Focused Ultrasound Enhances Central Nervous System Delivery of Bevacizumab for Malignant Glioma Treatment

Abstract

Purpose To demonstrate that magnetic resonance (MR) imaging-monitored transcranial focused ultrasound can enhance the delivery of the antiangiogenic monoclonal antibody bevacizumab into the central nervous system (CNS) for glioblastoma multiforme (GBM) treatment. Materials and Methods All animal experiments were approved by the animal committee and adhered to experimental animal care guidelines. Transcranial focused ultrasound exposure in the presence of microbubbles was used to open the blood-brain barrier (BBB) to enhance bevacizumab penetration into the CNS in healthy and glioma-bearing mice. Bevacizumab concentration was quantitated with high-performance liquid chromatography, and Western blot testing was performed to confirm the specific biologic form in the CNS. Penetration of bevacizumab into brain tissue was estimated in vivo by means of contrast material-enhanced MR imaging and quantitative gallium 68 ((68)Ga)-bevacizumab micro-positron emission tomography, and glioma progression was longitudinally followed with T2-weighted MR imaging. Hematoxylin-eosin staining and cluster of differentiation 31 immunostaining were used to assess morphologic changes and vascular inhibition at histologic examination. The two-tailed Student t test and the Mantel-Cox log-rank test were used for statistical analyses, with a significance level of .05. Results Focused ultrasound significantly enhanced bevacizumab penetration into the CNS by 5.7- to 56.7-fold compared with that in nonexposed brain (both P < .0001). Contrast-enhanced MR imaging indexes correlated with bevacizumab concentration (r = 0.748-0.857) in vivo. Focused ultrasound-enhanced bevacizumab delivery significantly retarded glioma progression, with a significantly increased median survival (median increase in survival time = 135% in the group treated with bevacizumab and focused ultrasound, P < .0001; as compared with 48% in the group treated with bevacizumab alone, P = .0002). Conclusion Focused ultrasound-enhanced bevacizumab delivery can provide an antivascularization normalization effect to suppress glioma. (©) RSNA, 2016 Online supplemental material is available for this article.

Directed evolution of a picomolar-affinity, high-specificity antibody targeting phosphorylated tau

“…2B, mean ± standard deviation), which is lower than the monovalent affinity for the full-length IgG (K d = 0.35 nM) generated using the same variable regions (27). Even though scFv constructs are highly advantageous for imaging (37) and delivery (38)(39)(40), a 5 to 15-fold reduction in affinity upon conversion of IgG to scFv had been reported (38,41), potentially due to higher stability and functional concentration of full IgGs. To confirm that the yeast displayed scFv was properly folded, we generated alanine point mutations in the CDR residues that interacted with the phosphoepitope (Supp.…”

“…This has led to significant enhancement in processes that rely on diffusion, such as tissue penetration. For example, when the blood-brain barrier was transiently opened through focused ultrasound, scFvs showed 5-to 57-fold higher uptake into the central nervous system compared to IgGs (40). In a mouse model of tauopathy, intravenously injected scFvs were detected in the brain tissue in significantly higher levels compared to that of IgGs (37).…”

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases

“…Delivery of doxorubicin to a brainstem was also recently shown to be feasible and safe for animals after histological and behavioral tests (50). Other chemotherapies investigated in conjunction with MRgFUS BBB opening in small (e.g., rat, rabbit) to large (e.g., nonhuman primates) animals include paclitaxel (60), methotrexate (61, 62), doxorubicin (50, 63, 64), cisplatin (65), bevacizumab (66), and carmustine (67) (Table 1). …”

The Future of Cranial Neurosurgery—Adapting New Approaches

“…This concept has been explored using multiple chemotherapeutics including doxorubicin (glioma), nitrosurea agents (glioma), bevacizumamab (glioma), and trastuzumab (breast metastasis). [14][15][16] These studies have demonstrated variable degrees of drug penetrance and tumoral killing. Currently, clinical trials (NCT02343991) are being conducted to evaluate the safety of MRFUS to transiently break down the BBB for delivery of intracranial doxorubicin.…”