High-intensity Focused Ultrasound Irradiation Research Articles

Suppressing HIFU interference in ultrasound images using 1D U-Net-based neural networks

Objective. One big challenge with high-intensity focused ultrasound (HIFU) is that the intense acoustic interference generated by HIFU irradiation overwhelms the B-mode monitoring images, compromising monitoring effectiveness. This study aims to overcome this problem using a one-dimensional (1D) deep convolutional neural network. Approach. U-Net-based networks have been proven to be effective in image reconstruction and denoising, and the two-dimensional (2D) U-Net has already been investigated for suppressing HIFU interference in ultrasound monitoring images. In this study, we propose that the one-dimensional (1D) convolution in U-Net-based networks is more suitable for removing HIFU artifacts and can better recover the contaminated B-mode images compared to 2D convolution. Ex vivo and in vivo HIFU experiments were performed on a clinically equivalent ultrasound-guided HIFU platform to collect image data, and the 1D convolution in U-Net, Attention U-Net, U-Net++, and FUS-Net was applied to verify our proposal. Main results. All 1D U-Net-based networks were more effective in suppressing HIFU interference than their 2D counterparts, with over 30% improvement in terms of structural similarity (SSIM) to the uncontaminated B-mode images. Additionally, 1D U-Nets trained using ex vivo datasets demonstrated better generalization performance in in vivo experiments. Significance. These findings indicate that the utilization of 1D convolution in U-Net-based networks offers great potential in addressing the challenges of monitoring in ultrasound-guided HIFU systems.

Quantitative analysis of heat-source estimation of high-intensity focused ultrasound using thermal strain imaging

For the clinical application of high-intensity focused ultrasound (HIFU), improvement in monitoring and guidance methods is necessary to enhance the treatment accuracy. Among the ultrasonic imaging techniques, thermal strain imaging has a potential to estimate temperature change based on the linear relationship between the thermally induced strain and temperature change via a tissue-dependent coefficient. In this study, the coefficient was experimentally measured and the temperature rise induced by the HIFU irradiation was estimated based on the measured coefficient in a tissue mimicking material phantom. The temperature rise estimated using the measured coefficient and that simulated based on a bioheat transfer equation showed a good agreement when the spatial averaged effect in the elevational direction was considered. The exponential decay time constants also agreed well within the range of measurement.

Drug-loaded nanoparticles conjugated with genetically engineered bacteria for cancer therapy

Drug-loaded nanoparticles have been widely used as synergists in high-intensity focused ultrasound (HIFU) tumor ablation therapy. However, these synergists have certain limitations, such as poor tumor targeting and low accumulation at the tumor site, that restrict the therapeutic efficacy of HIFU. In this study, we utilized drug-loaded nanoparticles conjugated with genetically engineered bacteria which can selectively colonize the hypoxic areas of tumor to facilitate HIFU ablation. Genetically modified Escherichia coli carrying gas vesicles (GVs-E. coli), which were gas-filled protein nanostructures, had a negatively charged surface and could specifically target into the tumor. In contrast, paclitaxel (PTX) and perfluorohexane (PFH) co-loaded cationic lipid nanoparticles (PTX-CLs) had a positively charged surface, hence, GVs-E. coli was used as a vehicle by conjugating with PTX-CLs via electrostatic adsorption and subsequently attracting more PTX-CLs to the tumor site. To improve the therapeutic efficiency of HIFU, the GVs in GVs-E. coli and PFH encapsulated in PTX-CLs could act as cavitation nuclei to enhance the HIFU cavitation effect, while PTX entrapped in PTX-CLs was released at the tumor site under HIFU irradiation, enhancing the therapeutic efficacy of HIFU and chemo-synergistic therapy. This novel combination strategy has great potential for cancer treatment.

