasound. In addition, interstitial ultrasound offers several advantages compared with conventional ablation technology (radiofrequency, microwaves, cryotherapy) in terms of penetration, speed of coagulation, ability to direct and control the thermal lesion and compatibility with image monitoring. The ultrasound source is brought as close as possible to the target in order to minimize the effects of attenuation and phase aberration along the ultrasound pathway. The present paper is a review of the interstitial applicators that were described during the last decade in the literature. It is presented in three sections. The technical aspects common to all applicators are first described. For example, most-described applicators are sideview applicators whose active element is water-cooled and operates at rather high frequency (above 3 MHz) in order to promote heating. Then the different potential techniques for monitoring treatment administered by the interstitial route are presented and illustrated through a review of image-guided interstitial thermal ablation. Three major techniques of imaging are used for guiding interstitial treatment: MRI, ultrasound and fluoroscopy. The third section goes in to further detail on diverse described medical applications.

64-element intraluminal ultrasound cylindrical phased array for transesophageal thermal ablation under fast MR temperature mapping: an ex vivo study.

This work was undertaken to investigate the feasibility of using a cylindrical phased array for transoesophaeal thermal ablation under magnetic resonance (MR) imaging guidance. Sixty-four transducers (0.45 mm wide by 15 mm tall), operating at 4.6 MHz, were spread around the periphery of a 10.6-mm-diam cylinder. The head of the applicator was covered with a 65-microm thick latex balloon attached using watertight seals. This envelope was inflated with degassed water to provide acoustic coupling between the transducer and the tissues. The underlying operating principle of this applicator is to rotate a plane ultrasound beam electronically. For this purpose, eight adjacent transducers were excited with appropriate delay times so as to generate a plane wave. The exposure direction was changed by exciting a different set of eight elements. Ex vivo experiments conducted on 47 samples of pig liver under MR temperature monitoring demonstrated the ability of this applicator to generate cylindrical or sector-based coagulation necroses at depths up to 19 mm with excellent angular precision by applying 20 W/cm2. MR thermometry was performed in "real-time" with segmented echo-planar imaging gradient echo sequences. The temporal resolution was approximately 3 s/ image. The average value for the temperature baseline in liver tissue close to the applicator was 0.3 degrees C (+/- 0.6 degrees C). The thermal dose delivered in tissues was computed on-line during temperature imaging. Excellent MR compatibility was demonstrated, all MR acquisitions were performed without susceptibility artifacts or radio-frequency interferences with the ultrasound device. Thermal lesions identified on post-treatment follow up showed good correlation with online MR thermometry data. The individual differences between measurements performed visually and using MRI thermal dose maps were about 11% of volume. This study demonstrated the feasibility of thermal ablation using a phased array intraluminal ultrasound applicator and on-line MR monitoring.

Testing of a HIFU probe for the treatment of superficial venous insufficiency by using MRI.

A new high intensity focused ultrasound (HIFU) probe has been designed and tested by using MRI. The probe is intended to be used by physicians to correct valvular dysfunction in the saphenous vein, which is known to be the cause of superficial venous insufficiency (SVI) and varicose veins. Treating SVI with HIFU is possible, since venous tissue undergoes localized partial shrinkage when subjected to HIFU. In vitro experiments have demonstrated that diameter shrinkage should be sufficient to restore valvular function, as is done in the more aggressive approach known as external valvuloplasty. Numerical simulations and optimization have led to a probe design with two HIFU elements that focus sound uniformly over a line of length 7 mm, at a depth of 15 mm from the skin. A prototype of the probe has been constructed, with a holder that provides space for an MRI-imaging antenna. The probe has been tested by measuring pressure and temperature fields. Results are in good agreement with those predicted by an analytical approach and numerical simulations.

Intraluminal ultrasound applicator compatible with magnetic resonance imaging "real-time" temperature mapping for the treatment of oesophageal tumours: an ex vivo study.

