Kullervo Hynynen

University of Toronto, Toronto, Ontario, Canada

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Publications (343)803.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50nm or 120nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors.
    Nanomedicine: nanotechnology, biology, and medicine 12/2013; · 6.93 Impact Factor
  • Daniel Pajek, Kullervo Hynynen
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    ABSTRACT: Purpose: Transcranial focused ultrasound is an emerging therapeutic modality that can be used to perform noninvasive neurosurgical procedures. The current clinical transcranial phased array operates at 650 kHz, however the development of a higher frequency array would enable more precision, while reducing the risk of standing waves. However, the smaller wavelength and the skull's increased distortion at this frequency are problematic. It would require an order of magnitude more elements to create such an array. Random sparse arrays enable steering of a therapeutic array with fewer elements. However, the tradeoffs inherent in the use of sparsity in a transcranial phased array have not been systematically investigated and so the objective of this simulation study is to investigate the effect of sparsity on transcranial arrays at a frequency of 1.5 MHz that provides small focal spots for precise exposure control.Methods: Transcranial sonication simulations were conducted using a multilayer Rayleigh-Sommerfeld propagation model. Element size and element population were varied and the phased array's ability to steer was assessed.Results: The focal pressures decreased proportionally as elements were removed. However, off-focus hotspots were generated if a high degree of steering was attempted with very sparse arrays. A phased array consisting of 1588 elements 3 mm in size, a 10% population, was appropriate for steering up to 4 cm in all directions. However, a higher element population would be required if near-skull sonication is desired.Conclusions: This study demonstrated that the development of a sparse, hemispherical array at 1.5 MHz could enable more precision in therapies that utilize lower intensity sonications.
    Medical Physics 12/2013; 40(12):122901. · 3.01 Impact Factor
  • Meaghan A O'Reilly, Kullervo Hynynen
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    ABSTRACT: Purpose: High-resolution vascular imaging has not been achieved in the brain due to limitations of current clinical imaging modalities. The authors present a method for transcranial ultrasound imaging of single micrometer-size bubbles within a tube phantom.Methods: Emissions from single bubbles within a tube phantom were mapped through an ex vivo human skull using a sparse hemispherical receiver array and a passive beamforming algorithm. Noninvasive phase and amplitude correction techniques were applied to compensate for the aberrating effects of the skull bone. The positions of the individual bubbles were estimated beyond the diffraction limit of ultrasound to produce a super-resolution image of the tube phantom, which was compared with microcomputed tomography (micro-CT).Results: The resulting super-resolution ultrasound image is comparable to results obtained via the micro-CT for small tissue specimen imaging.Conclusions: This method provides superior resolution to deep-tissue contrast ultrasound and has the potential to be extended to provide complete vascular network imaging in the brain.
    Medical Physics 11/2013; 40(11):110701. · 3.01 Impact Factor
  • Meaghan A O'Reilly, Ryan M Jones, Kullervo Hynynen
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    ABSTRACT: Bubble-mediated ultrasound therapies in the brain, such as targeted disruption of the blood-brain barrier (BBB) or cavitation-enhanced stroke treatments, are being increasingly investigated due to their potential to revolutionize the treatment of brain disorders. Due to the fact that they are non-thermal in nature, these therapies must be monitored by acoustic means to ensure efficacy and safety. A sparse, 128-element hemispherical receiver array (612 kHz) was integrated within a 306 kHz therapy array. The receiver arrangement was optimized through numerical simulations. The array was characterized on the benchtop to map the activity of bubbles in a tube phantom through an ex vivo human skullcap. In vivo the array was used to map bubble activity in small animal models during microbubble-mediated BBB disruption. The array was investigated as well for diagnostic purposes, imaging transcranial structures filled with very dilute concentrations of microbubbles. A spiral tube phantom with tube diameter of 255 [micro sign]m was imaged, using a non-invasive phase correction technique, through an ex vivo human skullcap by mapping the activity from single bubbles. Applying super-resolution techniques, an image of the spiral phantom was produced that was comparable to an image obtained in a small-specimen micro CT.
