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Pharmacodynamic analysis and concentration mapping for efficient delivery through the FUS-induced BBB opening in non-human primates in vivo
© Samiotaki et al; licensee BioMed Central Ltd. 2015
Published: 30 June 2015
FUS in conjunction with systemically administered microbubbles has been previously shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in non-human primates. However, a trans-BBB pharmacodynamic analysis has not been performed as of yet. The objective of this study was to perform such an analysis, i.e. permeability, relaxivity and gadolinium concentration mapping, of the NHP brain in vivo in order to further investigate the effect of FUS, and its dependence on the acoustic parameters used for safe and efficient drug-delivery as well as the gray vs. white matter occurrence.
Two brain structures, the caudate and the putamen, were targeted in three rhesus macaques using FUS (center frequency: 500 kHz; pulse length: 5,000 cycles; PRF: 2 Hz; sonication duration: 120 s; peak negative pressure: 300-500 kPa) immediately after the IV administration of monodisperse bubbles (diameter: 4-5 μm, 2.5*108#/kg). Following sonication, the macaques were placed in a 3T MR scanner (Philips Medical System, Andover, MA, USA). Five pre-contrast 3D Spoiled Gradient Echo (SPGR) images (TR/TE: 10/4ms, FA: 5o-35o, NEX: 3, matrix: 256x256, resolution: 1x1x1 mm3) were acquired and used for variable flip angle *VFA) based T1 relaxivity mapping. Subsequently, Dynamic Contrast Enhanced (DCE) imaging was performed, with the acquisition of 90 dynamic T1-weighted 3D repetitions (TR/TE: 4.2/1.7 ms; matrix: 256x256, resolution 1x1x2 mm3). The data of the DCE were processed off-line using a customized Matlab-based algorithm and fitted to the General Kinetic Model using the Patlak method to generate permeability maps.
Quantitative permeability changes (Ktrans) and the volume of BBB opening after excluding the vasculature were obtained based on the T1 relaxivity maps. The areas of gray and white matter where BBB opening was induced were also determined, since they have distinctive characteristic relaxivity times. Gadolinium concentration [Gd] maps were then calculated from the T1, pre map before MR-CA injection and the T1, post maps after MR-CA injection using the following equation: [Gd] =1/r_Gd (1/T_(1, post) -1/T_(1, pre)). Vasculature and CSF were excluded from the opening volume based on their T1 relaxivity which was measured to be above 1400 ms.
Results and conclusions
The authors wish to acknolwedge Matthew Downs and Carlos Sierra Sanchez for their input and help. Funding: National Institutes of Health (R01 EB009041 & R01AG038961), Wallas H. Coulter Foundation, Focused Ultrasound Foundation.
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