Real-time monitoring of high intensity focused ultrasound focal damage based on transducer driving signal

Real-time monitoring of high intensity focused ultrasound (HIFU) focal region is a key problem in clinical treatment of focused ultrasound. At present, the change of strong echo in B-ultrasound image is often used in clinical practice to monitor tissue damage in the focal area. However, the strong echo in B-ultrasound image is mostly related to cavitation and boiling bubbles in the focal area, which cannot monitor the treatment status accurately or in real time. In the HIFU treatment, the focal area tissue will be accompanied by changes in temperature, cavitation, boiling, and tissue characteristics. The acoustic load on the surface of the transducer is also constantly changing. To solve this problem, a real-time detection platform of transducer voltage and current is built in this work, which can sense the change of focal area tissue state by measuring the electrical parameters of the transducer. The experimental results show that the stability of the phase difference of the transducer driving signal will be different (the fluctuation amplitude will be different) when different media are placed on the surface of the transducer to change the acoustic load on the surface of the transducer. The fluctuation amplitude of the phase difference of the driving signal will be larger than that in the water when the iron plate is placed in the focal plane. However, the phase fluctuation amplitude will be much smaller than that in the water where the beef liver is placed. This shows that different acoustic loads can cause the electrical parameters of the transducer to change. The isolated bovine liver tissue is used as the HIFU irradiation object, and the results of the phase difference change are compared with the results of the isolated bovine liver tissue damage. The experimental results show that the phase of the transducer voltage and current will change from relatively stable to large fluctuations during the HIFU irradiation. At this time, obvious damage can be seen in the focal region when the irradiation is stopped, and the grayscale of B-ultrasound image has no significant change. In addition, when the cavitation occurs in the focal region, the fluctuation amplitude and range will turn larger. The damage area of the lower focal area under the monitoring method is smaller than that under B-ultrasonic monitoring, and the over input of radiation dose can be avoided. This method can provide a new research scheme and means for HIFU focal area tissue damage monitoring.

Experimental study on the induction of cytotoxic T lymphocyte killing effects and dendritic-cell-based tumor vaccine prepared by high-intensity focused ultrasound.

This study was conducted to explore the high-intensity focused ultrasound (HIFU) prepared antigen-sensitized dendritic cells (DC) and the induction of cytotoxic T lymphocyte (CTL) killing effects by DC and to observe their anti-tumor immunity effects on BALB/c mice. GM-CSF and IL-4 were used to culture the mouse bone marrow-derived DC. HIFU was used to prepare CT-26 tumor cell antigen-sensitive DC vaccines. The capability of T cell proliferation was detected by 3H-TdR, and the CTL cytotoxicity was detected using standard 4h51Cr release assay. The DC-based tumor vaccine prepared using HIFU irradiation was given to normal BALB/c mice. The mice were injected with CT-26 cancer cells subcutaneously seven days later. Further, the occurrence time of the tumor, its weight and volume on the 20th day was observed, and the allergic DC group challenged using repeated-freezing-thawing method alone with the normal saline control group (negative control group) were used to compare group differences. DC in the HIFU group, tumor cell freeze-thawing group, tumor supernatant group, and phosphate buffer solution (PBS) group could induce T cell proliferation in vitro. However, the ability to induce T cell proliferation of DC in the HIFU group and tumor cell freeze-thawing group was significantly higher than those in the tumor supernatant and PBS groups (P < 0. 05). CTL induced in vitro by DC in the HIFU group, and the tumor cell freeze-thawing group had significant cytotoxicity to colon cancer, being significantly different from those in the tumor supernatant and PBS groups (P < 0.05). There was no significant difference between the cytotoxicity of CTL induced in vitro in the HIFU group and the tumor cell freeze-thawing group (P > 0.05). Additionally, significant differences in the occurrence time of the tumor, its weight and volume on the 20th day, and the median survival time of mice among the HIFU group, the repeated-freezing-thawing group, and the negative control group were observed (P < 0.01 or P < 0.05). There was a significant difference between the HIFU and the repeated-freezing-thawing group (P < 0.05). HIFU prepared antigen-sensitized DC could cause substantial proliferation of T cells and CTL with strong anti-tumor effects. The DC-based tumor vaccine prepared using HIFU irradiation affected active immunization on the tumor occurrence in vitro and was better than the DC-based tumor vaccine prepared using the repeated-freezing-thawing method.