    The Journal of the Acoustical Society of America 11/2013; 134(5):3975. · 1.65 Impact Factor
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    ABSTRACT: Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for noninvasive image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for well controlled energy delivery will be discussed. In addition, some of the recent preclinical results for the treatments of brain tumors, stroke, and Alzheimer's disease will be reviewed. As conclusion, the advances in the image-guided focused ultrasound for the treatment of disease has been rapid and the future potential appears very promising.
    The Journal of the Acoustical Society of America 11/2013; 134(5):4088. · 1.65 Impact Factor
  • Ryan Alkins, Yuexi Huang, Dan Pajek, Kullervo Hynynen
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    ABSTRACT: Object Transcranial focused ultrasound is increasingly being investigated as a minimally invasive treatment for a range of intracranial pathologies. At higher peak rarefaction pressures than those used for thermal ablation, focused ultrasound can initiate inertial cavitation and create holes in the brain by fractionation of the tissue elements. The authors investigated the technical feasibility of using MRI-guided focused ultrasound to perform a third ventriculostomy as a possible noninvasive alternative to endoscopic third ventriculostomy for hydrocephalus. Methods A craniectomy was performed in male pigs weighing 13-19 kg to expose the supratentorial brain, leaving the dura mater intact. Seven pigs were treated through the craniectomy, while 2 pigs were treated through ex vivo human skulls placed in the beam path. Registration and targeting was done using T2-weighted MRI sequences. For transcranial treatments a CT scan was used to correct the beam from aberrations due to the skull and maintain a small, high-intensity focus. Sonications were performed at both 650 kHz and 230 kHz at a range of intensities, and the in situ pressures were estimated both from simulations and experimental data to establish a threshold for tissue fractionation in the brain. Results In craniectomized animals at 650 kHz, a peak pressure ≥ 22.7 MPa for 1 second was needed to reliably create a ventriculostomy. Transcranially at this frequency the ExAblate 4000 was unable to generate the required intensity to fractionate tissue, although cavitation was initiated. At 230 kHz, ventriculostomy was successful through the skull with a peak pressure of 8.8 MPa. Conclusions This is the first study to suggest that it is possible to perform a completely noninvasive third ventriculostomy using ultrasound. This may pave the way for future studies and eventually provide an alternative means for the creation of CSF communications in the brain, including perforation of the septum pellucidum or intraventricular membranes.
    Journal of Neurosurgery 09/2013; · 3.15 Impact Factor
  • Mathew Carias, Kullervo Hynynen
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    ABSTRACT: The purpose of this study was to develop steerable MR-compatible ultrasound catheters suitable for minimally invasive MRI-guided cardiac ablation therapies. MRI-compatible ultrasound steerable catheters were developed and tested for their overall tissue heating performance and safety. Ultrasound transducers were mounted on a monodirectional deflectable catheter tip that was made to be MRI-compatible. Catheter safety was assessed on the potential to form hot spots at the distal end of the catheter throughout fast spin echo and thermometry scans. Heating experiments were performed on phantoms and ex vivo porcine cardiac samples. During catheter safety experiments, a maximum temperature increase of 11.35 ± 0.83°C was evident after a 12-min, 40-s fast spin echo scan with a whole body specific absorption rate (SAR) of 1.9 W/kg and 1.07 ± 0.22°C during thermometry scans (flip angle = 90°; scan time = 12 min, 41 s; whole body SAR = 0.34 W/kg). Temperature elevations induced by the sonication were shown to be on the order of 38.1 ± 5.2°C for phantom experiments and 49.3 ± 9.7°C for ex vivo cardiac samples. Steerable ultrasound catheters have the potential to be safely placed in an MR system with little concern of catheter self-heating and driven to heat surrounding structures to cause ablations. In addition, these catheters have the added benefit of a deflectable tip that allows the treatment of multiple targets from within the bore of the MR scanner. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 09/2013; · 3.40 Impact Factor
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    ABSTRACT: Reversible and localized blood-brain barrier disruption (BBBD) using focused ultrasound (FUS) in combination with intravascularly administered microbubbles (MBs) has been established as a non-invasive method for drug delivery to the brain. Using two-photon fluorescence microscopy (2PFM), we imaged the cerebral vasculature during BBBD and observed the extravasation of fluorescent dye in real-time in vivo. We measured the enhanced permeability upon BBBD for both 10kDa and 70kDa dextran conjugated Texas Red (TR) at the acoustic pressure range of 0.2-0.8 MPa and found permeability constants of TR10kDa and TR70kDa vary from 0.0006 to 0.0359 min(-1) and 0.0003 to 0.0231 min(-1), respectively. For both substances, a linear regression was applied on the permeability constant against the acoustic pressure and the slope from best-fit was found to be 0.039±0.005 min(-1)/MPa and 0.018±0.005 min(-1)/MPa, respectively. In addition, the pressure threshold for successfully induced BBBD was confirmed to be 0.4-0.6 MPa. Finally, we identified two types of leakage kinetics (fast and slow) that exhibit distinct permeability constants and temporal disruption onsets, as well as demonstrated their correlations with the applied acoustic pressure and vessel diameter. Direct assessment of vascular permeability and insights on its dependency on acoustic pressure, vessel size and leakage kinetics are important for treatment strategies of BBBD-based drug delivery.
