Low-Intensity Pulsed Ultrasound Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity by Upregulating Neurotrophic Factors.

OBJECTIVE: Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited. Recent research has shown that low-intensity pulsed ultrasound (LIPUS) holds promise for treating neurodegenerative diseases and traumatic brain injuries. Our objective was to explore the therapeutic potential of LIPUS for HIBD. METHODS: Due to the lack of a suitable animal model for neonatal HIBD, we will initially simulate the therapeutic effects of LIPUS on neuronal cells under oxidative stress and neuroinflammation using cell experiments. Previous studies have investigated the biologic responses following intracranial injection of 6-hydroxydopamine (6-OHDA). In this experiment, we will focus on the biologic effects produced by LIPUS treatment on neuronal cells (specifically, SH-SY5Y cells) without the presence of other neuroglial cell assistance after stimulation with 6-OHDA. RESULTS: We found that (i) pulsed ultrasound exposure, specifically three-intermittent sonication at intensities ranging from 0.1 to 0.5 W/cm², did not lead to a significant decrease in viability among SH-SY5Y cells; (ii) LIPUS treatment exhibited a positive effect on cell viability, accompanied by an increase in glial cell-derived neurotrophic factor (GDNF) levels and a decrease in caspase three levels; (iii) the administration of 6-OHDA had a significant impact on cell viability, resulting in a decrease in both brain cell-derived neurotrophic factor (BDNF) and GDNF levels, while concurrently elevating caspase three and matrix metalloproteinase-9 (MMP-9) levels; and (iv) LIPUS treatment demonstrated its potential to alleviate the changes induced by 6-OHDA, particularly in the levels of BDNF, GDNF, and tyrosine hydroxylase (TH). CONCLUSION: LIPUS treatment may possess partial therapeutic capabilities for SH-SY5Y cells damaged by 6-OHDA neurotoxicity. Our findings enhance our understanding of the effects of LIPUS treatment on cell viability and its modulation of key factors involved in the pathophysiology of HIBD and show the promising potential of LIPUS as an alternative therapeutic approach for neonates with HIBD.

Application of transcranial brain stimulation in dementia.

The number of patients with dementia grows rapidly as the global population ages, which posits tremendous health-care burden to the society. Only cholinesterase inhibitors and a N-methyl-D-aspartate receptor antagonist have been approved for treating patients with Alzheimer's disease (AD), and their clinical effects remained limited. Medical devices serve as an alternative therapeutic approach to modulating neural activities and enhancing cognitive function. Four major brain stimulation technologies including deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS) have been applied to AD in a clinical trial setting. DBS allows electrical stimulation at the specified nucleus but remains resource-demanding, and after all, an invasive surgery; whereas TMS and tDCS are widely available and affordable but less ideal with respect to localization. The unique physical property of TUS, on the other hand, allows both thermal and mechanical energy to be transduced and focused for neuromodulation. In the context of dementia, using focused ultrasound to induce blood-brain barrier opening for delivering drugs and metabolizing amyloid protein has drawn great attention in recent years. Furthermore, low-intensity pulsed ultrasound has demonstrated its neuroprotective effects in both in vitro and in vivo studies, leading to ongoing clinical trials for AD. The potential and limitation of transcranial brain stimulation for treating patients with dementia would be discussed in this review.

Low-intensity pulsed ultrasound ameliorates glia-mediated inflammation and neuronal damage in experimental intracerebral hemorrhage conditions.