Preparation of doxorubicin-loaded metallic organic nanoparticles and their effect for enhancing efficacy of high-intensity focused ultrasound therapy in tumor-bearing mice

To prepare metallic organic nanoparticles that produce synergistic effect in high-intensity focused ultrasound (HIFU) therapy of tumors. Glucose oxidase (GOD), MnO2, ferric iron (Fe3+) and doxorubicin (DOX) were self-assembled by physical adsorption with previously prepared manganese dioxide (MnO2) nanoparticles to obtain GOD-MnO2-Fe3+-DOX nanoparticles (GMFD NPs). HepG2 tumor-bearing nude mouse models were given intravenous injections of normal saline or GMFD NPs followed 4 h later by HIFU at the acoustic power of 90 W with a total treatment time of 3 s. The changes of tumor gray value before and after HIFU irradiation were observed and 24 h after HIFU irradiation, coagulation necrosis in the tumor tissues was examined; the histological changes of the tumor tissues were observed with HE staining. We successfully prepared GMFD NPs, which had an average particle size of 131.23±0.84 nm with a surface potential of 21.87±1.72 mV. GMFD NPs, with a drug loading rate of 40.18%, was capable of releasing more than 77.2% of the loaded DOX within 4 h in acidic environment. In the tumor-bearing mouse models, HIFU irradiation following GMFD NP injection, as compared with saline injection, resulted in significantly enhanced gray value of the tumor (25.5±4.5 vs 18.7±3.9, P=0.04) and greater volume of coagulation necrosis (105.80 ± 1.21 mm3 vs 38.02 ± 0.34 mm3). The energy efficiency factor (EEF) was significantly lower in GMFD NPs group than in saline group (1.79 vs 4.97, P < 0.001). GMFD NPs prepared in this study can enhance tumor ablation efficacy of HIFU and release DOX for further treatment of the residual tumor tissue in mice.

Combining Mechanical High-Intensity Focused Ultrasound Ablation with Chemotherapy for Augmentation of Anticancer Immune Responses.

As a noninvasive therapy, high-intensity focused ultrasound (HIFU) shows great potential in inducing anticancer immune responses. However, the overall anticancer efficacy of HIFU is still limited due to the rapid attenuation of ultrasound waves and inadequacy of ultrasound waves to spread to the whole tumor. Here, we combined HIFU with the ultrasound contrast agent/chemotherapeutic drug co-delivery nanodroplets to achieve synergistic enhancement of anticancer efficacy. Different from the widely used thermal HIFU irradiation, by which excessive heating would result in inactivation of immune stimulatory molecules, we used short acoustic pulses to trigger HIFU (mechanical HIFU, mHIFU) to improve anticancer immune responses. The nanodroplets displayed a mHIFU/glutathione (GSH)-dual responsive drug release property, and their cellular uptake efficacy and toxicity against cancer cells increased upon mHIFU irradiation. The generated immunogenic debris successfully induced the exposure of damage-associated molecular patterns on the cell surface for dendritic cells (DCs) maturation. In vivo experiments with tumor-bearing mice showed that the co-delivery nanodroplets in combination with mHIFU could effectively inhibit tumor growth by inducing immunogenic cell death, activating DCs maturation, and enhancing the effector T-cell infiltration within tumors. This work reveals that combined treatment with nanodroplets and mHIFU is a promising approach to eradicate tumors.

Multifunctional l-arginine-based magnetic nanoparticles for multiple-synergistic tumor therapy.

