Ari Partanen

Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model.

Clinical-grade doxorubicin encapsulated low temperature sensitive liposomes (LTSLs) were combined with a clinical magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) platform to investigate in vivo image-guided drug delivery. Plasma pharmacokinetics were determined in 3 rabbits. Fifteen rabbits with Vx2 tumors within superficial thigh muscle were randomly assigned into three treatment groups: 1) free doxorubicin, 2) LTSL and 3) LTSL + MR-HIFU. For the LTSL + MR-HIFU group, mild hyperthermia (40-41 °C) was applied to the tumors using an MR-HIFU system. Image-guided non-invasive hyperthermia was applied for a total of 30 min, completed within 1h after LTSL infusion. High-pressure liquid chromatography (HPLC) analysis of the harvested tumor and organ/tissue homogenates was performed to determine doxorubicin concentration. Fluorescence microscopy was performed to determine doxorubicin spatial distribution in the tumors. Sonication of Vx2 tumors resulted in accurate (mean = 40.5 ± 0.1 °C) and spatially homogenous (SD = 1.0 °C) temperature control in the target region. LTSL + MR-HIFU resulted in significantly higher tumor doxorubicin concentrations (7.6- and 3.4-fold greater compared to free doxorubicin and LTSL respectively, p<0.05, Newman-Keuls). This improved tumor concentration was achieved despite heating <25% of the tumor volume. Free doxorubicin and LTSL treatments appeared to deliver more drug in the tumor periphery as compared to the tumor core. In contrast, LTSL + MR-HIFU treatment suggested an improved distribution with doxorubicin found in both the tumor periphery and core. Doxorubicin bio-distribution in non-tumor organs/tissues was fairly similar between treatment groups. This technique has potential for clinical translation as an image-guided method to deliver drug to a solid tumor.

Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound

Purpose: Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo. Methods: iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model. Results: iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs−1 when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region. Conclusion: An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.

Mild hyperthermia with magnetic resonance-guided high-intensity focused ultrasound for applications in drug delivery

Purpose: Mild hyperthermia (40–45°C) is a proven adjuvant for radiotherapy and chemotherapy. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) can non-invasively heat solid tumours under image guidance. Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (>40°C) and may improve drug delivery to solid tumours when combined with mild hyperthermia. The objective of this study was to develop and implement a clinically relevant MR-HIFU mild hyperthermia heating algorithm for combination with LTSLs. Materials and methods: Sonications were performed with a clinical MR-HIFU platform in a phantom and rabbits bearing VX2 tumours (target = 4–16 mm). A binary control algorithm was used for real-time mild hyperthermia feedback control (target = 40–41°C). Drug delivery with LTSLs was measured with HPLC. Data were compared to simulation results and analysed for spatial targeting accuracy (offset), temperature accuracy (mean), homogeneity of heating (standard deviation (SD), T10 and T90), and thermal dose (CEM43). Results: Sonications in a phantom resulted in better temperature control than in vivo. Sonications in VX2 tumours resulted in mean temperatures between 40.4°C and 41.3°C with a SD of 1.0–1.5°C (T10 = 41.7–43.7°C, T90 = 39.0–39.6°C), in agreement with simulations. 3D spatial offset was 0.1–3.2 mm in vitro and 0.6–4.8 mm in vivo. Combination of MR-HIFU hyperthermia and LTSLs demonstrated heterogeneous delivery to a partially heated VX2 tumour, as expected. Conclusions: An MR-HIFU mild hyperthermia heating algorithm was developed, resulting in accurate and homogeneous heating within the targeted region in vitro and in vivo, which is suitable for applications in drug delivery.

Targeted drug delivery by high intensity focused ultrasound mediated hyperthermia combined with temperature-sensitive liposomes: Computational modelling and preliminary in vivovalidation

Purpose: To develop and validate a computational model that simulates 1) tissue heating with high intensity focused ultrasound (HIFU), and 2) resulting hyperthermia-mediated drug delivery from temperature-sensitive liposomes (TSL). Materials and methods: HIFU heating in tissue was simulated using a heat transfer model based on the bioheat equation, including heat-induced cessation of perfusion. A spatio-temporal multi-compartment pharmacokinetic model simulated intravascular release of doxorubicin from TSL, its transport into interstitium, and cell uptake. Two heating schedules were simulated, each lasting 30 min: 1) hyperthermia at 43°C (HT) and 2) hyperthermia followed by a high temperature (50°C for 20 s) pulse (HT+). As preliminary model validation, in vivo studies were performed in thigh muscle of a New Zealand White rabbit, where local hyperthermia with a clinical magnetic resonance-guided HIFU system was applied following TSL administration. Results: HT produced a defined region of high doxorubicin concentration (cellular concentration ∼15–23 µg/g) in the target region. Cellular drug uptake was directly related to HT duration, with increasing doxorubicin uptake up to ∼2 h. HT+ enhanced drug delivery by ∼40% compared to HT alone. Temperature difference between model and experiment within the hyperthermia zone was on average 0.54°C. Doxorubicin concentration profile agreed qualitatively with in vivo fluorescence profile. Conclusions: Computational models can predict temperature and delivered drug from combination of HIFU with TSL. Drug delivery using TSL may be enhanced by prolonged hyperthermia up to 2 h or by local cessation of vascular perfusion with a high temperature pulse following hyperthermia.

