Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or 19F 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 (19F) MR contrast properties, which allows using multimodal imaging and 19F 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 19F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation two hours 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 (200 nm to 350 nm 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.

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.

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 PRF/T1 approach for simultaneously measuring proton resonance frequency (PRF) shift temperatures in water-based tissues and T1 changes in fat-based tissues. The hybrid PRF/T1 sequence is a standard RF 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 (VFA) approach. Simulation studies, ex vivo high intensity focused ultrasound (HIFU) 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. While several potential error sources exist for the T1 measurements, the approach is a promising start towards realizing quantitative temperature measurements in both water-based and fat-based tissues.

Purpose This paper develops a method to obtain optimal estimates of absolute magnetization phase from multiple-coil MRI data. Methods The element-specific phases of a multi-element receiver coil array are accounted for by using the phase of a real or virtual reference coil that is sensitive over the entire imaged volume. The virtual-reference coil is generated as a weighted combination of measurements from all receiver coils. The phase-corrected multiple coil complex images are combined using the inverse covariance matrix. These methods are tested on images of an agar phantom, an in vivo breast, and an anesthetized rabbit obtained using combinations of four, nine, and three receiver channels, respectively. Results The four- and three- channel acquisitions require formation of a virtual-reference receiver coil while one channel of the nine-channel receive array has a sensitivity profile covering the entire imaged volume. Referencing to a real or virtual coil gives receiver phases that are essentially identical except for the individual receiver channel noise. The resulting combined images, which account for receiver channel noise covariance, show the expected reduction in phase variance. Conclusions The proposed virtual reference coil method determines a phase distribution for each coil from which an optimal phase map can be obtained.

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 method’s SAR values determined for the entire 3-D focal region agree well with the experimental temperature elevations in a HIFU-heated tissue-mimicking phantom.

BackgroundMany aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism.MethodsFocused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated.ResultsPositive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation.ConclusionThis presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols.

A self-navigated 3D multiecho SOS sequence with dynamic KWIC reconstruction is a promising thermometry method that provides multiple temperature sensitive quantitative values. Magn Reson Med 79:1407-1419, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

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 realtime 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 62:406 -419, 2009.