BACKGROUND: Intracerebral hemorrhage (ICH) is a condition associated with high morbidity and mortality, and glia-mediated inflammation is a major contributor to neurological deficits. However, there is currently no proven effective treatment for clinical ICH. Recently, low-intensity pulsed ultrasound (LIPUS), a non-invasive method, has shown potential for neuroprotection in neurodegenerative diseases. This study aimed to investigate the neuroprotective effects and potential mechanisms of LIPUS on glia-mediated inflammation in ICH. METHODS: This study used 289 mice to investigate the effects of LIPUS on ICH. ICH was induced by injecting bacterial collagenase (type VII-S; 0.0375 U) into the striatum of the mice. LIPUS was applied noninvasively for 3 days, including a 2-h-delayed intervention to mimic clinical usage. The study evaluated neurological function, histology, brain water content, hemoglobin content, MRI, and protein expression of neurotrophic factors, inflammatory molecules, and apoptosis. In vitro studies investigated glia-mediated inflammation by adding thrombin (10 U/mL) or conditioned media to primary and cell line cultures. The PI3K inhibitor LY294002 was used to confirm the effects of PI3K/Akt signaling after LIPUS treatment. RESULTS: LIPUS treatment improved neurological deficits and reduced tissue loss, edema, and neurodegeneration after ICH. The protective effects of LIPUS resulted from decreased glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling, which reduced cytokine expression and attenuated microglial activation-induced neuronal damage in vitro. CONCLUSIONS: LIPUS treatment improved neurological outcomes and reduced glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling after ICH. LIPUS may provide a non-invasive potential management strategy for ICH.

Ultrasound reduces inflammation by modulating M1/M2 polarization of microglia through STAT1/STAT6/PPARγ signaling pathways.

INTRODUCTION: Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate pro-inflammatory responses in activated microglia. OBJECTIVE: This study aimed to investigate the effects of LIPUS on M1/M2 polarization of microglial cells and the regulatory mechanisms associated with signaling pathways. METHODS: BV-2 microglial cells were stimulated by lipopolysaccharide (LPS) to an M1 phenotype or by interleukin-4 (IL-4) to an M2 phenotype. Some microglial cells were exposed to LIPUS, while others were not. M1/M2 marker mRNA and protein expression were measured using real-time polymerase chain reaction and western blot, respectively. Immunofluorescence staining was performed to determine inducible nitric oxide synthase (iNOS)-/arginase-1 (Arg-1)- and CD68-/CD206-positive cells. RESULTS: LIPUS treatment significantly attenuated LPS-induced increases in inflammatory markers (iNOS, tumor necrosis factor-α, interleukin-1ß, and interleukin-6) as well as the expression of cell surface markers (CD86 and CD68) of M1-polarized microglia. In contrast, LIPUS treatment significantly enhanced the expression of M2-related markers (Arg-1, IL-10, and Ym1) and membrane protein (CD206). LIPUS treatment prevented M1 polarization of microglia and enhanced or sustained M2 polarization by regulating M1/M2 polarization through the signal transducer and activator of transcription 1/STAT6/peroxisome proliferator-activated receptor gamma pathways. CONCLUSIONS: Our findings suggest that LIPUS inhibits microglial polarization and switches microglia from the M1 to the M2 phenotype.

Muscle Loss During Androgen Deprivation Therapy Is Associated With Higher Risk of Non-Cancer Mortality in High-Risk Prostate Cancer.

The changes in body composition are early adverse effects of androgen deprivation therapy (ADT); however, their prognostic impact remains unclear in prostate cancer. This study aimed to evaluate the association between body composition changes and survival in patients with high-risk prostate cancer. We measured the skeletal muscle index (SMI) and total adipose tissue index (TATI) at the L3 vertebral level using computed tomography at baseline and within one year after initiating ADT in 125 patients with high-risk prostate cancer treated with radiotherapy and ADT between 2008 and 2018. Non-cancer mortality predictors were identified using Cox regression models. The median follow-up was 49 months. Patients experienced an average SMI loss of 5.5% over 180 days (95% confidence interval: -7.0 to -4.0; p<0.001) and TATI gain of 12.6% over 180 days (95% confidence interval: 9.0 to 16.2; p<0.001). Body mass index changes were highly and weakly correlated with changes in TATI and SMI, respectively (Spearman ρ for TATI, 0.78, p<0.001; ρ for SMI, 0.27, p=0.003). As a continuous variable, each 1% decrease in SMI was independently associated with a 9% increase in the risk of non-cancer mortality (hazard ratio: 1.09; p=0.007). Moreover, the risk of non-cancer mortality increased 5.6-fold in patients with SMI loss ≥5% compared to those with unchanged SMI (hazard ratio: 5.60; p=0.03). Body mass index and TATI were not associated with non-cancer mortality. Muscle loss during ADT is occult, independent of weight change, and independently associated with increased non-cancer mortality in patients with high-risk prostate cancer.

