Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection

Colleen T. Curley; Brian P. Mead; Karina Negron; Namho Kim; William J. Garrison; G. Wilson Miller; Kathryn M. Kingsmore; E. Andrew Thim; Ji Song; Jennifer M. Munson; Alexander L. Klibanov; Jung Soo Suk; Justin Hanes; Richard J. Price

doi:10.1126/sciadv.aay1344

Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection

Colleen T. Curley, Brian P. Mead, Karina Negron, Namho Kim, William J. Garrison, G. Wilson Miller, Kathryn M. Kingsmore, E. Andrew Thim, Ji Song, Jennifer M. Munson, Alexander L. Klibanov, Jung Soo Suk, Justin Hanes, Richard J. Price

School of Medicine

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

The delivery of systemically administered gene therapies to brain tumors is exceptionally difficult because of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). In addition, the adhesive and nanoporous tumor extracellular matrix hinders therapeutic dispersion. We first developed the use of magnetic resonance image (MRI)-guided focused ultrasound (FUS) and microbubbles as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered “brain-penetrating” nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with “per voxel” flow directions changing by an average of ~70° to 80°. Last, we observed that FUS-mediated BTB/BBB opening increased the dispersion of directly injected BPNs through tumor tissue by >100%. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.

Original language	English (US)
Article number	eaay1344
Journal	Science Advances
Volume	6
Issue number	18
DOIs	https://doi.org/10.1126/sciadv.aay1344
State	Published - Apr 2020

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Curley, C. T., Mead, B. P., Negron, K., Kim, N., Garrison, W. J., Wilson Miller, G., Kingsmore, K. M., Andrew Thim, E., Song, J., Munson, J. M., Klibanov, A. L., Suk, J. S., Hanes, J., & Price, R. J. (2020). Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection. Science Advances, 6(18), Article eaay1344. https://doi.org/10.1126/sciadv.aay1344

Curley, CT, Mead, BP, Negron, K, Kim, N, Garrison, WJ, Wilson Miller, G, Kingsmore, KM, Andrew Thim, E, Song, J, Munson, JM, Klibanov, AL, Suk, JS, Hanes, J & Price, RJ 2020, 'Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection', Science Advances, vol. 6, no. 18, eaay1344. https://doi.org/10.1126/sciadv.aay1344

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abstract = "The delivery of systemically administered gene therapies to brain tumors is exceptionally difficult because of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). In addition, the adhesive and nanoporous tumor extracellular matrix hinders therapeutic dispersion. We first developed the use of magnetic resonance image (MRI)-guided focused ultrasound (FUS) and microbubbles as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered “brain-penetrating” nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with “per voxel” flow directions changing by an average of ~70° to 80°. Last, we observed that FUS-mediated BTB/BBB opening increased the dispersion of directly injected BPNs through tumor tissue by >100%. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.",

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AU - Suk, Jung Soo

AU - Hanes, Justin

AU - Price, Richard J.

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N2 - The delivery of systemically administered gene therapies to brain tumors is exceptionally difficult because of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). In addition, the adhesive and nanoporous tumor extracellular matrix hinders therapeutic dispersion. We first developed the use of magnetic resonance image (MRI)-guided focused ultrasound (FUS) and microbubbles as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered “brain-penetrating” nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with “per voxel” flow directions changing by an average of ~70° to 80°. Last, we observed that FUS-mediated BTB/BBB opening increased the dispersion of directly injected BPNs through tumor tissue by >100%. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.

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Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection

Abstract

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