Focused ultrasound augments the delivery and penetration of model therapeutics into cerebral cavernous malformations

Abstract

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-microbubble treatment (FUS) arrests CCM formation and growth. Here, we build on this discovery and assess the ability of FUS to deliver model therapeutics into CCMs. T1 mapping MRI was 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. FUS elevated MH delivery rate in lesion cores (4.6-fold) and perilesional spaces (6.7-fold). For the model biologic (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. These findings indicate that FUS can serve as a powerful non-invasive platform for augmenting therapeutic delivery to CCM.

Keywords: Blood-brain barrier; Cerebral cavernous malformation; Drug and gene delivery; Focused ultrasound; T1 mapping.