Antenatal low-intensity pulsed ultrasound reduces neurobehavioral deficits and brain injury following dexamethasone-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality and morbidity, and IUGR survivors are at increased risk of neurodevelopmental deficits. No effective interventions are currently available to improve the structure and function of the IUGR brain before birth. This study investigated the protective effects of low-intensity pulsed ultrasound (LIPUS) on postnatal neurodevelopmental outcomes and brain injury using a rat model of IUGR induced by maternal exposure to dexamethasone (DEX). Pregnant rats were treated with DEX (200 µg/kg, s.c.) and LIPUS daily from gestational day (GD) 14 to 19. Behavioral assessments were performed on the IUGR offspring to examine neurological function. Neuropathology, levels of neurotrophic factors, and CaMKII-Akt-related molecules were assessed in the IUGR brain, and expression of glucose and amino acid transporters and neurotrophic factors were examined in the placenta. Maternal LIPUS treatment increased fetal weight, fetal liver weight, and placental weight following IUGR. LIPUS treatment also increased neuronal number and myelin protein expression in the IUGR brain, and attenuated neurodevelopmental deficits at postnatal day (PND) 18. However, the number of oligodendrocytes or microglia was not affected. These changes were associated with the upregulation of brain-derived neurotrophic factor (BDNF) and placental growth factor (PlGF) protein expression, and enhancement of neuronal CaMKII and Akt activation in the IUGR brain at PND 1. Additionally, LIPUS treatment promoted glucose transporter (GLUT) 1 production and BDNF expression in the placenta, but had no effects on GLUT3 or amino acid transporter expression. Our findings suggest that antenatal LIPUS treatment may reduce IUGR-induced brain injury via enhancing cerebral BDNF/CaMKII/Akt signaling. These data provide new evidence that LIPUS stimulation could be considered for antenatal neuroprotective therapy in IUGR.

Ultrasound Stimulation Suppresses LPS-Induced Proinflammatory Responses by Regulating NF-κB and CREB Activation in Microglial Cells.

The purpose of this study was to investigate the effects and underlying mechanisms of low-intensity pulsed ultrasound (LIPUS) against lipopolysaccharide (LPS)-induced neuroinflammation. BV-2 microglia subjected to LPS administration (1 µg/mL) were treated with LIPUS stimulation. The levels of inflammatory mediators and brain-derived neurotrophic factor (BDNF) were quantified using the western blot. The results showed that LIPUS stimulation promoted the associated cAMP response element-binding protein (CREB)/BDNF expression in the LPS-treated microglia. Meanwhile, LIPUS treatment effectively suppressed the LPS-induced production of tumor necrosis factor-α, interleukin-1ß, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the microglial cells, in addition to inhibiting the LPS-induced expressions of toll-like receptor 4 and myeloid differentiation factor 88, as well as the LPS-induced activation of c-Jun N-terminal kinase and nuclear factor kappa B. Furthermore, LIPUS significantly decreased the Bax/Bcl-2 ratio in the microglia following LPS treatment. Our data indicated that LIPUS attenuated the proinflammatory responses as well as the decline in BDNF in LPS-treated microglia. This study provides a better understanding of how LIPUS stimulation regulates anti-inflammatory actions in microglia, providing further evidence suggesting that such stimulation may be regarded as a novel strategy for the treatment of neuroinflammation.

