Delivery of drug-loaded microbubbles and disruption of blood-brain barrier by focused ultrasound in a xenograft rat glioma model

Abstract BACKGROUND Drug delivery remains a major obstacle in DIPG, as the blood brain barrier (BBB) limits the penetration of systemic therapies to the brainstem. Focused ultrasound (FUS) is an exciting new technology that, when combined with microbubbles, can open the BBB permitting the entry of drugs across the cerebrovasculature. Given that the utility of FUS in brainstem tumors remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. METHODS A syngeneic orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells (10,000/1ul) into the pons of B6 albino mice. A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier (acoustic pressure=0.7MPa) was used with concurrent intravenous microbubble injection (FUS+MB) to sonicate the tumor on post-injection day 14. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen (KIS) testing was completed to measure motor function. Mice were either immediately sacrificed for histopathological assessment or serially monitored for survival. RESULTS In mice treated with FUS (n=11), there was no measured deficit in KIS testing. Additionally, the degree of intra-tumoral hemorrhage and inflammation on H&E in control (n=5) and treated mice (n=5) was similar. Lastly, there was no difference in survival between the groups (control, n=6, median=26 days; FUS, n=6, median=25 days, p>0.05). CONCLUSION FUS+MB is a safe and feasible technique to open the BBB in a preclinical pontine glioma model.

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A quantitative study of blood-brain barrier permeability ultrastructure in a new rat glioma model

Acta Neuropathologica ◽

10.1007/bf00688129 ◽

1985 ◽

Vol 67 (1-2) ◽

pp. 96-102 ◽

Cited By ~ 69

Author(s):

P. A. Stewart ◽

K. Hayakawa ◽

E. Hayakawa ◽

C. L. Farrell ◽

R. F. Del Maestro

Keyword(s):

Blood Brain Barrier ◽

Quantitative Study ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Rat Glioma ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Glioma Model

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Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model

Scientific Reports ◽

10.1038/s41598-021-85180-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zachary K. Englander ◽

Hong-Jian Wei ◽

Antonios N. Pouliopoulos ◽

Ethan Bendau ◽

Pavan Upadhyayula ◽

...

Keyword(s):

Blood Brain Barrier ◽

Motor Function ◽

Focused Ultrasound ◽

Weight Lifting ◽

Brain Barrier ◽

Single Element ◽

Pontine Glioma ◽

Blood Brain ◽

Glioma Model ◽

Bbb Opening

AbstractDrug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-B+PTEN−/−p53−/− murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups (p > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.

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Improved Anti-Tumor Effect of Liposomal Doxorubicin After Targeted Blood-Brain Barrier Disruption by MRI-Guided Focused Ultrasound in Rat Glioma

Ultrasound in Medicine & Biology ◽

10.1016/j.ultrasmedbio.2012.04.015 ◽

2012 ◽

Vol 38 (10) ◽

pp. 1716-1725 ◽

Cited By ~ 138

Author(s):

Lisa H. Treat ◽

Nathan McDannold ◽

Yongzhi Zhang ◽

Natalia Vykhodtseva ◽

Kullervo Hynynen

Keyword(s):

Blood Brain Barrier ◽

Focused Ultrasound ◽

Liposomal Doxorubicin ◽

Brain Barrier ◽

Rat Glioma ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Mri Guided ◽

Brain Barrier Disruption

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Relation between polyporphyrin distribution and blood brain barrier changes in the rat glioma model

Lasers in Surgery and Medicine ◽

10.1002/lsm.1900120210 ◽

1992 ◽

Vol 12 (2) ◽

pp. 174-179 ◽

Cited By ~ 9

Author(s):

Ying Ji ◽

Diana L. Walstad ◽

J. Tony Brown ◽

Stephen K. Powers

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Rat Glioma ◽

Blood Brain ◽

Glioma Model

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RG2 Rat Glioma Model: Influence of the Blood-Brain Barrier on Biodistribution of Boronsulfhydryl

Advances in Neutron Capture Therapy ◽

10.1007/978-1-4615-2978-1_98 ◽

1993 ◽

pp. 485-490 ◽

Cited By ~ 2

Author(s):

D. Schuepbach ◽

P. R. Gavin ◽

L. G. Salford ◽

C. Ceberg ◽

H. Fankhauser

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Rat Glioma ◽

Blood Brain ◽

Glioma Model

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Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors

Science Advances ◽

10.1126/sciadv.abd0772 ◽

2021 ◽

Vol 7 (6) ◽

pp. eabd0772

Author(s):

Ko-Ting Chen ◽

Wen-Yen Chai ◽

Ya-Jui Lin ◽

Chia-Jung Lin ◽

Pin-Yuan Chen ◽

...

Keyword(s):

Blood Brain Barrier ◽

Immune Modulation ◽

Focused Ultrasound ◽

Pilot Trial ◽

Immunological Response ◽

Preliminary Evidence ◽

Recurrent Glioblastoma ◽

Brain Barrier ◽

Rat Glioma ◽

Blood Brain

Focused ultrasound (FUS) in the presence of microbubbles can transiently open the blood-brain barrier (BBB) to increase therapeutic agent penetration at the targeted brain site to benefit recurrent glioblastoma (rGBM) treatment. This study is a dose-escalating pilot trial using a device combining neuronavigation and a manually operated frameless FUS system to treat rGBM patients. The safety and feasibility were established, while a dose-dependent BBB-opening effect was observed, which reverted to baseline within 24 hours after treatment. No immunological response was observed clinically under the applied FUS level in humans; however, selecting a higher level in animals resulted in prolonged immunostimulation, as confirmed preclinically by the recruitment of lymphocytes into the tumor microenvironment (TME) in a rat glioma model. Our findings provide preliminary evidence of FUS-induced immune modulation as an additional therapeutic benefit by converting the immunosuppressive TME into an immunostimulatory TME via a higher but safe FUS dosage.

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