Focused Ultrasound Treatment Research Articles

Imaged-guided focused ultrasound in combination with various formulations of doxorubicin for the treatment of diffuse intrinsic pontine glioma

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a notoriously difficult tumor to treat, with an overall survival of DIPG patients being only 11 months. One of the major obstacles for the effective treatment of DIPG is the blood–brain barrier (BBB). In order to circumvent the BBB, drug delivery methods are needed that target the pontine area. One such approach is microbubble-mediated focused ultrasound (FUS)—a non-invasive method that can temporarily and locally open the BBB. Previously, it was shown that FUS is safe with minimal side effects and rapid recovery times in preclinical animal models with different DIPG tumors. However, recent studies have shown that combining FUS with a single treatment of the chemotherapeutic drug doxorubicin did not improve survival in a DIPG xenograft model. As the duration of doxorubicin exposure might play a role in tumor response, we hypothesized that the use of a long-circulation (PEGylated) liposomal formulation of doxorubicin could lead to improved overall survival through a longer exposure time to the tumor.MethodDIPG xenograft models were established with orthotopic injections of HSJD-DIPG-07 tumor cells into the pontine area of female athymic nude-foxn1nu mice. Tumor engraftment was confirmed with bioluminescence imaging (BLI) 40 days post-inoculation. Mice were randomized into groups receiving either liposomal formulations of doxorubicin (2B3-101 or Caelyx®) or free doxorubicin in combination with or without FUS treatment. Treatment groups received 5 mg/kg 2B3-101 or Caelyx® 1 h before FUS treatment or 5 mg/kg free doxorubicin immediately after FUS.ResultsHistological analysis, however, revealed liposome extravasation in healthy controls but not in HSJD-DIPG-07 xenograft 24 h after treatment. Furthermore, BLI monitoring did not show reduced signal after treatment, which was further illustrated with a survival analysis, showing no significant difference between treated and control animals (p = 0.3).ConclusionWe did not observe a treatment effect after a single dose of free doxorubicin or the liposomal formulations 2B3-101 or Caelyx® in combination with FUS in DIPG-bearing mice.

Focused Ultrasound for Pediatric Diseases.

Focused ultrasound (FUS) is a noninvasive therapeutic technology with multiple pediatric clinical applications. The ability of focused ultrasound to target tissues deep in the body without exposing children to the morbidities associated with conventional surgery, interventional procedures, or radiation offers significant advantages. In 2021, there are 10 clinical pediatric focused ultrasound studies evaluating various musculoskeletal, oncologic, neurologic, and vascular diseases of which 8 are actively recruiting and 2 are completed. Pediatric musculoskeletal applications of FUS include treatment of osteoid osteoma and bone metastases using thermal ablation and high-intensity FUS. Pediatric oncologic applications of FUS include treatment of soft tissue tumors including desmoid tumors, malignant sarcomas, and neuroblastoma with high-intensity FUS ablation alone, or in combination with targeted chemotherapy delivery. Pediatric neurologic applications include treatment of benign tumors such as hypothalamic hamartomas with thermal ablation and malignant diffuse intrinsic pontine glioma with low-intensity FUS for blood brain barrier opening and targeted drug delivery. Additionally, low-intensity FUS can be used to treat seizures. Pediatric vascular applications of FUS include treatment of arteriovenous malformations and twin-twin transfusion syndrome using ablation and vascular occlusion. FUS treatment appears safe and efficacious in pediatric populations across many subspecialties. Although there are 7 Food and Drug Administration-approved indications for adult applications of FUS, the first Food and Drug Administration approval for pediatric patients with osteoid osteoma was obtained in 2020. This review summarizes the preclinical and clinical research on focused ultrasound of potential benefit to pediatric populations.

Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke.