Characterization of a multi-element clinical HIFU system using acoustic holography and nonlinear modeling

High-intensity focused ultrasound (HIFU) is a treatment modality that relies on the delivery of acoustic energy to remote tissue sites to induce thermal and/or mechanical tissue ablation. To ensure the safety and efficacy of this medical technology, standard approaches are needed for accurately characterizing the acoustic pressures generated by clinical ultrasound sources under operating conditions. Characterization of HIFU fields is complicated by nonlinear wave propagation and the complexity of phased-array transducers. Previous work has described aspects of an approach that combines measurements and modeling, and here we demonstrate this approach for a clinical phased-array transducer. First, low amplitude hydrophone measurements were performed in water over a scan plane between the array and the focus. Second, these measurements were used to holographically reconstruct the surface vibrations of the transducer and to set a boundary condition for a 3-D acoustic propagation model. Finally, nonlinear simulations of the acoustic field were carried out over a range of source power levels. Simulation results were compared with pressure waveforms measured directly by hydrophone at both low and high power levels, demonstrating that details of the acoustic field, including shock formation, are quantitatively predicted.

Volumetric MR-HIFU ablation of uterine fibroids: Role of treatment cell size in the improvement of energy efficiency

PURPOSE To evaluate the energy efficiency of differently sized volumetric ablations in MR-guided high-intensity focused ultrasound (MR-HIFU) treatment of uterine fibroids. MATERIALS AND METHODS This study was approved by the institutional review board and informed consent was obtained from all participants. Ten symptomatic uterine fibroids (mean diameter 8.9 cm) in 10 women (mean age 42.2) were treated by volumetric MR-HIFU ablation under binary feedback control. The energy efficiency (mm3/J) of each sonication was calculated as the volume of lethal thermal dose (240 equivalent minutes at 43 °C) per unit acoustic energy applied. Operator-controllable parameters and signal intensity ratio of uterine fibroid to skeletal muscle on T2-weighted MR images were tested with univariate and multivariate analyses to discern which parameters significantly correlated with the ablation energy efficiency. RESULTS We analyzed a total of 236 sonications. The energy efficiency of the ablations was 0.42±0.25 mm3/J (range 0.004-1.18) with energy efficiency improving with the treatment cell size (4 mm, 0.06±0.06 mm3/J; 8 mm, 0.29±0.12 mm3/J; 12 mm, 0.58±0.18 mm3/J; 16 mm, 0.91±0.17 mm3/J). Treatment cell size (r=0.814, p<0.001), distance of ultrasound propagation (r=-0.151, p=0.020), sonication frequency (1.2 or 1.45 MHz; p<0.001), and signal intensity ratio (r=-0.205, p=0.002) proved to be significant by univariate analysis, while multivariate analysis revealed treatment cell size (B=0.075, p<0.001), US propagation distance (B=-6.928, p<0.001), and signal intensity ratio (B=-0.024, p=0.001) to be independently significant. CONCLUSION Energy efficiency in volumetric MR-HIFU ablation of uterine fibroids improves with increased treatment cell size, independent of other significant contributors such as distance of ultrasound propagation or signal intensity of the tumor on T2-weighted MR imaging.

Magnetic Resonance Imaging–guided Volumetric Ablation of Symptomatic Leiomyomata: Correlation of Imaging with Histology

PURPOSE To describe the preliminary safety and accuracy of a magnetic resonance (MR) imaging-guided high-intensity-focused ultrasound (HIFU) system employing new technical developments, including ablation control via volumetric thermal feedback, for the treatment of uterine leiomyomata with histopathologic correlation. MATERIALS AND METHODS In this phase I clinical trial, 11 women underwent MR-guided HIFU ablation (Sonalleve 1.5T; Philips Medical Systems, Vantaa, Finland), followed by hysterectomy within 30 days. Adverse events, imaging findings, and pathologic confirmation of ablation were assessed. The relationship between MR imaging findings, thermal dose estimates, and pathology and HIFU spatial accuracy were assessed using Bland-Altman analyses and intraclass correlations. RESULTS There were 12 leiomyomata treated. No serious adverse events were observed. Two subjects decided against having hysterectomy and withdrew from the study before surgery. Of 11 women, 9 underwent hysterectomy; all leiomyomata demonstrated treatment in the expected location. A mean ablation volume of 6.92 cm(3) ± 10.7 was observed at histopathologic examination. No significant differences between MR imaging nonperfused volumes, thermal dose estimates, and histopathology ablation volumes were observed (P > .05). Mean misregistration values perpendicular to the ultrasound beam axis were 0.8 mm ± 1.2 in feet-head direction and 0.1 mm ± 1.0 in and left-right direction and -0.7 mm ± 3.1 along the axis. CONCLUSIONS Safe, accurate ablation of uterine leiomyomata was achieved with an MR-guided HIFU system with novel treatment monitoring capabilities, including ablation control via volumetric thermal feedback.

