Journal
SCIENCE ADVANCES
Volume 6, Issue 18, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aay1344
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Funding
- NIH [R01EB023055, R01CA164789, R01CA197111, R01CA204968, R01EB020147, R372222563]
- NSFGRF
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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 extra-cellular 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 similar to 70 degrees to 80 degrees. 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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