Tumor therapy is facing the big challenge of insufficient treatment. Here, we report high-intensity focused ultrasound (HIFU)-responsive magnetic nanoparticles based on superparamagnetic iron oxide (SPIO, Fe3O4 NPs) as the shell and l-arginine (LA) as the core entrapped by poly-lactide-co-glycolide (PLGA) nanoparticles (Fe3O4@PLGA/LA NPs) for synergistic breast cancer therapy. These NPs can significantly enhance therapeutic performance due to their enhanced accumulation and prolonged retention at the tumor site under magnetic guidance. The Fe3O4@PLGA/LA NPs exhibited synergistic therapeutic effects by the rational combination of HIFU-based tumor ablation and nitric oxide (NO) assisted antitumor gas therapy. Both Fe3O4 NPs and LA could be released rapidly under HIFU irradiation, where Fe3O4 NPs can promote HIFU-based tumor ablation by changing the acoustic properties of the tumor tissues and LA can spontaneously react with hydrogen peroxide (H2O2) in the tumor microenvironment to generate NO for gas therapy. Moreover, Fe3O4 NPs can react with H2O2 to produce highly reactive oxygen-containing species (ROS) to accelerate the oxidation of LA and the release of NO. This novel strategy showed synergistic tumor growth suppression as compared with individual HIFU therapy or gas therapy. This can be attributed to the rational design of multifunctional NPs with magnetic targeting and multi-modality imaging properties.

Designing intelligent nano-bomb with on-demand site-specific drug burst release to synergize with high-intensity focused ultrasound cancer ablation

High intensity focused ultrasound (HIFU) has been widely used in clinical treatment of cervical cancer for its non-invasiveness and sharp treatment margins with very low complication rates. However, how to intensify the therapeutic efficacy of HIFU by specifically focusing the ultrasound energy on targeting pathological tissues is still a bottleneck for it to realize successful cancer ablation. Herein, a multifunctional organic-inorganic hybrid nanovesicles, by coating ultrathin silica shell on the surface of poly (lactic-co-glycolic acid) (PLGA) loaded with perfluorocarbon (PFOB), hydrophobic antitumor ruthenium complex (RuPOP) and superparamagnetic Fe3O4, has been designed to achieve synchronous ultrasound (US)/magnetic resonance imaging (MR) dual mode imaging-guided HIFU-triggered chemotherapy. The introduction of PFOB in this nanosystem could cause phase transition and make it gasification to cause collapse of the outer ultrathin silicon shell under HIFU irradiation, which results in enhanced intensive mechanical stress during blasting and enhanced therapeutic effect. The blasting behavior of this nanosystem triggered by HIFU also induced the on-demand RuPOP burst release in tumor site, thus maximizing the inhibition on residual tumor induced by inhomogeneous HIFU ablation. Taken together, this treatment strategy could overcome the inevitable tumor recurrence and significantly reduces systemic side effects of HIFU, thus could be further developed for noninvasive cancer therapy.

Feasibility between Bifidobacteria Targeting and Changes in the Acoustic Environment of tumor Tissue for Synergistic HIFU

High intensity focused ultrasound (HIFU) has been recently shown as a rapidly developing new technique for non-invasive ablation of local tumors whose therapeutic efficiency can be significantly improved by changing the tissue acoustic environment (AET). Currently, the method of changing AET is mainly to introduce a medium with high acoustic impedance, but there are some disadvantages such as low retention of the introduced medium in the target area and a short residence time during the process. In our strategy, anaerobic bacterium Bifidobacterium longum (B. longum) which can colonize selectively in hypoxic regions of the animal body was successfully localized and shown to proliferate in the hypoxic zone of tumor tissue, overcoming the above disadvantages. This study aimed to explore the effects of Bifidobacteria on AET (including the structure and acoustic properties of tumor tissues) and HIFU ablation at different time. The results show that the injection of Bifidobacteria increased the collagen fibre number, elastic modulus and sound velocity and decreased neovascularization in tumor tissues. The number of collagen fibres and neovascularization decreased significantly over time. Under the same HIFU irradiation intensity, the B. longum injection increased the coagulative necrosis volume and decreased the energy efficiency factor (EEF). This study confirmed that Bifidobacteria can change the AET and increase the deposition of ultrasonic energy and thereby the efficiency of HIFU. In addition, the time that Bifidobacteria stay in the tumor area after injection is an important factor. This research provides a novel approach for synergistic biologically targeted HIFU therapy.