Preventive Effect of Low Intensity Pulsed Ultrasound against Experimental Cerebral Ischemia/Reperfusion Injury via Apoptosis Reduction and Brain-derived Neurotrophic Factor Induction.

Stroke is known as the top 10 causes of death worldwide. Development of effectively neuroprotective or preventive strategies for ischemia stroke is imperative. For the purpose of stroke prevention, we tested the neuroprotective effects of low-intensity pulsed ultrasound (LIPUS) on ischemic stroke. Adult C57BL/6 mice were used to daily treatment with LIPUS for 5 days on left hemisphere before middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injury. Western blotting and immunohistochemistry were performed to assess the protein expressions of signaling molecules. Pretreatment with LIPUS significantly ameliorated the brain ischemic damage, including the reduction of neurological deficit score, infarct area, histopathological score, and showed a better performance in neurological and behavior functions. LIPUS pretreatment could also significantly decrease the neuronal cell apoptosis and upregulation of apoptosis-related signaling molecules and downregulation of brain-derived neurotrophic factor (BDNF) in brain tissues of MCAO-treated mice. Furthermore, LIPUS significantly prevented the decreased cell viability, the increased caspase-3 cleavage, and the decreased BDNF expression in ischemia/reperfusion-treated microglial cells. These results demonstrate that LIPUS effectively prevented the cerebral ischemia/reperfusion injury through apoptosis reduction and BDNF induction in a MCAO mouse model. The neuroprotective potential of LIPUS may provide a novel preventive strategy for ischemic stroke in high-risk patients.

Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis.

The goal of this study was to investigate the in vivo extracellular kinetics of doxorubicin (Dox) in glioblastoma multiforme (GBM)-bearing mice following focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption using microdialysis. An intracranial brain tumor model in NOD-scid mice using human brain GBM 8401 cells was used in this study. Prior to each sonication, simultaneous intravenous administration of Dox and microbubbles, and the Dox concentration in the brains was quantified by high performance liquid chromatography (HPLC). Drug administration with sonication elevated the tumor-to-normal brain Dox ratio of the target tumors by about 2.35-fold compared with the control tumors. The mean peak concentration of Dox in the sonicated GBM dialysate was 10 times greater than without sonication, and the area under the concentration-time curve was 3.3 times greater. This study demonstrates that intracerebral microdialysis is an effective means of evaluating real-time target BBB transport profiles and offers the possibility of investigating the pharmacokinetics of drug delivery in the sonicated brain.

Low-intensity pulsed ultrasound improves behavioral and histological outcomes after experimental traumatic brain injury.

The purpose of this study was to investigate the neuroprotective effects of low-intensity pulsed ultrasound (LIPUS) on behavioral and histological outcomes in a mouse model of traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury were treated with LIPUS in the injured region daily for a period of 4 weeks. The effects of LIPUS on edema were observed by MR imaging in the mouse brain at 1 and 4 days following TBI. Brain water content, blood-brain barrier permeability, histology analysis, and behavioral studies were performed to assess the effects of LIPUS. Two-way analysis of variance and Student t test were used for statistical analyses, with a significant level of 0.05. Treatment with LIPUS significantly attenuated brain edema, blood-brain barrier permeability, and neuronal degeneration beginning at day 1. Compared with the TBI group, LIPUS also significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Post-injury LIPUS treatment reduced brain edema and improved behavioral and histological outcomes following TBI. The neuroprotective effects of LIPUS may be a promising new technique for treating TBI.

Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury.

