title: Paramagnetic perfluorocarbon-filled albumin-(Gd-DTPA) microbubbles for the induction of focused-ultrasound-induced blood-brain barrier opening and concurrent MR and 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 blood-brain 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(9) MBs ml(-1) using albumin-(Gd-DTPA) and by sonication with perfluorocarbon (C(3)F(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(1) and r(2) relaxivities for Gd-DTPA were 7.69 and 21.35 s(-1)mM(-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.
authors.affiliation: Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.
authors.forename: Ai-Ho
authors.initials: AH
authors.lastname: Liao
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Su
authors.forename: Mu-Yi
authors.initials: MY
authors.lastname: Hua
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Yang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Weng
authors.forename: Po-Hung
authors.initials: PH
authors.lastname: Hsu
authors.forename: Sheng-Min
authors.initials: SM
authors.lastname: Huang
authors.forename: Shih-Yen
authors.initials: SY
authors.lastname: Wu
authors.forename: Hsin-Ell
authors.initials: HE
authors.lastname: Wang
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Pai-Chi
authors.initials: PC
authors.lastname: Li
mesh_terms: D000418:Albumins / Q000737:chemistry*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D003287:Contrast Media; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005466:Fluorocarbons / Q000737:chemistry*; D019786:Gadolinium DTPA / Q000737:chemistry; D006801:Humans; D060328:Magnetic Phenomena; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008863:Microspheres; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography / Q000379:methods*
chemical_list: D000418:Albumins; D003287:Contrast Media; D005466:Fluorocarbons; D019786:Gadolinium DTPA