Experimental Study on Targeted Methotrexate Delivery to the Rabbit Brain via Magnetic Resonance Imaging-Guided Focused Ultrasound

Mei, Jie; Yuan, Chao; Yu, Shaoming; Yang, Yanqing; Wang, Feng; Liu, Yingjiang; Wang, Zhibiao

doi:10.7863/jum.2009.28.7.871

Cited by 108 publications

(66 citation statements)

References 18 publications

(19 reference statements)

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“…They observed the extravasated red blood cells and tissue necrosis by H&E staining (11,15,21), DNA fragmentation and apoptotic bodies in the cells by TUNEL staining (5,11,21), major ischemic changes by vanadium acid fuchsin-toluidine blue staining (5,14), and the occurrence of an inflammatory response by fluorescein isothiocyanate-coated CD-11b fluorescent antibody labeling and Prussian blue staining (30). In some studies, lesions induced by focus ultrasound were also examined histologically by electron microscopy (19,21,31).…”

Section: Nonhemorrhagic Vs Biosafety Conditionsmentioning

confidence: 99%

“…This increase in BBB permeability can be detected by contrast-enhanced MRI using gadolinium-based (8,9) or iron oxide-based contrast agents (10) or by single-photon emission computed tomography with 99m Tc-based radiotracers (11). Using these imaging methods to guide FUS sonication, BBB at the targeted brain regions can be disrupted accurately, facilitating the delivery of diagnostic or therapeutic agents (12)(13)(14)(15)(16)(17).Although FUS sonication is promising in facilitating drug delivery across BBB, increasing concerns have been raised regarding its potential adverse effects on the brain. Indeed, FUS sonication could damage the brain tissue via FUS-induced edema, hemorrhage, ischemia, and apoptosis (10,18,19).…”

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Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

Weng

Lin

et al. 2010

Magnetic Resonance in Med

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Focused ultrasound combined with an intravascular ultrasound contrast agent can induce transient disruption of the blood-brain barrier, and the blood-brain barrier disruption can be detected by contrast-enhanced MRI. There is, however, no study investigating the ability of various MR methods to detect focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage. Sonication was applied to 15 rat brains with four different doses of ultrasound contrast agent (0, 10, 30, or 50 mL/kg), and contrast-enhanced T1-weighted spin echo, gradient echo images, and longitudinal relaxation rate mapping along with effective transverse relaxation time-weighted and susceptibility-weighted images were acquired. Volume-of-interest-based and threshold-based analyses were performed to quantify the contrast enhancement, which was then correlated with the ultrasound contrast agent dose and with the amount of Evans blue extravasation. Both effective transverse relaxation time-weighted and susceptibility-weighted images did not detect histology-proved intracranial hemorrhage at 10 mL/kg, but MRI failed to detect mild intracranial hemorrhage at 30 mL/kg. All tested sequences showed detectable contrast enhancement increasing with ultrasound contrast agent dose. In correlating with Evans blue extravasation, the gradient echo sequence was slightly better than the spin echo sequence and was comparable to longitudinal relaxation rate mapping. In conclusion, both gradient echo and spin echo sequences were all reliable in indicating the degree of focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage. Magn Reson Med 65:802-811, 2011. V C 2010 Wiley-Liss, Inc.Key words: magnetic resonance imaging; focused ultrasound; blood-brain barrier; ultrasound contrast agent; microbubbles; R 1 mappingThe blood-brain barrier (BBB) results from the selectivity of the tight junctions between endothelial cells in central nervous system vessels. It limits the passage of most potential diagnostically and therapeutically useful molecules from circulation into the brain parenchyma and precludes their use in diagnosis or treatment in the central nervous system (1-3). Recently, focused ultrasound (FUS) combined with intravascular ultrasound contrast agent (UCA) has been shown to transiently increase the transport of molecules across the BBB (4-7). This increase in BBB permeability can be detected by contrast-enhanced MRI using gadolinium-based (8,9) or iron oxide-based contrast agents (10) or by single-photon emission computed tomography with 99m Tc-based radiotracers (11). Using these imaging methods to guide FUS sonication, BBB at the targeted brain regions can be disrupted accurately, facilitating the delivery of diagnostic or therapeutic agents (12)(13)(14)(15)(16)(17).Although FUS sonication is promising in facilitating drug delivery across BBB, increasing concerns have been raised regarding its potential adverse effects on the brain. Indeed, FUS sonication could damage the brain tissue via FUS-induced edema, hem...

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Section: Nonhemorrhagic Vs Biosafety Conditionsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

Weng

Lin

et al. 2010

Magnetic Resonance in Med

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“…The recovery of the BBB functionality has been reported to be between 6 and 24 h for small tracer molecules such as gadolinium, 61,62 and by 12 h the levels of tight junctional proteins have been restored. 63 Contrast enhanced MRI has shown that once the BBB is closed following FUS, the barrier remains impenetrable up to 4 weeks later.…”

Section: ■ Cellular Mechanisms Of Fusmentioning

confidence: 99%

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

Burgess

Hynynen

2013

ACS Chem. Neurosci.

115

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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. KEYWORDS:Focused ultrasound, blood-brain barrier, drug delivery B rain diseases, including psychiatric disorders, neurodegenerative diseases, and cancer, are among the most prevalent diseases worldwide. It has been estimated that 35% of all disease burden is attributable to brain disorders.1 Despite advancing research, which better understands the etiology and underlying mechanisms of disease, most of these diseases do not have effective treatments and essentially no cures exist.Designing therapeutic agents for the brain is very challenging. The brain is a well-protected organ, completely encased by the skull, making surgical access difficult and direct application of drugs impractical. However, perhaps the most limiting factor to successful treatment of brain disease is the blood-brain barrier (BBB) which prevents access of ∼98% of current pharmaceutical agents to the brain when delivered intravenously. ■ THE BLOOD-BRAIN BARRIER (BBB)The BBB is a specialized structure between the cerebral capillaries and the brain parenchyma that is relatively impermeable except for a selection of very small (<400 Da), lipophilic compounds. 3 The BBB is different from the barriers between the peripheral vasculature and other organs in the body due mainly to the presence of tight junctions between adjacent endothelial cells.3 Cell adhesion molecules, most notably claudins and occludins, connect the endothelial cells together to create the tight junctions. The intracellular domains of the proteins are anchored to the cytoskeleton and the extracellular domains form homodimers with proteins on adjacent endothelial cells. These independent tight junctional proteins work in concert to make the endothelial cellular layer impermeable to fluid thereby limiting paracellular transport mechanisms.

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“…53 For example, MRgFUS delivered intravenous methotrexate to the brains of healthy rabbits at concentrations 13 times higher than intravenous methotrexate delivery alone (p < 0.01) and more than 3 times higher than methotrexate delivery via the internal carotid artery without MRgFUS (p < 0.01). 40 Thus, MRgFUS can reduce side effects of chemotherapeutic agents by requiring a lower systemic dose to reach a desired brain tumor tissue concentration. MRI guidance allows for not only identification of the lesion to be targeted but also dynamic feedback on the extent of BBB disruption via contrast leakage.…”

Section: Mrgfus and Microbubbles Focally Disrupt The Bbbmentioning

confidence: 99%

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

Lamsam¹,

Johnson²,

Connolly³

et al. 2018

Neurosurgical Focus

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Magnetic resonance–guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.

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Experimental Study on Targeted Methotrexate Delivery to the Rabbit Brain via Magnetic Resonance Imaging-Guided Focused Ultrasound

Cited by 108 publications

References 18 publications

Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

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