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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.27.609060
preprint
1
Article
Focused Ultrasound Impels the Delivery and Penetration of Model Therapeutics into Cerebral Cavernous Malformations
Fisher Delaney G.
Hoch Matthew R.
Gorick Catherine M.
Huchthausen Claire
Breza Victoria R.
Sharifi Khadijeh A.
Tvrdik Petr
Miller G. Wilson
Price Richard J. http://orcid.org/0000-0002-0237-2102

28 8 2024
2024.08.27.609060https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.27.609060
nihpp-2024.08.27.609060.pdf
Abstract

BACKGROUND

Cerebral cavernous malformations (CCMs) are vascular neoplasms in the brain that can cause debilitating symptoms. Current treatments pose significant risks to some patients, motivating the development of new nonsurgical options. We recently discovered that focused ultrasound-mediated blood-brain barrier opening (FUS) arrests CCM formation and growth. Here, we build on this discovery and assess the ability of FUS to deliver model therapeutics into CCMs.

METHODS

Quantitative T1 mapping MRI sequences were used with 1 kDa (MultiHance; MH) and 17 kDa (GadoSpin D; GDS) contrast agents to assess the FUS-mediated delivery and penetration of model small molecule drugs and biologics, respectively, into CCMs of Krit1 mutant mice.

RESULTS

FUS elevated the rate of MH delivery to both the lesion core (4.6-fold) and perilesional space (6.7-fold). Total MH delivery more than doubled in the lesion core and tripled in the perilesional space when FUS was applied immediately prior to MH injection. For the model biologic drug (i.e. GDS), FUS was of greater relative benefit, resulting in 21.7-fold and 3.8-fold delivery increases to the intralesional and perilesional spaces, respectively

CONCLUSIONS

FUS is capable of impelling the delivery and penetration of therapeutics into the complex and disorganized CCM microenvironment. Benefits to small molecule drug delivery are more evident in the perilesional space, while benefits to biologic delivery are more evident in CCM cores. These findings, when combined with ability of FUS alone to control CCMs, highlight the potential of FUS to serve as a powerful non-invasive therapeutic platform for CCM.
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pmc
