Paramagnetic Perfluorocarbon-Filled Albumin-(Gd-DTPA) Microbubbles for the Induction of Focused-Ultrasound-Induced Blood─Brain Barrier Opening Concurrent MR Ultrasound Imaging

Abstract

This paper presents new albumin-shelled Gd-DTPA microbubbles (MBs) that can concurrently serve as a dual-modality contrast agent for ultrasound (US) imaging and magnetic resonance (MR) imaging to assist bloodbrain barrier (BBB) opening and detect intracerebral hemorrhage (ICH) during focused ultrasound brain drug delivery. Perfluorocarbon-filled albumin-(Gd-DTPA) MBs were prepared with a mean diameter of 2320 nm and concentration of 2.903×10 9MBs ml -1using albumin-(Gd-DTPA) and by sonication with perfluorocarbon (C 3F 8) gas. The albumin-(Gd-DTPA) MBs were then centrifuged and the procedure was repeated until the free Gd 3+ions were eliminated (which were detected by the xylenol orange sodium salt solution). The albumin-(Gd-DTPA) MBs were also characterized and evaluated both in vitro and in vivo by US and MR imaging. Focused US was used with the albumin-(Gd-DTPA) MBs to induce disruption of the BBB in 18 rats. BBB disruption was confirmed with contrast-enhanced T 1-weighted turbo-spin-echo sequence MR imaging. Heavy T 2*-weighted 3D fast low-angle shot sequence MR imaging was used to detect ICH. In vitro US imaging experiments showed that albumin-(Gd-DTPA) MBs can significantly enhance the US contrast in T 1-, T 2- and T 2*-weighted MR images. The r 1and r 2relaxivities for Gd-DTPA were 7.69 and 21.35 s -1mM -1, respectively, indicating that the MBs represent a positive contrast agent in T 1-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 disruption of the BBB and detect ICH. To compare the signal intensity change between pure BBB opening and BBB opening accompanying ICH, albumin-(Gd-DTPA) MB imaging can provide a ratio of 5.14 with significant difference (p = 0.026), whereas Gd-DTPA imaging only provides a ratio of 2.13 and without significant difference (p = 0.108). The results indicate that albumin-(Gd-DTPA) MBs have potential as a US/MR dual-modality contrast agent for BBB opening and differentiating focused-US-induced BBB opening from ICH, and can monitor the focused ultrasound brain drug delivery process. ? 2012 Institute of Physics and Engineering in Medicine.