Objective and Impact Statement. This study examined the efficacy and safety of pulsed, low-intensity focused ultrasound (LIFU) and determined its ability to provide neuroprotection in a murine permanent middle cerebral artery occlusion (pMCAO) model. Introduction. Focused ultrasound (FUS) has emerged as a new therapeutic strategy for the treatment of ischemic stroke; however, its nonthrombolytic properties remain ill-defined. Therefore, we examined how LIFU influenced neuroprotection and vascular changes following stroke. Due to the critical role of leptomeningeal anastomoses or pial collateral vessels, in cerebral blood flow restoration and tissue protection following ischemic stroke, we also investigated their growth and remodeling. Methods. Mice were exposed to transcranial LIFU (fundamental frequency: 1.1 MHz, sonication duration: 300 ms, interstimulus interval: 3 s, pulse repetition frequency: 1 kHz, duty cycle per pulse: 50%, and peak negative pressure: -2.0 MPa) for 30 minutes following induction of pMCAO and then evaluated for infarct volume, blood-brain barrier (BBB) disruption, and pial collateral remodeling at 24 hrs post-pMCAO. Results. We found significant neuroprotection in mice exposed to LIFU compared to mock treatment. These findings correlated with a reduced area of IgG deposition in the cerebral cortex, suggesting attenuation of BBB breakdown under LIFU conditions. We also observed increased diameter of CD31-postive microvessels in the ischemic cortex. We observed no significant difference in pial collateral vessel size between FUS and mock treatment at 24 hrs post-pMCAO. Conclusion. Our data suggests that therapeutic use of LIFU may induce protection through microvascular remodeling that is not related to its thrombolytic activity.

Focused Ultrasound Stimulation of Microbubbles in Combination With Radiotherapy for Acute Damage of Breast Cancer Xenograft Model.

Objective: Several studies have focused on the use of ultrasound-stimulated microbubbles (USMB) to induce vascular damage in order to enhance tumor response to radiation. Methods: In this study, power Doppler imaging was used along with immunohistochemistry to investigate the effects of combining radiation therapy (XRT) and USMB using an ultrasound-guided focused ultrasound (FUS) therapy system in a breast cancer xenograft model. Specifically, MDA-MB-231 breast cancer xenograft tumors were induced in severe combined immuno-deficient female mice. The mice were treated with FUS alone, ultrasound and microbubbles (FUS + MB) alone, 8 Gy XRT alone, or a combined treatment consisting of ultrasound, microbubbles, and XRT (FUS + MB + XRT). Power Doppler imaging was conducted before and 24 h after treatment, at which time mice were sacrificed and tumors assessed histologically. The immunohistochemical analysis included terminal deoxynucleotidyl transferase dUTP nick end labeling, hematoxylin and eosin, cluster of differentiation-31 (CD31), Ki-67, carbonic anhydrase (CA-9), and ceramide labeling. Results: Tumors receiving treatment of FUS + MB combined with XRT demonstrated significant increase in cell death (p = 0.0006) compared to control group. Furthermore, CD31 and Power Doppler analysis revealed reduced tumor vascularization with combined treatment indicating (P < .0001) and (P = .0001), respectively compared to the control group. Additionally, lesser number of proliferating cells with enhanced tumor hypoxia, and ceramide content were also reported in group receiving a treatment of FUS + MB + XRT. Conclusion: The study results demonstrate that the combination of USMB with XRT enhances treatment outcomes.

Factors Associated with Energy Efficiency of Focused Ultrasound Through the Skull: A Study of 3D-Printed Skull Phantoms and Its Comparison with Clinical Experiences.

While focused ultrasound (FUS) is non-invasive, the ultrasound energy is attenuated by the skull which results in differences in energy efficiency among patients. In this study, we investigated the effect of skull variables on the energy efficiency of FUS. The thickness and density of the skull and proportion of the trabecular bone were selected as factors that could affect ultrasound energy transmittance. Sixteen 3D-printed skull models were designed and fabricated to reflect the three factors. The energy of each phantom was measured using an ultrasonic sound field energy measurement system. The thickness and proportion of trabecular bone affected the attenuation of transmitted energy. There was no difference in the density of the trabecular bone. In clinical data, the trabecular bone ratio showed a significantly greater correlation with dose/delivered energy than that of thickness and the skull density ratio. Currently, for clinical non-thermal FUS, the data are not sufficient, but we believe that the results of this study will be helpful in selecting patients and appropriate parameters for FUS treatment.

Pilot study of focused ultrasound for drug-resistant epilepsy.

