This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The delivery of large molecular agents into the central nervous system (CMS) via the blood supply is often impossible because the blood brain barrier (BBB) protects the brain tissue from foreign molecules. The factors that determine penetration of substances from the blood to the CNS are lipid solubility, molecular size, and charge. The BBB prevents penetration of ionized water-soluble materials with molecular weight greater than 180. Thus most of the potential molecular imaging agents cannot reach the brain tissue via the blood supply. A technique that allows these agents to reach the brain tissue will open the door to new possibilities for the diagnosis and monitoring of brain disorders that currently cannot be performed. Such a technique would also result in a new research tool to investigate brain function and disorders in animal models using molecular imaging. Optimization of ultrasound-induced BBB disruption To optimize the procedure, we will first investigate different acoustic parameters to determine the best values for BBB disruption. In experiments in rabbits, we will vary the ultrasound frequency, burst length, repetition frequency, and sonication duration, and gauge the BBB disruption using MRI contrast agents, or as needed, other tracers. Further, we will investigate different commercially-available ultrasound contrast agents. The goal will be to determine which parameters result in the largest BBB disruption without causing unwanted damage to the brain. At the end of this work, we anticipate that we will have the parameters that will be used clinically. We will also characterize what sized agents we can deliver to the brain using fluorescent microspheres (from a vendor such as Invitrogen, Carlsbad, CA). These spheres can be purchased at different diameters (and excitation and emission wavelengths) and imaged and quantified with fluorescent microscopy. Spheres that are excited or fluoresce at different wavelengths can be injected at the same time, thereby providing quantitative images of the extent of the distribution of different size agents. We will inject the microspheres immediately after sonication and at later times to investigate the time course of the resealing of the BBB. These times will be determined from the experiments in the first aim: we will inject the spheres at the times when the BBB is roughly 25% and 50% closed. From those measurements we can evaluate whether the molecular size of the agent that can be delivered depends on the time after sonication. We will also be able to determine whether the closing of the BBB depends on the size of the tracer or if it closes to all agents at the same time. Finally, we will continue our work investigating methods to monitor the procedure using acoustic emission signals. In our preliminary work, we found that a sharp increase in harmonics of the ultrasound frequency occurred during sonications that resulted in BBB disruption. Based on this work, we will develop an automated system that uses the emission signals in real time to control the ultrasound bursts and we hope to be able to determine online the correct ultrasound intensities to use to maximize the BBB disruption without inducing inertial cavitation. Having such a method to guide the procedure will be important because it is difficult to determine the acoustic intensity when focusing deep into living tissue especially when the sonications are delivered through the intact skull. Delivery of therapeutics in animal models In this work, we will continue our efforts in delivering therapeutics to the animal brain through the ultrasound-induced BBB disruption. In our preliminary work, we have demonstrated that we can deliver clinically relevant dosages of a chemotherapy agent (liposomal doxorubicin Doxil ) to the normal rat brain, and we have demonstrated that we can deliver antibodies (dopamine D4 receptor-targeting antibodies) into the brains of mice. We will test the delivery of Doxil into gliomas inoculated in rat brain. We will compare the growth of these tumors for cases with and without BBB disruption of the tissue surrounding the tumors through serial MRI studies. We will also quantify the amount of doxorubicin delivered to the brain using fluorometry (excitation: 480 nm; emission: 590 nm). In addition, we will investigate the delivery of Herceptin , a humanized anti-human epidermal growth-factor receptor 2 (HER2 / c-erbB2) monoclonal antibody that is used clinically used to treat breast cancer patients and has shown great success in controlling local and distal breast cancer lesions. When these cancers metastasize to the brain, however, this effectiveness of this agent has been limited because of the BBB. First, we will demonstrate that we can deliver this antibody into the normal brain in experiments in mice. Next, we will inoculate breast cancer tumors in the brains of nude rats to test the effectiveness of this agent when its delivery is combined with BBB disruption. Methods For the experiments, the transducer will be attached to our MRI-compatible positioning device and submerged in a tank of degassed, deionized water. We currently have systems available for our clinical 1.5 and 3T clinical scanners. In the upcoming year, we will also construct a system for our 4.7T animal magnet as well. The anesthetized animal will be placed on its back on a plastic a tray. Acoustic coupling between the water tank and the animal s head will be achieved with plastic bag filled with water. The hair in the beam path will be removed prior to the experiments. Before the animal is placed on the system, the focal position will be located in the MRI coordinate space by imaging the heating produced by sonications in a tissue-mimicking phantom. Based on this registration, we can accurately target the focus in the brain with an accuracy of ~0.5 mm using anatomical MR images as a guide. BBB opening can be confirmed immediately after sonication using standard MRI contrast agents (such as Magnevist , Berlex Inc., Wayne NJ).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Cooperative Agreements (U41)
Project #
5U41RR019703-02
Application #
7360388
Study Section
Special Emphasis Panel (ZRG1-SBIB-L (40))
Project Start
2006-08-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$13,449
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Schmidt, Ehud J; Halperin, Henry R (2018) MRI use for atrial tissue characterization in arrhythmias and for EP procedure guidance. Int J Cardiovasc Imaging 34:81-95
George, E; Liacouras, P; Lee, T C et al. (2017) 3D-Printed Patient-Specific Models for CT- and MRI-Guided Procedure Planning. AJNR Am J Neuroradiol 38:E46-E47
Mitsouras, Dimitris; Lee, Thomas C; Liacouras, Peter et al. (2017) Three-dimensional printing of MRI-visible phantoms and MR image-guided therapy simulation. Magn Reson Med 77:613-622
Guenette, Jeffrey P; Himes, Nathan; Giannopoulos, Andreas A et al. (2016) Computer-Based Vertebral Tumor Cryoablation Planning and Procedure Simulation Involving Two Cases Using MRI-Visible 3D Printing and Advanced Visualization. AJR Am J Roentgenol 207:1128-1131
Mitsouras, Dimitris; Mulkern, Robert V; Maier, Stephan E (2016) Multicomponent T2 relaxation studies of the avian egg. Magn Reson Med 75:2156-64
Li, Mao; Miller, Karol; Joldes, Grand Roman et al. (2016) Biomechanical model for computing deformations for whole-body image registration: A meshless approach. Int J Numer Method Biomed Eng 32:
Schmidt, Ehud J; Watkins, Ronald D; Zviman, Menekhem M et al. (2016) A Magnetic Resonance Imaging-Conditional External Cardiac Defibrillator for Resuscitation Within the Magnetic Resonance Imaging Scanner Bore. Circ Cardiovasc Imaging 9:
Patil, Vaibhav; Gupta, Rajiv; San José Estépar, Raúl et al. (2015) Smart stylet: the development and use of a bedside external ventricular drain image-guidance system. Stereotact Funct Neurosurg 93:50-8
Garlapati, Revanth Reddy; Mostayed, Ahmed; Joldes, Grand Roman et al. (2015) Towards measuring neuroimage misalignment. Comput Biol Med 64:12-23
Lu, Yi; Yeung, Cecil; Radmanesh, Alireza et al. (2015) Comparative effectiveness of frame-based, frameless, and intraoperative magnetic resonance imaging-guided brain biopsy techniques. World Neurosurg 83:261-8

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