Effect of Bifidobacterium-induced changes in tumor tissue acoustic properties on efficacy of high-intensity focused ultrasound ablation

To investigate the effects of Bifidobacterium on the acoustic characteristics of tumor tissue and how such acoustic changes affect the efficacy of high-intensity focused ultrasound (HIFU) ablation in nude mice. Forty mice bearing human breast cancer cell (MDA-MB-231) xenograft were randomized into experimental group (n=20) and control group (n=20) for intravenous injection of Bifidobacterium suspension (200 μL, 4 × 108 cfu/mL) and PBS (200 μL) for 3 consecutive days, respectively. Before and at 3 and 7 days after the first injection, shear wave elastography was used to evaluate the hardness of the tumor tissue. On day 7 after the first injection, 10 mice from each group were sacrificed and the sound velocity and sound attenuation of the tumor tissues were measured. The changes in the collagen fibers in the tumors were evaluated using Masson staining, and neovascularization in the tumor was assessed with immunohistochemistry for platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31). The remaining 10 tumor-bearing mice in each group were subjected to HIFU ablation, and the ablation efficiency was evaluated by assessing the changes in irradiation gray values, coagulative necrosis volume, energy efficiency factor (EEF) and irradiation area and by pathological examination with HE staining. In the experimental group, the collagen fibers in the tumor tissues were strong and densely aligned, and the tumors contained fewer new blood vessels showing strip-or spot-like morphologies. In the control group, the collagen fibers in the tumors were thin and loosely arranged, and the tumors showed abundant elongated or round new blood vessels. Bifidobacterium colonized in the tumor 7 days after the injection, and the tumor hardness was significantly greater in the experimental group than in the control group (P=0.01); the acoustic velocity (P=0.001) and the acoustic attenuation (P=0.000) of the tumor tissues were also greater in the experimental group. HIFU irradiation resulted in significantly greater changes in the gray scale of tumor (P=0.0006) and larger coagulative necrosis volume (P=0.0045) in the experimental group than in the control group, and the EEF was significantly smaller in the experimental group (P=0.0134). Bifidobacterium can cause changes in collagen fiber content, acoustic velocity and attenuation in the tumor tissue and reduce the EEF of HIFU irradiation, thereby improving the efficacy of HIFU irradiation.

Sonodynamic Therapy With Anticancer Micelles and High-Intensity Focused Ultrasound in Treatment of Canine Cancer.

Sonodynamic therapy (SDT) is a minimally invasive anticancer therapy involving a chemical sonosensitizer and high-intensity focused ultrasound (HIFU). SDT enables the reduction of drug dose and HIFU irradiation power compared to those of conventional monotherapies. In our previous study, mouse models of colon and pancreatic cancer were used to confirm the effectiveness of SDT vs. drug-only or HIFU-only therapy. To validate its usefulness, we performed a clinical trial of SDT using an anticancer micelle (NC-6300) and our HIFU system in four pet dogs with spontaneous tumors, including chondrosarcoma, osteosarcoma, hepatocellular cancer, and prostate cancer. The fact that no adverse events were observed, suggests the usefulness of SDT.

