US/MRI dual modality contrast agent for concurrent MR and ultrasonic imaging of focused-ultrasound induced blood-brian barrier opening

Targeted drug delivery by magnetic resonance (MR)-guided ultrasound (US)-induced blood-brain barrier (BBB) disruption has been developed using focused US in combination with encapsulated gas-filled microbubbles (MBs). However, the occurrence of intracerebral hemorrhage may hamper the usefulness of US-induced BBB opening, which is effectively indicated by gadolinium (Gd)-based contrast enhancement in T₁-weighted MR scans. This paper reports the dual function of paramagnetic particles of perfluorocarbon-filled albumin-gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) MBs for BBB opening and for distinguishing between focused-US-induced BBB opening and intracerebral hemorrhage in MR contrast images. Perfluorocarbon-filled albumin-(Gd-DTPA) MBs were prepared with a mean diameter of 2320 nm and concentration of 2.903×10⁹MBs/ml using albumin-(Gd-DTPA) and by sonication with perfluorocarbon (C₃F₈) gas. The albumin-(Gd-DTPA) MBs were then centrifuged and the procedure was repeated until the free Gd³⁺ ions were eliminated (which were detected by xylenol orange sodium salt solution). In vitro US imaging experiments showed that albumin-(Gd-DTPA) MBs can significantly enhance the US contrast in T₁-, T₂-, and T₂*-weighted MR images. The r₁ and r₂ relaxivities for Gd-DTPA were 7.69 and 21.35 s^-1mM^-1, respectively, indicating that the MBs represent a positive contrast agent in T₁-weighted images. In vivo MR imaging experiments on 18 rats showed that focused US combined with albumin-(Gd-DTPA) MBs can be used to both induce and detect disruption of the BBB. After disrupting the BBB, the leakage of albumin-(Gd-DTPA) MBs shells can be detected for distinguishing between focused-US-induced disruption of the BBB and intracerebral hemorrhage in T₁-weighted images. The results indicate that albumin-(Gd-DTPA) MBs have pote- - ntial as a US/MR dual-modality contrast agent for BBB opening and differentiating focused-US-induced BBB opening from intracerebral hemorrhage.