    Journal of Controlled Release 09/2013; · 7.63 Impact Factor
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    ABSTRACT: While it is well established that ultrasound stimulated microbubbles (USMBs) can potentiate blood clot lysis, the mechanisms are not well understood. Here we examine the interaction between USMBs and fibrin clots, which are comprised of fibrin networks that maintain the mechanical integrity of blood clots. High speed camera observations demonstrated that USMBs can penetrate fibrin clots. Two-photon microscopy revealed that penetrating bubbles can leave behind patent “tunnels” along their paths and that fluid can be transported into the clots. Finally, it is observed that primary radiation forces associated with USMBs can induce local deformation and macroscopic translation of clot boundaries.
    Applied Physics Letters 07/2013; 103(5). · 3.52 Impact Factor
  • Ryan M Jones, Meaghan A O'Reilly, Kullervo Hynynen
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    ABSTRACT: The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337-43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source's emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system's resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (FUS) treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring techniques currently exist.
    Physics in Medicine and Biology 06/2013; 58(14):4981-5005. · 2.92 Impact Factor
  • Yuexi Huang, Natalia I Vykhodtseva, Kullervo Hynynen
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    ABSTRACT: Low-intensity focused ultrasound was applied with microbubbles (Definity, Lantheus Medical Imaging, North Billerica, MA, USA; 0.02 mL/kg) to produce brain lesions in 50 rats at 558 kHz. Burst sonications (burst length: 10 ms; pulse repetition frequency: 1 Hz; total exposure: 5 min; acoustic power: 0.47-1.3 W) generated ischemic or hemorrhagic lesions at the focal volume revealed by both magnetic resonance imaging and histology. Shorter burst time (2 ms) or shorter sonication time (1 min) reduced the probability of lesion production. Longer pulses (200 ms, 500 ms and continuous wave) caused significant near-field damage. Using microbubbles with focused ultrasound significantly reduced acoustic power levels and, therefore, avoided skull heating issues and potentially can extend the treatable volume of transcranial focused ultrasound to brain tissues close to the skull.
    Ultrasound in medicine & biology 06/2013; · 2.46 Impact Factor
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    ABSTRACT: Noninvasive, targeted drug delivery to the brain can be achieved using transcranial focused ultrasound (FUS), which transiently increases the permeability of the blood-brain barrier (BBB) for localized delivery of therapeutics from the blood to the brain. Previously, we have demonstrated that FUS can deliver intravenously-administered antibodies to the brain of a mouse model of Alzheimer's disease (AD) and rapidly reduce plaques composed of amyloid-ß peptides (Aß). Here, we investigated two potential effects of transcranial FUS itself that could contribute to a reduction of plaque pathology, namely the delivery of endogenous antibodies to the brain and the activation of glial cells. We demonstrate that transcranial FUS application leads to a significant reduction in plaque burden four days after a single treatment in the TgCRND8 mouse model of AD and that endogenous antibodies are found bound to Aß plaques. Immunohistochemical and western blot analyses showed an increase in endogenous immunoglobulins within the FUS-targeted cortex. Subsequently, microglia and astrocytes in FUS-treated cortical regions show signs of activation through increases in protein expression and changes in glial size, without changes in glial cell numbers. Enhanced activation of glia correlated with increased internalization of Aβ in microglia and astrocytes. Together these data demonstrate that FUS improved bioavailability of endogenous antibodies and a temporal activation of glial cells, providing evidence towards antibody- and glia-dependent mechanisms of FUS-mediated plaque reduction.