High-intensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers

While study in the field of polymer mechanochemistry has yielded mechanophores that perform various chemical reactions in response to mechanical stimuli, there is not yet a triggering method compatible with biological systems. Applications such as using mechanoluminescence to generate localized photon flux in vivo for optogenetics would greatly benefit from such an approach. Here we introduce a method of triggering mechanophores by using high-intensity focused ultrasound (HIFU) as a remote energy source to drive the spatially and temporally resolved mechanical-to-chemical transduction of mechanoresponsive polymers. A HIFU setup capable of controlling the excitation pressure, spatial location, and duration of exposure is employed to activate mechanochemical reactions in a cross-linked elastomeric polymer in a noninvasive fashion. One reaction is the chromogenic isomerization of a naphthopyran mechanophore embedded in a polydimethylsiloxane (PDMS) network. Under HIFU irradiation evidence of the mechanochemical transduction is the observation of a reversible color change as expected for the isomerization. The elastomer exhibits this distinguishable color change at the focal spot, depending on ultrasonic exposure conditions. A second reaction is the demonstration that HIFU irradiation successfully triggers a luminescent dioxetane, resulting in localized generation of visible blue light at the focal spot. In contrast to conventional stimuli such as UV light, heat, and uniaxial compression/tension testing, HIFU irradiation provides spatiotemporal control of the mechanochemical activation through targeted but noninvasive ultrasonic energy deposition. Targeted, remote light generation is potentially useful in biomedical applications such as optogenetics where a light source is used to trigger a cellular response.

Bactericidal effects of high intensity focused ultrasound on Bacillus Calmette–Guerin in vivo and in vitro

Purpose: The objective of this study was to investigate the bactericidal effects of high intensity focused ultrasound (HIFU) on Bacillus Calmette–Guerin (BCG, a substitute for Mycobacterium tuberculosis) in vitro and in vivo, and to explore the underlying mechanisms.Materials and methods: HIFU, at a fixed frequency of 1 MHz, was applied to both BCG culture suspensions and subcutaneous BCG abscesses in rats.Results: HIFU irradiation significantly reduced the bacterial survival rate and caused temperature elevations both in vitro and in vivo. Furthermore, BCG suspensions irradiated for 15 s at 3185 and 6369 W/cm2 had increased cell wall damage, which resulted in morphological changes compared to the untreated control group. Additionally, we observed histological changes in the rat subcutaneous abscesses after HIFU ablation at 6369 W/cm2. H&E staining of infected lesions showed coagulative necrosis with central nucleus dissolution and increased infiltration of inflammatory cells, as well as nuclear pyknosis and nuclear fragmentation in the periphery. The volumes of the subcutaneous abscesses in the HIFU-treated group were significantly lower than those in the sham-treated group.Conclusion: HIFU has the therapeutic potential to treat BCG-infected tissues in rats. We theorize that a combination of mechanical, cavitation, and thermal effects most efficiently inactivate BCG bacteria via HIFU. This study is expected to provide a bio-plausible basis for a noninvasive and effective treatment for tuberculosis.

Experimental study in vivo ablation of swine pancreas using high-intensity focused ultrasound.

The objective of this study is to evaluate the feasibility and safety of high-intensity focused ultrasound (HIFU) for ablation of swine pancreas and to detect the pathological variations in pancreas damage. (a) Eight swine were involved and randomly divided into two groups (Group A and B). HIFU was applied on swine in both groups for in vivo ablation of pancreas. The animals were anesthetized, and the artificial acoustic window was built. Then, the irradiation of FEP-BY02 type HIFU on pancreas was applied. (b) Swine in Group A were euthanized immediately after treating with HIFU to examine variations in pancreas. The biochemical evidence of pancreatitis was evaluated by blood samples collected from swine in Group B before and after HIFU. Then, the pancreas of swine in Group B was euthanized on day 5 after treatment to examine the pancreas. All specimens were visually inspected for both ultrasonic focal damage region (UFDR) and pathological routine by a skilled pathologist. (a) The vital signs of all animals were stable during HIFU treatment and recovered well after treatment. (b) UFDR were observed in all HIFU irradiation region of the specimens, without significant size difference between the two groups. The coagulation nucleus pyknosis, cytochylema vacuolation, and nucleus membrane disruption were observed after HIFU in both groups. Membranous structure dissolution and inflammatory cell infiltration were also found after HIFU in swine of Group B. (c) There was no significant difference in the levels of blood amylase in swine of Group B before and after HIFU treatment. It was feasible and safe to use HIFU for ablation of the pancreas in swine.

