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  • Author or Editor: Alexander L. Klibanov x
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Caitlin W. Burke, Alexander L. Klibanov, Jason P. Sheehan, and Richard J. Price

Object

In this study, the authors sought determine whether microbubble (MB) destruction with pulsed low duty cycle ultrasound can be used to reduce brain tumor perfusion and growth through nonthermal microvascular ablation.

Methods

Studies using C57BLJ6/Rag-1 mice inoculated subcutaneously with C6 glioma cells were approved by the institutional animal care and use committee. Microbubbles were injected intravenously, and 1 MHz ultrasound was applied with varying duty cycles to the tumor every 5 seconds for 60 minutes. During treatment, tumor heating was quantified. Following treatment, tumor growth, hemodynamics, necrosis, and apoptosis were measured.

Results

Tumor blood flow was significantly reduced immediately after treatment, with posttreatment flow ranging from 36% (0.00002 duty cycle) to 4% (0.01 duty cycle) of pretreatment flow. Seven days after treatment, tumor necrosis and apoptosis were significantly increased in all treatment groups, while treatment with ultrasound duty cycles of 0.005 and 0.01 inhibited tumor growth by 63% and 75%, respectively, compared with untreated tumors. While a modest duty cycle–dependent increase in intratumor temperature was observed, it is unlikely that thermal tissue ablation occurred.

Conclusions

In a subcutaneous C6 glioma model, MB destruction with low–duty cycle 1-MHz ultrasound can be used to markedly inhibit growth, without substantial tumor tissue heating. These results may have a bearing on the development of transcranial high-intensity focused ultrasound treatments for brain tumors that are not amenable to thermal ablation.

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Yi Wang, Matthew J. Anzivino, Yanrong Zhang, Edward H. Bertram, James Woznak, Alexander L. Klibanov, Erik Dumont, Max Wintermark, and Kevin S. Lee

OBJECTIVE

Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage.

METHODS

Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB.

RESULTS

Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure.

CONCLUSIONS

These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.