    Experimental Neurology 05/2013; · 4.62 Impact Factor
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    ABSTRACT: Background Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a (10)B-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that (10)B-enriched L-4-boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f.Methods With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. (10)B concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy.ResultsThe tumor to brain ratio of (10)B was 6.7 ± 0.5 with focused ultrasound and only 4.1 ± 0.4 in the control group (P < .01), corresponding to a mean tumor [(10)B] of 123 ± 25 ppm and 85 ± 29 ppm, respectively. (10)B uptake in infiltrating clusters treated with ultrasound was 0.86 ± 0.10 times the main tumor concentration, compared with only 0.29 ± 0.08 in controls.Conclusions Ultrasound increases the accumulation of (10)B in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma.
    Neuro-Oncology 05/2013; · 5.29 Impact Factor
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    ABSTRACT: Huntington's disease is caused by a mutation in the Huntingtin (Htt) gene, which leads to neuronal dysfunction and cell death. Silencing of the Htt gene can halt or reverse the progression of the disease indicating that RNA interference is the most effective strategy for disease treatment. However, small interfering RNA (siRNA) does not cross the blood-brain barrier and therefore delivery to the brain is limited. Here, we demonstrate that focused ultrasound (FUS), combined with intravascular delivery of microbubble contrast agent, was used to locally and transiently disrupt the BBB in the right striatum of adult rats. 48 hours following treatment with siRNA, the right (treated) and left (control) striatum was dissected and analyzed for Htt mRNA levels. We demonstrate that FUS can non-invasively deliver siRNA-Htt directly to the striatum leading to a significant reduction of Htt expression in a dose dependent manner. Furthermore, we show that reduction of Htt with siRNA-Htt was greater when the extent of BBB disruption was increased. This study demonstrates that siRNA treatment for knockdown of mutant Htt is feasible without the surgical intervention previously required for direct delivery to the brain. Non-invasive delivery of siRNA through the blood-brain barrier (BBB) would be a significant advantage for translating this therapy to HD patients.
    The Journal of the Acoustical Society of America 05/2013; 133(5):3408. · 1.65 Impact Factor
  • Ryan Jones, Meaghan O'Reilly, Kullervo Hynynen
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    ABSTRACT: Passive acoustic mapping (PAM) is receiving increasing interest as a method for monitoring focused ultrasound (FUS) therapy. PAM would be beneficial during transcranial cavitation-enhanced FUS treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring technique currently exists. However, the use of PAM in the brain is complicated by the presence of the skull bone. If not properly accounted for, skull-induced aberrations of propagating cavitation emissions will lead to image distortion and artifacts upon reconstruction. Through the use of numerical simulations, this study investigated the feasibility of transcranial PAM via hemispherical sparse hydrophone arrays. A multi-layered ray acoustic transcranial ultrasound propagation model based on computed tomography-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm [Norton and Won, IEEE Trans. Geosci. Remote Sens. 38, 1337-1343 (2000)], simulated acoustic source fields were spatially mapped through digitized human skulls. The effects of array sparsity and receiver element configuration on the formation of passive acoustic maps were examined. Multiple source locations were simulated to determine the imageable volume within the skull cavity. Finally, the reconstruction algorithm's sensitivity to noise was explored.
    The Journal of the Acoustical Society of America 05/2013; 133(5):3262. · 1.65 Impact Factor
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    ABSTRACT: BACKGROUND: Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. METHODS: Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. FINDINGS: Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. INTERPRETATION: MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. FUNDING: Focused Ultrasound Foundation.