High intensity ultrasound has shown considerable ability to produce precise and deep thermal coagulation necrosis. Focused, cylindrical, spherical or plane transducers have been used to induce high temperatures in tissues to coagulate proteins and kill cells. Recently magnetic resonance imaging (MRI) has been used, with extracorporeal or intracavitary focused transducers and cylindrical interstitial applicators, to monitor temperature distribution and provide feedback during heating procedures. If intraluminal applicators are used, the active part is in contact with the region of interest and it is essential to provide an accurate view of heat deposition and the extent of coagulation necrosis close to the transducer. The purpose of this study was to develop a 10 mm diameter intraluminal ultrasound applicator, designed to treat oesophageal cancers and compatible with MRI "real-time" temperature mapping. The active part of the ultrasound applicator, covered by a latex balloon, is a 15 X 8 mm2 plane transducer, which is in contact with the tumours during treatment. Each ultrasound exposure generates coagulation necrosis, in an area with the approximate shape of a rectangular parallelepiped up to 10 mm deep. When the exposures were repeated by rotating the applicator on its axis, sector-based or cylindrical volumes of necrosis could be produced, matching the shape of oesophageal cancers. Ex vivo trials were performed to demonstrate the applicator's compatibility with a clinical MRI scanner (1.5 T). MRI signals were acquired without any magnetic susceptibility distortion, even close to the applicator. Fast (0.72 images per second) 2D temperature mapping was performed during ultrasound exposure, using temperature-related proton resonance frequency shift at a resolution of 0.5 degrees C. Coagulation necrosis viewed with inversion recovery sequences, were in good agreement with the qualitative macroscopic observations made for the few cases tested in this study.

Image-guided control of transgene expression based on local hyperthermia.

Spatial and temporal control of transgene expression is one of the major prerequisites of efficient gene therapy. Recently, a noninvasive, physical approach has been presented based on local heat in combination with a heat-sensitive promoter. This strategy requires tight temperature control in vivo. Here, we use MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control on a whole-body clinical MRI system for a completely automatic execution of a predefined temperature-time trajectory in the focal point. Feasibility studies on expression control were carried out on subcutaneously implanted rat tumors. A stable modified C6 glioma cell line was used carrying a fused gene coding for thymidine kinase (TK) and green fluorescent protein (GFP) under control of the human heat-shock protein 70 (HSP70) promoter. In vitro studies showed strong induction of the TK-GFP gene expression upon heat shock under various conditions and localization of the protein product in the nucleus. In vivo tumors were subjected to a 3-min temperature elevation using MRI-FUS with a constant temperature, and were analysed 24 hr after the heat shock with respect to GFP fluorescence. Preliminary results showed strong local induction in regions heated above 40 degrees C, and a good correspondence between temperature maps at the end of the heating period and elevated expression of TK-GFP.

Spatial and temporal control of transgene expression in vivo using a heat-sensitive promoter and MRI-guided focused ultrasound.

BACKGROUND: Among the techniques used to induce and control gene expression, a non-invasive, physical approach based on local heat in combination with a heat-sensitive promoter represents a promising alternative but requires accurate temperature control in vivo. MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control allows automatic execution of a predefined temperature-time trajectory. The purpose of this study was to demonstrate temporal and spatial control of transgene expression based on a well-defined local hyperthermia generated by MRI-FUS. METHODS: Expression of the green fluorescent protein (GFP) marker gene was used. Two cell lines were derived from C6 glioma cells. The GFP expression of the first one is under the control of the CMV promoter, whereas it is under the control of the HSP70 promoter in the second one and thus inducible by heat. Subcutaneous tumours were generated by injection in immuno-deficient mice and rats. Tumours were subjected to temperatures varying from 42 to 50 degrees C for 3 to 25 min controlled by MRI-FUS and analyzed 24 h after the heat-shock. Endogenous HSP70 expression and C6 cell distribution were also analyzed. RESULTS: The results demonstrate strong expression at 50 degrees C applied during a short time period (3 min) without affecting cell viability. Induced expression was also clearly shown for temperature in the range 44-48 degrees C but not at 42 degrees C. CONCLUSIONS: Heating with MRI-FUS allows a tight and non-invasive control of transgene expression in a tumour.