BACKGROUND: The protein expressions of brain-derived neurotrophic factor (BDNF) can be elevated by transcranial ultrasound stimulation in the rat brain. OBJECTIVE: The purpose of this study was to investigate the effects and underlying mechanisms of BDNF enhancement by low-intensity pulsed ultrasound (LIPUS) on traumatic brain injury (TBI). METHODS: Mice subjected to controlled cortical impact injury were treated with LIPUS in the injured region daily for a period of 4 days. Western blot analysis and immunohistochemistry were performed to assess the effects of LIPUS. RESULTS: The results showed that the LIPUS treatment significantly promoted the neurotrophic factors BDNF and vascular endothelial growth factor (VEGF) at day 4 after TBI. Meanwhile, LIPUS also enhanced the phosphorylation of Tropomyosin-related kinase B (TrkB), Akt, and cAMP-response element binding protein (CREB). Furthermore, treatment with LIPUS significantly decreased the level of cleaved caspase-3. The reduction of apoptotic process was inhibited by the anti-BDNF antibody. CONCLUSIONS: In short, post-injury LIPUS treatment increased BDNF protein levels and inhibited the progression of apoptosis following TBI. The neuroprotective effects of LIPUS may be associated with enhancements of the protein levels of neurotrophic factors, at least partially via the TrkB/Akt-CREB signaling pathway.

Ultrasound Enhances the Expression of Brain-Derived Neurotrophic Factor in Astrocyte Through Activation of TrkB-Akt and Calcium-CaMK Signaling Pathways.

Low-intensity pulsed ultrasound (LIPUS) stimulation has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in astrocytes of an in vitro model and rat brains of an in vivo model; however, their molecular mechanisms are still not well clarified. Here, we investigated the underlying mechanisms of BDNF enhancement by LIPUS in rat cerebral cortex astrocytes. After LIPUS stimulation in astrocytes, the protein and mRNA expressions were measured by western blot and RT-PCR, respectively. The concentration of intracellular calcium was determined spectrophotometrically. The results showed that LIPUS enhanced the phosphorylation of tropomyosin-related kinase B (TrkB) and Akt but had no effect on Erk1/2 phosphorylation. Additionally, LIPUS increased the intracellular concentration of calcium and enhanced the protein levels of calmodulin-dependent kinase (CaMK) II and CaMKIV. LIPUS also activated the phosphorylation of NF-κB-p65 but did not promote the activation of cAMP response element-binding protein (CREB). Taken together, our results suggest that LIPUS stimulation upregulates BDNF production in astrocytes through the activation of NF-κB via the TrkB/PI3K/Akt and calcium/CaMK signaling pathways. BDNF has emerged as a major molecular player in the regulation of neural circuit development and function. Therefore, LIPUS stimulation may play a crucial and beneficial role in neurodegenerative diseases.

Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.

It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain.

Focused ultrasound enhanced molecular imaging and gene therapy for multifusion reporter gene in glioma-bearing rat model.

The ability to monitor the responses of and inhibit the growth of brain tumors during gene therapy has been severely limited due to the blood-brain barrier (BBB). A previous study has demonstrated the feasibility of noninvasive in vivo imaging with 123I-2'-fluoro-2'-deoxy-5-iodo-1-ß-D-arabinofuranosyluracil (123I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here, we tested the enhancement of SPECT with 123I-FIAU and ganciclovir (GCV) treatment in brain tumors after BBB disruption induced by focused ultrasound (FUS) in the presence of microbubbles. We established an orthotopic F98 glioma-bearing rat model with trifusion reporter genes. The results of this study showed that the rat model of HSV1-tk-expressing glioma cells could be successfully detected by SPECT imaging after FUS-induced BBB disruption on day 10 after implantation. Compared to the control group, animals receiving the GCV with or without sonication exhibited a significant antitumor activity (P < 0.05) of glioma cells on day 16 after implantation. Moreover, combining sonication with GCV significantly inhibited tumor growth compared with GCV alone. This study demonstrated that FUS may be used to deliver a wide variety of theranostic agents to the brain for molecular imaging and gene therapy in brain diseases.

Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model.