The Influence of Dynamic Tissue Properties on HIFU Hyperthermia: A Numerical Simulation Study

Accurate temperature and thermal dose prediction are crucial to high-intensity focused ultrasound (HIFU) hyperthermia, which has been used successfully for the non-invasive treatment of solid tumors. For the conventional method of prediction, the tissue properties are usually set as constants. However, the temperature rise induced by HIFU irradiation in tissues will cause changes in the tissue properties that in turn affect the acoustic and temperature field. Herein, an acoustic–thermal coupling model is presented to predict the temperature and thermal damage zone in tissue in terms of the Westervelt equation and Pennes bioheat transfer equation, and the individual influence of each dynamic tissue property and the joint effect of all of the dynamic tissue properties are studied. The simulation results show that the dynamic acoustic absorption coefficient has the greatest influence on the temperature and thermal damage zone among all of the individual dynamic tissue properties. In addition, compared with the conventional method, the dynamic acoustic absorption coefficient leads to a higher focal temperature and a larger thermal damage zone; on the contrary, the dynamic blood perfusion leads to a lower focal temperature and a smaller thermal damage zone. Moreover, the conventional method underestimates the focal temperature and the thermal damage zone, compared with the simulation that was performed using all of the dynamic tissue properties. The results of this study will be helpful to guide the doctors to develop more accurate clinical protocols for HIFU treatment planning.

A High-Precision US-Guided Robot-Assisted HIFU Treatment System for Breast Cancer

Abstract Breast cancer is the most commonly diagnosed cancer in women. A strong treatment candidate is high-intensity focused ultrasound (HIFU), a non-invasive therapeutic method that has already demonstrated its promise. To improve the precision and lower the cost of HIFU treatment, our group has developed an ultrasound (US)-guided, five-degree-of-freedom (DOF), robot-assisted HIFU system. We constructed a fully functional prototype enabling easy three-dimensional (3D) US image reconstruction, target segmentation, treatment path generation, and automatic HIFU irradiation. The position was calibrated using a wire phantom and the coagulated area was assessed on heterogeneous tissue phantoms. Under the US guidance, the centroids of the HIFU-ablated area deviated by less than 2 mm from the planned treatment region. The overshoot around the planned region was well below the tolerance of clinical usage. Our system is considered to be sufficiently accurate for breast cancer treatment.

On-Demand Drug Release from Dual-Targeting Small Nanoparticles Triggered by High-Intensity Focused Ultrasound Enhanced Glioblastoma-Targeting Therapy.

Glioblastoma is one of the most challenging and intractable tumors with the difficult treatment and poor prognosis. Unsatisfactory traditional systemic chemotherapies for glioblastoma are mainly attributed to the insufficient and nonspecific drug delivery into the brain tumors as well as the incomplete drug release at the tumor sites. Inspired by the facts that angiopep-2 peptide is an acknowledged dual-targeting moiety for brain tumor-targeting delivery and high-intensity focused ultrasound (HIFU) is an ideal trigger for drug release with an ultrahigh energy and millimeter-sized focus ability, in the present study, a novel HIFU-responsive angiopep-2-modified small poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) drug delivery system holding doxorubicin/perfluorooctyl bromide (ANP-D/P) was designed to increase the intratumoral drug accumulation, further trigger on-demand drug release at the glioblastoma sites, and enhance glioblastoma therapy. It was shown that the ANP-D/P was stable and had a small size of 41 nm. The angiopep-2 modification endowed the ANP-D/P with improved blood-brain barrier transportation and specific accumulation in glioblastoma tissues by 17 folds and 13.4 folds compared with unmodified NPs, respectively. Under HIFU irradiation, the ANP-D/P could release 47% of the drug within 2 min and induce the apoptosis of most tumor cells. HIFU-triggered instantaneous drug release at the glioblastoma sites eventually enabled the ANP-D/P to achieve the strongest antiglioblastoma efficacy with the longest median survival time (56 days) of glioblastoma-bearing mice and the minimum vestiges of tumor cells in the pathological slices among all groups. In conclusion, the HIFU-responsive ANP-D/P in this study provided a new way for glioblastoma therapy with a great potential for clinical applications.