ObjectiveThe neuromodulatory effects of focused ultrasound (FUS) have been demonstrated in animal epilepsy models; however, the safety and efficacy of FUS in humans with epilepsy have not been well established. Patients with drug‐resistant epilepsy (DRE) undergoing stereo‐electroencephalography (SEEG) provide an opportunity to investigate the neuromodulatory effects of FUS in humans.MethodsPatients with DRE undergoing SEEG for localization of the seizure onset zone (SOZ) were prospectively enrolled. FUS was delivered to the SOZ using a neuronavigation‐guided FUS system (ceiling spatial‐peak temporal‐average intensity level = 2.8 W/cm2, duty cycle = 30%, modulating duration = 10 min). Simultaneous SEEG recordings were obtained during sonication and for 3 days after treatment. Seizures, interictal epileptiform discharges, and adverse events after FUS were monitored.ResultsSix patients met the eligibility criteria and completed FUS treatment. A decrease in seizure frequency was observed in two patients within the 3‐day follow‐up; however, one patient presented an increase in the frequency of subclinical seizures. Posttreatment magnetic resonance imaging revealed neither lesion nor brain edema. Significant changes in spectral power of SEEG were noted at the targeted electrodes during FUS treatment. One patient reported subjective scalp heating during FUS, and one patient developed transient naming and memory impairment that resolved within 3 weeks after FUS.SignificanceFUS can be safely delivered to the SOZ of patients with DRE, resulting in significant changes in spectral power of SEEG. A larger sample cohort and pursuing optimal sonication parameters will be required to elucidate the neuromodulatory effects of FUS when used for seizure control.

Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

Image-guided thermosensitive liposomes for focused ultrasound enhanced co-delivery of carboplatin and SN-38 against triple negative breast cancer in mice

Triggerable nanocarriers have the potential to significantly improve the therapeutic index of existing anticancer agents. They allow for highly localised delivery and release of therapeutic cargos, reducing off-target toxicity and increasing anti-tumour activity. Liposomes may be engineered to respond to an externally applied stimulus such as focused ultrasound (FUS). Here, we report the first co-delivery of SN-38 (irinotecan's super-active metabolite) and carboplatin, using an MRI-visible thermosensitive liposome (iTSL). MR contrast enhancement was achieved by the incorporation of a gadolinium lipid conjugate in the liposome bilayer along with a dye-labelled lipid for near infrared fluorescence bioimaging. The resulting iTSL were successfully loaded with SN-38 in the lipid bilayer and carboplatin in the aqueous core - allowing co-delivery of both. The iTSL demonstrated both thermosensitivity and MR-imageability. In addition, they showed effective local targeted co-delivery of carboplatin and SN-38 after triggered release with brief FUS treatments. A single dosage induced significant improvement of anti-tumour activity (over either the free drugs or the iTSL without FUS-activation) in triple negative breast cancer xenografts tumours in mice.

Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain

The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

The Applications of Focused Ultrasound (FUS) in Alzheimer's Disease Treatment: A Systematic Review on Both Animal and Human Studies.

Alzheimer’s disease (AD) affects the basic ability to function and has imposed an immense burden on the community and health care system. Focused ultrasound (FUS) has recently been proposed as a novel noninvasive therapeutic approach for AD. However, systematic reviews on the FUS application in AD treatment have not been forthcoming. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria to summarize the techniques associated with safety and efficacy, as well as possible underlying mechanisms of FUS effects on AD in animal and human studies. Animal studies demonstrated FUS with microbubbles (FUS-MB) induced blood-brain-barrier (BBB) opening that could facilitate various therapeutic agents entering the brain. Repeated FUS-MB and FUS stimulation can relieve AD pathology and improve cognitive and memory function. Human studies showed repeated FUS-MB are well tolerated with few adverse events and FUS stimulation could enhance local perfusion and neural function, which correlated with cognitive improvement. We conclude that FUS is a feasible and safe therapeutic and drug delivery strategy for AD. However, FUS treatment on humans is still in the early stages and requires further optimization and standardization.

Contrast-Free Detection of Focused Ultrasound-Induced Blood-Brain Barrier Opening Using Diffusion Tensor Imaging.

Focused ultrasound (FUS) has emerged as a non-invasive technique to locally and reversibly disrupt the blood-brain barrier (BBB). Here, we investigate the use of diffusion tensor imaging (DTI) as a means of detecting FUS-induced BBB opening at the absence of an MRI contrast agent. A non-human primate (NHP) was repeatedly treated with FUS and preformed circulating microbubbles to transiently disrupt the BBB (n = 4). T1- and diffusion-weighted MRI scans were acquired after the ultrasound treatment, with and without gadolinium-based contrast agent, respectively. Both scans were registered with a high-resolution T1-weighted scan of the NHP to investigate signal correlations. DTI detected an increase in fractional anisotropy from 0.21 ± 0.02 to 0.38 ± 0.03 (82.6 ± 5.2% change) within the targeted area one hour after BBB opening. Enhanced DTI contrast overlapped by 77.22 ± 9.2% with hyper-intense areas of gadolinium-enhanced T1-weighted scans, indicating diffusion anisotropy enhancement only within the BBB opening volume. Diffusion was highly anisotropic and unidirectional within the treated brain region, as indicated by the direction of the principal diffusion eigenvectors. Polar and azimuthal angle ranges decreased by 35.6% and 82.4%, respectively, following BBB opening. Evaluation of the detection methodology on a second NHP (n = 1) confirmed the across-animal feasibility of the technique. In conclusion, DTI may be used as a contrast-free MR imaging modality in lieu of contrast-enhanced T1 mapping for detecting BBB opening during focused-ultrasound treatment or evaluating BBB integrity in brain-related pathologies.