Reduction of peak acoustic pressure and shaping of heated region by use of multifoci sonications in MR-guided high-intensity focused ultrasound mediated mild hyperthermia.

PURPOSE Ablative hyperthermia (>55 °C) has been used as a definitive treatment for accessible solid tumors not amenable to surgery, whereas mild hyperthermia (40-45 °C) has been shown effective as an adjuvant for both radiotherapy and chemotherapy. An optimal mild hyperthermia treatment is spatially accurate, with precise and homogeneous heating limited to the target region while also limiting the likelihood of unwanted thermal or mechanical bioeffects (tissue damage, vascular shutoff). Magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) can noninvasively heat solid tumors under image-guidance. In a mild hyperthermia setting, a sonication approach utilizing multiple concurrent foci may provide the benefit of reducing acoustic pressure in the focal region (leading to reduced or no mechanical effects), while providing better control over the heating. The objective of this study was to design, implement, and characterize a multifoci sonication approach in combination with a mild hyperthermia heating algorithm, and compare it to the more conventional method of electronically sweeping a single focus. METHODS Simulations (acoustic and thermal) and measurements (acoustic, with needle hydrophone) were performed. In addition, heating performance of multifoci and single focus sonications was compared using a clinical MR-HIFU platform in a phantom (target = 4-16 mm), in normal rabbit thigh muscle (target = 8 mm), and in a Vx2 tumor (target = 8 mm). A binary control algorithm was used for real-time mild hyperthermia feedback control (target range = 40.5-41 °C). Data were analyzed for peak acoustic pressure and intensity, heating energy efficiency, temperature accuracy (mean), homogeneity of heating (standard deviation [SD], T10 and T90), diameter and length of the heated region, and thermal dose (CEM(43)). RESULTS Compared to the single focus approach, multifoci sonications showed significantly lower (67% reduction) peak acoustic pressures in simulations and hydrophone measurements. In a rabbit Vx2 tumor, both single focus and multifoci heating approaches were accurate (mean = 40.82±0.12 °C [single] and 40.70±0.09 °C [multi]) and precise (standard deviation = 0.65±0.05 °C [single] and 0.64±0.04 °C [multi]), producing homogeneous heating (T(10-90) = 1.62 °C [single] and 1.41 °C [multi]). Heated regions were significantly shorter in the beam path direction (35% reduction, p < 0.05, Tukey) for multifoci sonications, i.e., resulting in an aspect ratio closer to one. Energy efficiency was lower for the multifoci approach. Similar results were achieved in phantom and rabbit muscle heating experiments. CONCLUSIONS A multifoci sonication approach was combined with a mild hyperthermia heating algorithm, and implemented on a clinical MR-HIFU platform. This approach resulted in accurate and precise heating within the targeted region with significantly lower acoustic pressures and spatially more confined heating in the beam path direction compared to the single focus sonication method.The reduction in acoustic pressure and improvement in spatial control suggest that multifoci heating is a useful tool in mild hyperthermia applications for clinical oncology.

Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: A preclinical study with radiological and pathological correlation using customised MRI-based moulds

To characterise the feasibility and safety of a novel transurethral ultrasound (US)‐therapy device combined with real‐time multi‐plane magnetic resonance imaging (MRI)‐based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra‐procedural cumulative thermal damage estimates, post‐procedural MRI, and histopathology.

Feasibility of Agar‐Silica Phantoms in Quality Assurance of MRgHIFU

Although many phantom types for magnetic resonance guided high intensity focused ultrasound (MRgHIFU) exist, the number of reusable phantoms for quality assurance (QA) purposes is limited. For reliability, the phantom should be structurally and compositionally uniform, and acoustically isotropic. It should also be cheap and easy to produce, and maintain its physical and chemical properties even in long‐term use. Various authors have used water, agar, and silicon‐dioxide (silica) to produce phantoms with ultrasound attenuation coefficient in a range typical of soft tissues. However, their applicability in MRgHIFU use has not been investigated systematically or verified in previous studies. In this study, agar‐gel‐based tissue‐mimicking heating phantom material is optimized and its MRgHIFU‐usability is tested and verified. Acoustic properties of the phantom material with different concentrations of silica were determined experimentally. The ultrasound attenuation coefficient was found to be linearly and pos...