Efficacy enhancement of folate-receptor targeted phasetransition contrast agent for HIFU ablation of tumor in vivo

Objective To explore the value of Folate-receptor targeted phaseransition nanoparticle contrast agent (FR-PNPCA) in increasing efficacy of high intensity focused ultrasound (HIFU) ablation of xerograft tumor in vivo. Methods Firstly, the FR-PNPCA and non-targeted phasetransition nanoparticle contrast agent (PNPCA) were prepared by a two-step emulsification method respectively. Then 36 nude mice bearing xerograft ovary tumor were randomly divided into 3 groups and underwent HIFU ablation respectively. Group A was the control group, which was irradiated at 2 h after the injection of saline by the tail vein. Group B was the untargeted group, which was irradiated at 2 h after the injection of PNPCA. Group C was the targeted group, which was irradiated at 2 h after the injection of FR-PNPCA.The gray-scale changes of irradiating areas in tumors were observed during ablation. Some mice were sacrificed at 1 h after ablation and the tumors were resected to observe the coagulative necrosis by TTC staining and HE staining. Lastly, The remain mice were sacrificed at 24 h after ablation, and the tumor sections were analyzed with immunohistochemical method including PCNA and TUNEL to explore the effect of HIFU ablation on tumor cell proliferating and necrosis. Results Obvious gray-scale changes could be seen in all tumors in group B and C immediately after HIFU irradiation, but almost no changes were founded in group A. The differences of gray-scale change values and squares between group B and C were statistically significant (P<0.05). Coagulative necrosis with irregular shape and clear boundary was observed in group B and C after irradiation, and the range of necrosis in group C was much larger than that in group B (P<0.01), but little necrosis was founded in group A. In addition, the differences of proliferating rate and necrosis rate between group B and C were statistically significant (P<0.05). Conclusions FR-PNPCA can not only significantly enhance the efficacy, but also can help monitoring the process during HIFU ablation of tumor ablation. Therefore, it is a promising synergistic agent for HIFU ablation. Key words: High-intensity focused ultrasound; Microbubbles; Nanoechnology; Folate-receptor

Ultrasound image based visual servoing for moving target ablation by high intensity focused ultrasound.

BackgroundAlthough high intensity focused ultrasound (HIFU) is a promising technology for tumor treatment, a moving abdominal target is still a challenge in current HIFU systems. In particular, respiratory‐induced organ motion can reduce the treatment efficiency and negatively influence the treatment result. In this research, we present: (1) a methodology for integration of ultrasound (US) image based visual servoing in a HIFU system; and (2) the experimental results obtained using the developed system.Materials and methodsIn the visual servoing system, target motion is monitored by biplane US imaging and tracked in real time (40 Hz) by registration with a preoperative 3D model. The distance between the target and the current HIFU focal position is calculated in every US frame and a three‐axis robot physically compensates for differences. Because simultaneous HIFU irradiation disturbs US target imaging, a sophisticated interlacing strategy was constructed.ResultsIn the experiments, respiratory‐induced organ motion was simulated in a water tank with a linear actuator and kidney‐shaped phantom model. Motion compensation with HIFU irradiation was applied to the moving phantom model. Based on the experimental results, visual servoing exhibited a motion compensation accuracy of 1.7 mm (RMS) on average. Moreover, the integrated system could make a spherical HIFU‐ablated lesion in the desired position of the respiratory‐moving phantom model.ConclusionsWe have demonstrated the feasibility of our US image based visual servoing technique in a HIFU system for moving target treatment.