Allison Payne

Ultrasound-Mediated Tumor Imaging and Nanotherapy using Drug Loaded, Block Copolymer Stabilized Perfluorocarbon Nanoemulsions

Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.

The effects of spatial sampling choices on MR temperature measurements

The purpose of this article is to quantify the effects that spatial sampling parameters have on the accuracy of magnetic resonance temperature measurements during high intensity focused ultrasound treatments. Spatial resolution and position of the sampling grid were considered using experimental and simulated data for two different types of high intensity focused ultrasound heating trajectories (a single point and a 4‐mm circle) with maximum measured temperature and thermal dose volume as the metrics. It is demonstrated that measurement accuracy is related to the curvature of the temperature distribution, where regions with larger spatial second derivatives require higher resolution. The location of the sampling grid relative temperature distribution has a significant effect on the measured values. When imaging at 1.0 × 1.0 × 3.0 mm3 resolution, the measured values for maximum temperature and volume dosed to 240 cumulative equivalent minutes (CEM) or greater varied by 17% and 33%, respectively, for the single‐point heating case, and by 5% and 18%, respectively, for the 4‐mm circle heating case. Accurate measurement of the maximum temperature required imaging at 1.0 × 1.0 × 3.0 mm3 resolution for the single‐point heating case and 2.0 × 2.0 × 5.0 mm3 resolution for the 4‐mm circle heating case. Magn Reson Med, 2011.

Model predictive filtering for improved temporal resolution in MRI temperature imaging.

A novel method for reconstructing MRI temperature maps from undersampled data is presented. The method, model predictive filtering, combines temperature predictions from a preidentified thermal model with undersampled k‐space data to create temperature maps in near real time. The model predictive filtering algorithm was implemented in three ways: using retrospectively undersampled k‐space data from a fully sampled two‐dimensional gradient echo (GRE) sequence (reduction factors R = 2.7 to R = 7.1), using actually undersampled data from a two‐dimensional GRE sequence (R = 4.8), and using actually undersampled data from a three‐dimensional GRE sequence (R = 12.1). Thirty‐nine high‐intensity focused ultrasound heating experiments were performed under MRI monitoring to test the model predictive filtering technique against the current gold standard for MR temperature mapping, the proton resonance frequency shift method. For both of the two‐dimensional implementations, the average error over the five hottest voxels from the hottest time frame remained between ±0.8°C and the temperature root mean square error over a 24 × 7 × 3 × 25‐voxel region of interest remained below 0.35°C. The largest errors for the three‐dimensional implementation were slightly worse: −1.4°C for the mean error of the five hottest voxels and 0.61°C for the temperature root mean square error. Magn Reson Med 63:1269–1279, 2010.

Temporally constrained reconstruction applied to MRI temperature data

The monitoring of thermal ablation procedures would benefit from an acceleration in the rate at which MRI temperature maps are acquired. Constrained reconstruction techniques have been shown to be capable of generating high quality images using only a fraction of the k‐space data. Here, we present a temporally constrained reconstruction (TCR) algorithm applied to proton resonance frequency shift (PRF) data. The algorithm generates images from undersampled data by iteratively minimizing a cost function. The unique challenges of using an iterative constrained reconstruction technique to generate real‐time images were addressed. For a set of eight heating experiments on ex vivo porcine tissue, a maximum reduction factor of 4 was achieved while keeping the root mean square error (RMSE) of the temperature below 0.5°C. For a set of three heating experiments on in vivo canine muscle tissue, the maximum reduction factor achieved was 3 while keeping the temperature RMSE below 1.0°C. At these reduction factors, the TCR algorithm underpredicted the thermal dose by an average of 6% for the ex vivo data and 28% for the in vivo data. Compared with sliding window and low resolution reconstructions, the RMSE of the TCR algorithm was significantly lower (P < 0.05 in all cases). Magn Reson Med, 2009.