Focused Ultrasound-Induced Cavitation Sensitizes Cancer Cells to Radiation Therapy and Hyperthermia.

Focused ultrasound (FUS) has become an important non-invasive therapy for solid tumor ablation via thermal effects. The cavitation effect induced by FUS is thereby avoided but applied for lithotripsy, support drug delivery and the induction of blood vessel destruction for cancer therapy. In this study, head and neck cancer (FaDu), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS by using an in vitro FUS system followed by single-dose X-ray radiation therapy (RT) or water bath hyperthermia (HT). Sensitization effects of short FUS shots with cavitation (FUS-Cav) or without cavitation (FUS) to RT or HT (45 °C, 30 min) were evaluated. FUS-Cav significantly increases the sensitivity of cancer cells to RT and HT by reducing long-term clonogenic survival, short-term cell metabolic activity, cell invasion, and induction of sonoporation. Our results demonstrated that short FUS treatment with cavitation has good potential to sensitize cancer cells to RT and HT non-invasively.

β-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood-Brain Barrier Opening in Alzheimer's Disease.

The blood–brain barrier (BBB) limits therapeutic delivery in Alzheimer’s disease (AD) and other neurological disorders. Animal models have demonstrated safe BBB opening and reduction in β-amyloid plaque with focused ultrasound (FUS). We recently demonstrated the feasibility, safety, and reversibility of FUS-induced BBB opening in the hippocampus and entorhinal cortex in six participants with early AD. We now report the effect of BBB opening with FUS treatment on β-amyloid plaque. Six participants underwent 18F-Florbetaben PET scan at baseline and 1 week after the completion of the third FUS treatment (60 days interval). PET analysis comparing the hippocampus and entorhinal cortex in the treated and untreated hemispheres revealed a decrease in the ratio of 18F-Florbetaben ligand binding. The standard uptake value ratios (SUVr) reduction ranged from 2.7% to 10% with an average of 5.05% (±2.76) suggesting a decrease in β-amyloid plaque.

Transcranial cavitation localization by time difference of arrival algorithm using four sensors

Cavitation is widely existing in focused ultrasound (FUS)-mediated therapies in the brain, such as FUS in combination with microbubble-induced blood-brain barrier disruption, nonthermal ablation, as well as transcranial histotripsy therapy. Accurately knowing the 3-D location of cavitation in real time can improve the treatment targeting accuracy and avoid off-target tissue damage. However, the skull induces strong phase and amplitude aberration to the cavitation signals and presents a significant challenge to the transcranial cavitation localization. Existing techniques for 3-D cavitation localization use hemispherical multi-element arrays combined with passive beamforming and adaptive skull-specific correction algorithm. However, these techniques require expensive equipment and treatment planning. Their time-consuming computations limit applications in real-time cavitation monitoring, which is critically needed to ensure the safety and efficacy of the FUS treatment. The object of this study was to investigate the feasibility of using a four-sensor network to transcranially locate the cavitation source in 3-D by time difference of arrival algorithm. The positional error of transcranial cavitation localization with the human skull along x, y, and z axes were 1.7 ± 1.2 mm, 1.6 ± 1.7 mm, and 4.1 ± 1.5 mm, respectively. For comparison, the positional error of without the human skull were 1.2 ± 1.8 mm, 0.9 ± 1.6 mm, and 3.1 ± 2.3 mm, respectively.