On-line correction and visualization of motion during MRI-controlled hyperthermia.

Displacement of tissue during MRI-controlled hyperthermia therapy can cause significant problems. Errors in calculated temperature may result from motion-related image artifacts and inter-image object displacement, leading to incorrect spatial temperature reference. Here, cyclic navigator echoes were incorporated in rapid gradient-echo MRI sequences, used for temperature mapping based on the proton resonance frequency. On-line evaluation of navigator information was used in three ways. First, motion artifacts were minimized in echo-shifted (TE > TR) gradient-echo images using the phase information of the navigator echo. Second, navigator profiles were matched for a quantitative evaluation of displacement. Together with a novel processing method, this information was employed to correct the reference temperature maps, thereby avoiding persistence of motion-related temperature errors throughout the hyperthermic period. Third, on-line visualization of displacement, together with temperature maps and thermal dose images, was developed, allowing physician intervention at all times. Examples are given of on-line corrections during hyperthermia procedures with focused ultrasound and radiofrequency heat sources. Magn Reson Med 45:128-137, 2001.

Thermal therapies in interventional MR imaging. Focused ultrasound.

MR image-guided focused ultrasound (FUS) provides an entirely noninvasive approach for local thermal therapies. MR imaging allows target definition and continuous temperature mapping. Therefore, the heating procedure can be controlled spatially and temporally based on automatic feedback to the FUS apparatus. Phased-array ultrasound technology will further help the development. MR imaging/FUS may be applied not only for tissue ablation, but also for local drug delivery, gene therapy, and drug activation.

Local hyperthermia with MR-guided focused ultrasound: spiral trajectory of the focal point optimized for temperature uniformity in the target region.

The objective of hyperthermia treatment is to deliver a similar therapeutic thermal dose throughout the target volume within a minimum amount of time. We describe a noninvasive approach to this goal based on magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) with a spherical transducer that can be moved along two directions inside the bed of a clinical MR imager and that has an adjustable focal length in the third dimension. Absorption of FUS gives rise to a highly localized thermal buildup, which then spreads by heat diffusion and blood perfusion. A uniform temperature within a large target volume can be obtained using a double spiral trajectory of the transducer focal point together with constant and maximum FUS power. Differences between the real and target temperatures during the first spiral are evaluated in real time with temperature MRI and corrected for during the second spiral trajectory employing FUS focal point velocity modulation. Once a uniform temperature distribution is reached within the entire volume, FUS heating is applied only at the region's boundaries to maintain the raised temperature levels. Heat conduction, together with the design and timing of the trajectories, therefore ensures a similar thermal dose for the entire target region. Good agreement is obtained between theory and experimental results in vitro on gel phantoms, ex vivo on meat samples, and in vivo on rabbit thigh muscle. Edema in muscle was visible 1 hour after hyperthermia as a spatially uniform rise of the signal intensity in T(2)-weighted images.

Hyperthermia by MR-guided focused ultrasound: accurate temperature control based on fast MRI and a physical model of local energy deposition and heat conduction.

Temperature regulation in MR-guided focused ultrasound requires rapid MR temperature mapping and automatic feedback control of the ultrasound output. Here, a regulation method is proposed based on a physical model of local energy deposition and heat conduction. The real-time evaluation of local temperature gradients from temperature maps is an essential element of the control system. Each time a new image is available, ultrasound power is adjusted on-the-fly in order to obtain the desired evolution of the focal point temperature. In vitro and in vivo performance indicated fast and accurate control of temperature and a large tolerance of errors in initial estimates of ultrasound absorption and heat conduction. When using correct estimates for the physical parameters of the model, focal point temperature was controlled within the measurement noise limit. Initial errors in absorption and diffusion parameters are compensated for exponentially with a user-defined response time, which is suggested to be on the order of 10 sec.