Design and characterization of a laterally mounted phased-array transducer breast-specific MRgHIFU device with integrated 11-channel receiver array

PURPOSE This work presents the design and preliminary evaluation of a new laterally mounted phased-array MRI-guided high-intensity focused ultrasound (MRgHIFU) system with an integrated 11-channel phased-array radio frequency (RF) coil intended for breast cancer treatment. The design goals for the system included the ability to treat the majority of tumor locations, to increase the MR images signal-to-noise ratio (SNR) throughout the treatment volume and to provide adequate comfort for the patient. METHODS In order to treat the majority of the breast volume, the device was designed such that the treated breast is suspended in a 17-cm diameter treatment cylinder. A laterally shooting 1-MHz, 256-element phased-array ultrasound transducer with flexible positioning is mounted outside the treatment cylinder. This configuration achieves a reduced water volume to minimize RF coil loading effects, to position the coils closer to the breast for increased signal sensitivity, and to reduce the MR image noise associated with using water as the coupling fluid. This design uses an 11-channel phased-array RF coil that is placed on the outer surface of the cylinder surrounding the breast. Mechanical positioning of the transducer and electronic steering of the focal spot enable placement of the ultrasound focus at arbitrary locations throughout the suspended breast. The treatment platform allows the patient to lie prone in a face-down position. The system was tested for comfort with 18 normal volunteers and SNR capabilities in one normal volunteer and for heating accuracy and stability in homogeneous phantom and inhomogeneous ex vivo porcine tissue. RESULTS There was a 61% increase in mean relative SNR achieved in a homogeneous phantom using the 11-channel RF coil when compared to using only a single-loop coil around the chest wall. The repeatability of the systems energy delivery in a single location was excellent, with less than 3% variability between repeated temperature measurements at the same location. The execution of a continuously sonicated, predefined 48-point, 8-min trajectory path resulted in an ablation volume of 8.17 cm(3), with one standard deviation of 0.35 cm(3) between inhomogeneous ex vivo tissue samples. Comfort testing resulted in negligible side effects for all volunteers. CONCLUSIONS The initial results suggest that this new device will potentially be suitable for MRgHIFU treatment in a wide range of breast sizes and tumor locations.

Characterization and evaluation of tissue-mimicking gelatin phantoms for use with MRgFUS

BackgroundA tissue-mimicking phantom that accurately represents human-tissue properties is important for safety testing and for validating new imaging techniques. To achieve a variety of desired human-tissue properties, we have fabricated and tested several variations of gelatin phantoms. These phantoms are simple to manufacture and have properties in the same order of magnitude as those of soft tissues. This is important for quality-assurance verification as well as validation of magnetic resonance-guided focused ultrasound (MRgFUS) treatment techniques.MethodsThe phantoms presented in this work were constructed from gelatin powders with three different bloom values (125, 175, and 250), each one allowing for a different mechanical stiffness of the phantom. Evaporated milk was used to replace half of the water in the recipe for the gelatin phantoms in order to achieve attenuation and speed of sound values in soft tissue ranges. These acoustic properties, along with MR (T1 and T2*), mechanical (density and Young’s modulus), and thermal properties (thermal diffusivity and specific heat capacity), were obtained through independent measurements for all three bloom types to characterize the gelatin phantoms. Thermal repeatability of the phantoms was also assessed using MRgFUS and MR thermometry.ResultsAll the measured values fell within the literature-reported ranges of soft tissues. In heating tests using low-power (6.6 W) sonications, interleaved with high-power (up to 22.0 W) sonications, each of the three different bloom phantoms demonstrated repeatable temperature increases (10.4 ± 0.3 °C for 125-bloom, 10.2 ± 0.3 °C for 175-bloom, and 10.8 ± 0.2 °C for 250-bloom for all 6.6-W sonications) for heating durations of 18.1 s.ConclusionThese evaporated milk-modified gelatin phantoms should serve as reliable, general soft tissue-mimicking MRgFUS phantoms.