The protein expressions of neurotrophic factors can be enhanced by low-intensity pulsed ultrasound (LIPUS) stimulation in the brain. The purpose of this study was to demonstrate the protective effect of LIPUS stimulation against aluminum-induced cerebral damage in Alzheimer's disease rat model. LIPUS was administered 7 days before each aluminum chloride (AlCl3) administration, and concomitantly given with AlCl3 daily for a period of 6 weeks. Neurotrophic factors in hippocampus were measured by western blot analysis. Behavioral changes in the Morris water maze and elevated plus maze were examined in rats after administration of AlCl3. Various biochemical analyses were performed to evaluate the extent of brain damages. LIPUS is capable of prompting levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in rat brain. AlCl3 administration resulted in a significant increase in the aluminum concentration, acetylcholinesterase activity and beta-amyloid (Aß) deposition in AlCl3 treated rats. LIPUS stimulation significantly attenuated aluminum concentration, acetylcholinesterase activity, Aß deposition and karyopyknosis in AlCl3 treated rats. Furthermore, LIPUS significantly improved memory retention in AlCl3-induced memory impairment. These experimental results indicate that LIPUS has neuroprotective effects against AlCl3-induced cerebral damages and cognitive dysfunction.

Pharmacokinetics of BPA in gliomas with ultrasound induced blood-brain barrier disruption as measured by microdialysis.

The blood-brain barrier (BBB) can be transiently disrupted by focused ultrasound (FUS) in the presence of microbubbles for targeted drug delivery. Previous studies have illustrated the pharmacokinetics of drug delivery across the BBB after sonication using indirect visualization techniques. In this study, we investigated the in vivo extracellular kinetics of boronophenylalanine-fructose (BPA-f) in glioma-bearing rats with FUS-induced BBB disruption by microdialysis. After simultaneous intravenous administration of BPA and FUS exposure, the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. With FUS, the mean peak concentration of BPA-f in the glioma dialysate was 3.6 times greater than without FUS, and the area under the concentration-time curve was 2.1 times greater. This study demonstrates that intracerebral microdialysis can be used to assess local BBB transport profiles of drugs in a sonicated site. Applying microdialysis to the study of metabolism and pharmacokinetics is useful for obtaining selective information within a specific brain site after FUS-induced BBB disruption.

Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI.

Focused ultrasound (FUS) combined with microbubbles has been shown to be a noninvasive and targeted drug delivery technique for brain tumor treatment. The purpose of this study was to measure the kinetics of Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) in glioma-bearing rats in the presence of FUS-induced blood-brain barrier disruption (BBB-D) by magnetic resonance imaging (MRI). A total of ten glioma-bearing rats (9-12 weeks, 290-340 g) were used in this study. Using dynamic contrast-enhanced (DCE)-MRI, the spatial permeability of FUS-induced BBB-D was evaluated and the kinetic parameters were calculated by a general kinetic model (GKM). The results demonstrate that the mean Ktrans of the sonicated tumor (0.128±0.019 at 20 min and 0.103±0.023 at 24 h after sonication, respectively) was significantly higher than (2.46-fold at 20 min and 1.78-fold at 24 h) that of the contralateral (non-sonicated) tumor (0.052±0.019 at 20 min and 0.058±0.012 at 24 h after sonication, respectively). In addition, the transfer constant Ktrans in the sonicated tumor correlated strongly with tissue EB extravasation (R = 0.95), which suggests that DCE-MRI may reflect drug accumulation in the brain. Histological observations showed no macroscopic damage except for a few small erythrocyte extravasations. The current study demonstrates that DCE-MRI can monitor the dynamics of the FUS-induced BBB-D process and constitutes a useful tool for quantifying BBB permeability in tumors.

Pharmacokinetic analysis and uptake of 18F-FBPA-Fr after ultrasound-induced blood-brain barrier disruption for potential enhancement of boron delivery for neutron capture therapy.

