Contrast-Enhanced Magnetic Resonance Imaging Guided Focused-Ultrasound for Blood-Brain Barrier Opening and in-vivo Brain-Tumor Targeting

It has been recently discovered that focused ultrasound can locally and reversibly disrupt blood-brain barrier, which opens new frontier toward delivering therapeutic agents or drugs for CNS disorder treatment especially for those which cannot penetrate into brain parenchyma. To monitor the BBB opening process from MRI, current approach is to employ contrast-enhanced T1-weighted MR imaging by using gadopentetate dimeglumine injection intravenously. However, the contrast enhancement is typically 20%, unable to distinct safe BBB disruption from hemorrhage, its unknown toxicity when entering into brain parenchyma, and difficult to modify the particle to be specific-molecule or specific-antibody targetable for molecular/ disease targeting imaging purpose. Our research team recently showed that the superparamagnetic iron-oxide (SPIO) nanoparticles as a contrast agent in contrast-enhanced T2- or T2*-weighted MRI can be another approach in the detection of focused-ultrasound induced BBB opening. Major advantages of this approach includes (1) the sequence is superior in the detection of potential microhemorrhage during the sonication process, (2) a higher contrast change (typically ＞ 50%), and more importantly, (3) the flexibility in the surface modification to coat specific ligand or antibody and for the use of targeting imaging. As a sub-project of the general goal on “establishing a molecular imaging-based translational platform for pre-clinical studies of drug delivery”, our specific role here is to establish the core technology – focused ultrasound induced BBB-opening – and successfully transfer it to other sub-projects for their novel imaging technology developments. Specific aim of this proposal includes: (1) to establish the technology of SPIO-enhanced MRI for monitoring focused ultrasound induced BBB-opening, and (2) to develop the EGFR-antibody-coated SPIO nanoparticles for brain tumor targeting during the focused ultrasound treatment for further investigation of tumor drug-delivery strategy. Three year working progress is proposed. The specific aim of the first year is to established the MRI-guided focused ultrasound treatment platform; in the second year, we aim to embed the SPIO-enhanced MRI technology into the platform; in the third year, we aim to develop EGFR-antibody-coated SPIO nanoparticles as image-targeting tool no only image BBB-opening but also image brain tumor distribution for further investigation on brain-tumor drug-delivered planning.

Project ID:PB10001-0143
External Project ID:NSC98-2221-E182-045-MY3