Reconstruction of fully three‐dimensional high spatial and temporal resolution MR temperature maps for retrospective applications

Many areas of MR‐guided thermal therapy research would benefit from temperature maps with high spatial and temporal resolution that cover a large three‐dimensional volume. This article describes an approach to achieve these goals, which is suitable for research applications where retrospective reconstruction of the temperature maps is acceptable. The method acquires undersampled data from a modified three‐dimensional segmented echo‐planar imaging sequence and creates images using a temporally constrained reconstruction algorithm. The three‐dimensional images can be zero‐filled to arbitrarily small voxel spacing in all directions and then converted into temperature maps using the standard proton resonance frequency shift technique. During high intensity focused ultrasound heating experiments, the proposed method was used to obtain temperature maps with 1.5 mm × 1.5 mm × 3.0 mm resolution, 288 mm × 162 mm × 78 mm field of view, and 1.7 s temporal resolution. The approach is validated to demonstrate that it can accurately capture the spatial characteristics and time dynamics of rapidly changing high intensity focused ultrasound‐induced temperature distributions. Example applications from MR‐guided high intensity focused ultrasound research are shown to demonstrate the benefits of the large coverage fully three‐dimensional temperature maps, including characterization of volumetric heating trajectories and near‐ and far‐field heating. Magn Reson Med, 2012.

Toward Real-Time Availability of 3D Temperature Maps Created with Temporally Constrained Reconstruction

To extend the previously developed temporally constrained reconstruction (TCR) algorithm to allow for real‐time availability of three‐dimensional (3D) temperature maps capable of monitoring MR‐guided high intensity focused ultrasound applications.

An analytical solution for improved HIFU SAR estimation.

Accurate determination of the specific absorption rates (SARs) present during high intensity focused ultrasound (HIFU) experiments and treatments provides a solid physical basis for scientific comparison of results among HIFU studies and is necessary to validate and improve SAR predictive software, which will improve patient treatment planning, control and evaluation. This study develops and tests an analytical solution that significantly improves the accuracy of SAR values obtained from HIFU temperature data. SAR estimates are obtained by fitting the analytical temperature solution for a one-dimensional radial Gaussian heating pattern to the temperature versus time data following a step in applied power and evaluating the initial slope of the analytical solution. The analytical method is evaluated in multiple parametric simulations for which it consistently (except at high perfusions) yields maximum errors of less than 10% at the center of the focal zone compared with errors up to 90% and 55% for the commonly used linear method and an exponential method, respectively. For high perfusion, an extension of the analytical method estimates SAR with less than 10% error. The analytical method is validated experimentally by showing that the temperature elevations predicted using the analytical methods SAR values determined for the entire 3D focal region agree well with the experimental temperature elevations in a HIFU-heated tissue-mimicking phantom.

Hybrid proton resonance frequency/T1 technique for simultaneous temperature monitoring in adipose and aqueous tissues

Thermal therapy procedures being carried out under MR guidance would be safer if temperature changes could be accurately monitored in both water‐based and fat‐based tissues. To this end, we present a hybrid proton resonance frequency (PRF)/T1 approach for simultaneously measuring PRF shift temperatures in water‐based tissues and T1 changes in fat‐based tissues. The hybrid PRF/T1 sequence is a standard radiofrequency spoiled gradient echo sequence executed in a dynamic mode with two flip angles alternating every time frame. The PRF information is extracted every time frame using the image phase in the standard approach, and the T1 information is extracted every two time frames using a variable flip angle approach. Simulation studies, ex vivo high intensity focused ultrasound heating experiments, and in vivo stability experiments were performed to test the feasibility of the approach. The results indicate that the hybrid PRF/T1 approach provides PRF temperature maps of the same quality as those obtained by traditional PRF methods while simultaneously being able to track T1 changes in fat‐based tissues. Although several potential error sources exist for the T1 measurements, the approach is a promising start toward realizing quantitative temperature measurements in both water‐based and fat‐based tissues. Magn Reson Med, 2013.