Abstract LB-078: Effect of a combined immune checkpoint inhibitor and mechanical focused ultrasound treatment on intratumoral immune response in a MC38 preclinical model

Abstract Recent preclinical and clinical data suggest that Focused ultrasound (FUS) can enhance host antitumor immune response. FUS is a minimally invasive therapy focusing beams of high power ultrasound to locally induce tissue damage such as thermal necrosis or apoptosis, approved for treatment of some solid malignancies. As a result, there is an interest in combining FUS and immune checkpoint inhibitors (ICI) to enhance ICI response. However, the effect of such combined treatment on the immune response remains unclear. We have evaluated the combination of anti-PD1 and FUS in the MC38 preclinical colon cancer model. FUS was delivered using a confocal device generating and monitoring mechanical cavitational ultrasound (peak negative pressure -20.5MPa). Mice were treated each week with FUS three days before injections of anti-PD1 antibodies. A longitudinal follow-up of tumor growth and overall survival was performed. Lymphoid and myeloid intratumoral immune cells were assessed by flow cytometry on days one, three and six after the start of the combined treatment, including expression levels of co-inhibitory and co-stimulatory molecules such as PD1, PDL-1, TIGIT, LAG3, TIM3 and ICOS. Combined treatment of FUS and ICI led to significant increased survival (up to three-fold for the combination compared to control) and improved tumor growth control. Flow cytometry revealed various changes in lymphoid as well as myeloid populations. The CD8+ TNFa+ / CD4+ FoxP3+ cells ratio was increased for combined group compared to non-treated, the fraction of CD11b+ cells in treated groups was increased and could be explained by an increase in the granulocyte population. Moreover, ICI and FUS combination may lead to increased antigen priming as increased CD11c+ CMHIIhigh conventional dendritic cells (DC), activated CD8- and Sirpa-CD24- subpopulations were found. As for co-inhibitory and co-stimulatory molecules expression at cell surface, flow cytometry showed increased PD1 and LAG3 expression by CD8+ cells on day 1 (respectively two- and three-fold increases for combined group compared to control); an increased TIM3 expression by CD4+ cells for combined group on day 3;an increased PD1 expression by CD4+ cells for FUS-treated groups and by tumor cells for combined group on day 6; increased PDL1 and TIGIT expression by CD8+ cells on day 6. Combination of therapeutic ultrasound and anti PD1 results in a significant improvement in tumor growth control and survival, possibly through significant changes in immune infiltrate such as increased activated CD8+ cells / inhibitory CD4+ cells ratio, an important clinical biomarker of response, increased granulocyte cell populations and an increased DC-mediated response. However, the combined treatment led to increased PD1 expression, as well as of other co-inhibitory molecules, by CD4+, CD8+ and tumor cells possibly explaining the transient effect of the combination. Our observation carries important implications for future FUS/ICI therapies at clinical and mechanistic levels. Citation Format: Cécile Fant, Chloé Grasselly, Morgane Denis, Doriane Mathé, Pierre-Antoine Choffour, Loic Daunizeau, Jean-Louis Mestas, Cyril Lafon, Christophe Caux, Stéphane Depil, Charles Dumontet, Frédéric Padilla. Effect of a combined immune checkpoint inhibitor and mechanical focused ultrasound treatment on intratumoral immune response in a MC38 preclinical model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-078.

Precision Targeted Ablation of Fine Neurovascular Structures In Vivo Using Dual-mode Ultrasound Arrays

Carotid bodies (CBs) are chemoreceptors that monitor and register changes in the blood, including the levels of oxygen, carbon dioxide, and pH, and regulate breathing. Enhanced activity of CBs was shown to correlate with a significant elevation in the blood pressure of patients with hypertension. CB removal or denervation were previously shown to reduce hypertension. Here we demonstrate the feasibility of a dual-mode ultrasound array (DMUA) system to safely ablate the CB in vivo in a spontaneously hypertensive rat (SHR) model of hypertension. DMUA imaging was used for guiding and monitoring focused ultrasound (FUS) energy delivered to the target region. In particular, 3D imaging was used to identify the carotid bifurcation for targeting the CBs. Intermittent, high frame rate imaging during image-guided FUS (IgFUS) delivery was used for monitoring the lesion formation. DMUA imaging provided feedback for closed-loop control (CLC) of the lesion formation process to avoid overexposure. The procedure was tolerated well in over 100 SHR and normotensive rats that received unilateral and bilateral treatments. The measured mean arterial pressure (MAP) exhibited measurable deviation from baseline 2–4 weeks post IgFUS treatment. The results suggest that the direct unilateral FUS treatment of the CB might be sufficient to reduce the blood pressure in hypertensive rats and justify further investigation in large animals and eventually in human patients.

Multifunctional Nanoparticles Encapsulating Astragalus Polysaccharide and Gold Nanorods in Combination with Focused Ultrasound for the Treatment of Breast Cancer.

