DRUG DELIVERY ACROSS THE BLOOD-BRAIN BARRIER COULD CHANGE THE PARADIGM FOR TREATING BRAIN DISORDERS.
Recently Scientific American Mind Magazine (Nov/Dec 2014) reported on focused ultrasound and its use to help deliver drugs and other treatments directly to the brain.
The brain is protected from external damage by the skull and internally by the blood-brain barrier. This barrier has always been regarded as an impermeable gateway keeping pathogens and foreign substances from reaching the central nervous system. Research into breaching this final frontier was akin to searching for the Holy Grail.
According to the magazine, medical physicist Kullervo Hynyem at Sunnybrook Research Institute in Toronto, is working with a team of physicians to investigate a technique that involves giving patients a drug followed by an injection of microscopic gas-filled bubbles.
The patients wear a special cap that directs sound waves to specific brain locations – an approach called high-intensity focused ultrasound. The waves cause the bubbles to vibrate, temporarily forcing apart the cells of the blood-brain barrier and allowing the medication to infiltrate the brain. Hynyem and his colleagues are currently testing whether this method can be used to deliver chemotherapy to patients with brain tumours.
The plan is to undertake similar trials for patients with other brain disorders, including Alzheimer’s disease, neuropathic pain and obsessive-compulsive disorder.
Literature Review
Local and reversible blood– brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications
Kullervo Hynynen, Nathan McDannold, Nickolai A. Sheikov, Ferenc A. Jolesz, Natalia Vykhodtseva Department of Radiology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA USA. 2004
Abstract
The purpose of this study was to test the hypothesis that burst ultrasound in the presence of an ultrasound contrast agent can disrupt the blood–brain barrier (BBB) with acoustic parameters suitable for completely noninvasive exposure through the skull. The 10- ms exposures were targeted in the brains of 22 rabbits with a frequency of 690 kHz, a repetition frequency of 1 Hz, and peak rarefactional pressure amplitudes up to 3.1 MPa. The total exposure (sonication) time was 20 s. Prior to each sonication, a bolus of ultrasound contrast agent was injected intravenously. Contrast-enhanced MR images were obtained after the sonications to detect localized BBB disruption via local enhancement in the brain. Brain sections were stained with H&E, TUNEL, and vanadium acid fuchsin (VAF)–toluidine blue staining. In addition, horseradish peroxidase (HRP) was injected into four rabbits prior to sonications and transmission electron microscopy was performed. The MRI contrast enhancement demonstrated BBB disruption at pressure amplitudes starting at 0.4 MPa with approximately 50%; at 0.8 MPa, 90%; and at 1.4 MPa, 100% of the sonicated locations showed enhancement. The histology findings following 4 h survival indicated that brain tissue necrosis was induced in approximately 70–80% of the sonicated locations at a pressure amplitude level of 2.3 MPa or higher. At lower pressure amplitudes, however, small areas of erythrocyte extravasation were seen. The electron microscopy findings demonstrated HRP passage through vessel walls via both transendothelial and paraendothelial routes. These results demonstrate that completely noninvasive focal disruption of the BBB is possible.
Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound- induced blood–brain barrier disruption
Manabu Kinoshita, Nathan McDannold, Ferenc A. Jolesz, Kullervo Hynynen Comm. by Floyd Dunn, Uni of Illinois at Urbana–Champaign, Urbana, IL. 2006
Abstract
Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c- erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood–brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood–brain barrier under image guidance by using an MRI-guided focused ultrasound blood–brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI- monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the CNS.
Targeted delivery of antibodies through the blood–brain barrier by MRI-guided focused ultrasound
Manabu Kinoshita, Nathan McDannold, Ferenc A. Jolesz, Kullervo Hynynen, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2005
Abstract
The blood–brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D4receptor- targeting antibody crossed the BBB and recognized its antigens.
Using MRI, we were able to monitor the extent of BBB disruption.
This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.
Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles
Nickolai Sheikov, Nathan McDannold, Natalia Vykhodtseva, Ferenc Jolesz, Kullervo Hynynen
Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. 2004
Abstract
Local blood-brain barrier (BBB) opening is an advantageous approach for targeted drug delivery to the brain. Recently, it has been shown that focused ultrasound (US) exposures (sonications), when applied in the presence of preformed gas bubbles, caused magnetic- resonance (MR) proven reversible opening of the BBB in targeted locations. The cellular mechanisms of such transient barrier disruption are largely unknown. We investigated US-induced changes in endothelial cell fine morphology that resulted in the BBB opening in rabbits. To obtain evidence for the passage of blood- borne macromolecules through the opened transvascular routes, an immunocytochemical procedure for endogenous immunoglobulinG (IgG) was performed, in addition to the routine electron microscopy. An increased number of vesicles and vacuoles, fenestration and channel formation, as well as opening of some tight junctions, were seen in capillaries after low-power (0.55 W) sonication. Immunosignals presented in some of the vesicles and vacuoles, in the cytoplasmic channels and, so rarely, in intercellular clefts; immunosignals could also be seen in neuropil around the blood vessels. Damage to the cellular ultrastructure was not seen in these areas. However, cell destruction and leakage of IgG through defects of the endothelial lining took place at 3 W sonications. The data reveals that several mechanisms of transcapillary passage are possible after such sonications:
- transcytosis;
- endothelial cell cytoplasmic openings—fenestration and channel formation;
- opening of a part of tight junctions; and
- free passage through the injured endothelium (with the higher power sonications).
These findings could be considered in further development of the strategy for drug delivery to brain parenchyma.
Targeted delivery of antibodies through the blood–brain barrier by MRI-guided focused ultrasound
Manabu Kinoshita, Nathan McDannold, Ferenc A. Jolesz, Kullervo Hynynen, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2005
Abstract
The blood–brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D4receptor- targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption.
This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.