UNLABELLED: Boronophenylalanine has been applied in clinical boron neutron capture therapy for the treatment of high-grade gliomas. The purpose of this study was to evaluate the pharmacokinetics of 4-borono-2-(18)F-fluoro-L-phenylalanine-fructose ((18)F-FBPA-Fr) in F98 glioma-bearing Fischer 344 rats by means of intravenous injection of (18)F-FBPA-Fr both with and without blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). METHODS: Dynamic PET imaging of (18)F-FBPA-Fr was performed on the ninth day after tumor implantation. Blood samples were collected to obtain an arterial input function for tracer kinetic modeling. Ten animals were scanned for approximately 3 h to estimate the uptake of (18)F radioactivity with respect to time for the pharmacokinetic analysis. Rate constants were calculated by use of a 3-compartment model. RESULTS: The accumulation of (18)F-FBPA-Fr in brain tumors and the tumor-to-contralateral brain ratio were significantly elevated after intravenous injection of (18)F-FBPA-Fr with BBB-D. (18)F-FBPA-Fr administration after sonication showed that the tumor-to-contralateral brain ratio for the sonicated tumors (3.5) was approximately 1.75-fold higher than that for the control tumors (2.0). Furthermore, the K1/k2 pharmacokinetic ratio after intravenous injection of (18)F-FBPA-Fr with BBB-D was significantly higher than that after intravenous injection without BBB-D. CONCLUSION: This study demonstrated that radioactivity in tumors and the tumor-to-normal brain ratio after intravenous injection of (18)F-FBPA-Fr with sonication were significantly higher than those in tumors without sonication. The K1/k2 ratio may be useful for indicating the degree of BBB-D induced by FUS. Further studies are needed to determine whether FUS may be useful for enhancing the delivery of boronophenylalanine in patients with high-grade gliomas.

Pulsed-focused ultrasound enhances boron drug accumulation in a human head and neck cancer xenograft-bearing mouse model.

PURPOSE: This study aims to demonstrate that pulsed high-intensity focused ultrasound (pulsed-HIFU) may enhance the fructose-conjugated 4-borono-L-phenylalanine (BPA-Fr) accumulation in tumor lesion using (18)F-FBPA-Fr microPET scans. PROCEDURES: To the mice bearing orthotopic SASC03 human tongue squamous carcinoma xenograft, a 2-min pulsed-HIFU was applied to tumor. Immediately after pulsed-HIFU treatment, (18)F-FBPA-Fr was intravenously injected, and biological characterizations including microPET imaging and biodistribution were conducted. RESULTS: Both biodistribution studies and microPET imaging performed after intravenous injection of (18)F-FBPA-Fr revealed higher tumor uptake in HIFU-treated mice than that of the control. CD31 and Ki-67 histochemical staining of tumor sections and H&E staining of nearby normal tissues revealed no significant difference between the pulsed-HIFU-treated mice and the control. CONCLUSION: This study demonstrated that pulsed-HIFU was beneficial to the accumulation of boron drug in the head and neck tumor lesion and may enhance the therapeutic efficacy of clinical BNCT.

Chemotherapy of glioblastoma by targeted liposomal platinum compounds with focused ultrasound.

Giloblastoma multiforme (GBM) is the most aggressive brain neoplasm, and patients have a poor prognosis after radiation and chemotherapy. The chemotherapy protocols still marginally improve the anti-tumor effect of patients with glioblastoma because the therapeutic dosage of many drugs is impeded by the blood-brain barrier (BBB). The use of liposomal drugs to GBM treatment might benefit from a more crossing of the BBB due to the lipid nature achieving higher doses of drug at the tumor sites. Human GBM-bearing mice were injected intravenously with cisplatin encapsulated in atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes or unconjugated liposome. Moreover, the administration of AP-1 liposomal cisplatin (lipoplatin) followed by focused ultrasound (FUS)-induced BBB disruption. Tumor progression was monitored by biophotonic imaging. The preliminary data demonstrated that the GBM chemotherapy with AP-1 lipoplatin followed by pulsed FUS showed a modest improvement of tumor growth in the brain compared to the group treated with lipoplatin alone. Further investigations are needed to use this new targeted lipoplatin in treatment of malignancies.