PurposeFocused ultrasound (FUS) is a noninvasive method to produce thermal and mechanical destruction along with an immune-stimulatory effect against cancer. However, FUS ablation alone appears insufficient to generate consistent antitumor immunity. In this study, a multifunctional nanoparticle was designed to boost FUS-induced immune effects and achieve systemic, long-lasting antitumor immunity, along with imaging and thermal enhancement.Materials and MethodsPEGylated PLGA nanoparticles encapsulating astragalus polysaccharides (APS) and gold nanorods (AuNRs) were constructed by a simple double emulsion method, characterized, and tested for cytotoxicity. The abilities of PA imaging and thermal-synergetic ablation efficiency were analyzed in vitro and in vivo. The immune-synergistic effect on dendritic cell (DC) differentiation in vitro and the immune response in vivo were also evaluated.ResultsThe obtained APS/AuNR/PLGA-PEG nanoparticles have an average diameter of 255.00±0.1717 nm and an APS-loading efficiency of 54.89±2.07%, demonstrating their PA imaging capability and high biocompatibility both in vitro and in vivo. In addition, the as-prepared nanoparticles achieved a higher necrosis cell rate and induced apoptosis rate in an in vitro cell suspension assay, greater necrosis area and decreased energy efficiency factor (EEF) in an in vivo rabbit liver assay, and remarkable thermal-synergic performance. In particular, the nanoparticles upregulated the expression of MHC-II, CD80 and CD86 on cocultured DCs in vitro, followed by declining phagocytic function and enhanced interleukin (IL)-12 and interferon (INF)-γ production. Furthermore, they boosted the production of tumor necrosis factor (TNF)-α, IFN-γ, IL-4, IL-10, and IgG1 (P< 0.001) but not IgG2a. Immune promotion peaked on day 3 after FUS in vivo.ConclusionThe multifunctional APS/AuNR/PLGA-PEG nanoparticles can serve as an excellent synergistic agent for FUS therapy, facilitating real-time imaging, promoting thermal ablation effects, and boosting FUS-induced immune effects, which have the potential to be used for further clinical FUS treatment.

Focused ultrasound ablation of solid tumors: Feasibility of planning tissue-selective treatments.

e15600 Background: Focused ultrasound (FUS) is a noninvasive, nonionizing, repeatable local ablative therapy that induces mechanical fractionation or thermal necrosis of a variety of solid tumors including hepatocellular carcinoma, prostate cancer, and desmoid fibromatosis. Recent feasibility studies in animal models have demonstrated the possibility of designing focused ultrasound treatments that are selective (e.g. spare healthy tissue, nerves, and blood vessels) due to differences in tissue and tumor mechanical properties. Given wide variation in individual tumor and patient characteristics, mechanics-based predictions of ablation zone features in different tissues under a range of FUS device settings are needed to permit personalized treatment planning. Methods: A finite difference computational method is used to simulate FUS ablation of tissues with variable mechanical properties (shear moduli of 0.6 – 200 kPa) under different FUS sonication parameters (frequency and peak pressure). The model calculates strain fields contributing to tissue ablation in FUS treatments which are used to predict ablation zone radii and boundary characteristics. Simulation predictions in model tissues are then compared to histology obtained from FUS-treated porcine tissue samples with similar mechanical properties. Results: The mechanical properties of model tissues and FUS treatment parameters have distinct effects on predicted minimum ablation zone radii. For example, smaller ablation zone radii are achieved in stiffer vessel wall than liver under given FUS sonication parameters. In each tissue, lower frequency and higher peak pressure FUS sonication predict a larger ablation zone. Combined variation of sonication frequency and peak pressure are found to achieve wider variation in ablation zone radius than previously achieved with frequency variation alone. Predicted ablation zone radii and boundary characteristics are consistent with the observed histology of FUS-treated tissues. Conclusions: Results show that simulations accounting for tissue mechanical properties and device settings can predict tissue selectivity and ablation zone characteristics observed in FUS procedures. This study demonstrates the potential of using noninvasive measurements of tissue and tumor properties obtained, for example, via shear wave elastography, in combination with micromechanical tissue ablation simulations to develop personalized, selective focused ultrasound treatments for solid tumors.

Vasomodulation of peripheral blood flow by focused ultrasound potentiates improvement of diabetic neuropathy

ObjectiveEffective treatment methods for diabetic peripheral neuropathy are still lacking. Here, a focused ultrasound (FUS) technique was developed to improve blood flow in diabetic peripheral vessels and potentially treat diabetic...