    The Lancet Neurology 03/2013; · 21.82 Impact Factor
  • Alison Burgess, Kullervo Hynynen
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    ABSTRACT: Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer's disease. The requirements for clinical translation of FUS will be discussed.
    ACS Chemical Neuroscience 02/2013; · 4.21 Impact Factor
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    ABSTRACT: There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.
    Proceedings of SPIE - The International Society for Optical Engineering 02/2013; · 0.20 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are cytotoxic lymphocytes involved in innate immunity. NK-92, a human NK cell line, may be targeted to tumor-associated antigens in solid malignancies where it exhibits antitumor efficacy, but its clinical utility for treating brain tumors is limited by an inability to cross the blood-brain barrier (BBB). We investigated the potential for focused ultrasound (FUS) to deliver targeted NK-92 cells to the brain using a model of metastatic breast cancer. HER-2-expressing human breast tumor cells were implanted into the brain of nude rats. The NK-92-scFv(FRP5)-zeta cell line expressing a chimeric HER-2 antigen receptor was transfected with super-paramagnetic iron oxide nanoparticles before intravenous injection, before and following BBB-disruption using focused ultrasound (551.5 kHz focused transducer, 0.33 MPa average peak rarefaction pressure) in the presence of a microbubble contrast agent. Baseline and post-treatment 1.5T and 7T MR imaging was performed, and histology used to identify NK-92 cells post-mortem. Contrast-enhanced MRI showed reproducible and consistent BBB-disruption. 7T MR images obtained at 16 hours post-treatment revealed a significant reduction in signal indicating the presence of iron-loaded NK-92 cells at the tumor site. The average ratio of NK-92 to tumor cells was 1:100 when NK cells were present in the vasculature at the time of sonication, versus 2:1000 and 1:1000 when delivered after sonication and without BBB-disruption, respectively. Our results offer a preclinical proof-of-concept that FUS can improve the targeting of immune cell therapy of brain metastases.
    Cancer Research 01/2013; 73(6). · 9.28 Impact Factor
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    ABSTRACT: Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of 'antivascular' USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX-only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4-6, and significant growth inhibition and survival prolongation relative to the control (p<0.001), USMB-only (p<0.01) and DTX-only treatment groups (p<0.01). These results suggest the potential of enhancing the antitumor activity of docetaxel by combining it with antivascular USMB effects.
    PLoS ONE 12/2012; 7(12):e52307. · 3.53 Impact Factor
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Publication Stats

9k Citations
803.16 Total Impact Points

Institutions

  • 2007–2015
    • University of Toronto
      • Department of Medical Biophysics
      Toronto, Ontario, Canada
  • 2010–2014
    • University of Eastern Finland
      • Department of Physics and Mathematics
      Kuopio, Eastern Finland Province, Finland
  • 2006–2014
    • Sunnybrook Health Sciences Centre
      • • Department of Physical Sciences
      • • Centre for Research in Image-Guided Therapeutics (CeRIGT)
      Toronto, Ontario, Canada
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 2012
    • SickKids
      • Division of Neurosurgery
      Toronto, Ontario, Canada
  • 1994–2012
    • Brigham and Women's Hospital
      • • Department of Radiology
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, Massachusetts, United States
  • 2011
    • Lakehead University Thunder Bay Campus
      Thunder Bay, Ontario, Canada
  • 1996–2011
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2009
    • Thunder Bay Regional Research Institute
      Thunder Bay, Ontario, Canada
  • 2005–2008
    • University of Kuopio
      • • Department of Physics
      • • Department of Applied Physics
      Kuopio, Eastern Finland Province, Finland
  • 1997–2008
    • Boston Children's Hospital
      • Department of Radiology
      Boston, MA, United States
  • 1996–2007
    • Massachusetts Institute of Technology
      • Division of Health Sciences and Technology
      Cambridge, MA, United States
  • 2004–2005
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2002–2005
    • Dana-Farber Cancer Institute
      • Department of Radiation Oncology
      Boston, MA, United States
  • 2003
    • Foundation for Biomedical Research and Innovation
      Kōbe, Hyōgo, Japan
  • 1998
    • Tufts University
      • Department of Physics and Astronomy
      Medford, MA, United States