- Poster presentation
- Open Access
Quantitative evaluation of blood-tumor-barrier response following focused ultrasound and microbubble treatment in rat glioma: can we improve drug delivery to brain tumors?
- Hassaan Ahmed1
© Ahmed; licensee BioMed Central Ltd. 2015
- Published: 30 June 2015
- Cerebral Blood Flow
- Cerebral Blood Volume
- Mean Transit Time
- Vasogenic Edema
- Focus Ultrasound
The increased interstitial fluid pressure (IFP) from vasogenic edema, which results from a leaky blood-tumor-barrier (BTB), creates a barrier for transvascular drug delivery, particularly larger molecules that are unable to diffuse across and must resort to bulk fluid flow. We have previously used dynamic contrast enhanced-computed tomography (DCE-CT) to quantitatively evaluate the blood-brain-barrier (BBB) response in normal brain - and have shown that focused ultrasound (FUS) and microbubble (MB) treatment in a rat brain demonstrates a 3-4 times transient increase at our optimized parameters. The purpose of this study was to quantitatively evaluate the BTB response following FUS and MB treatment in rat glioma, in the context of improving drug delivery to brain tumors.
At 10-15 days before treatment, 1 x 106 C6 glioma cells are surgically implanted using a stereotactic frame into a region in the right cerebral hemisphere of a Wistar rat. The rats were broken into 2 groups before treatment: 1) evaluating the acute response out to 4 h post for tumor and normal hemispheres (n=3), and 2) recovery at 2 h post followed by scans at 24 and 72 h post (n=5). The tumor is transcranially sonicated at previously optimized parameters that demonstrate transient opening in the normal BBB without any vascular or tissue damage - 10 ms burst length with 1 Hz repetition frequency for 120s, with an applied power of 0.5 W, using a 0.563-MHz FUS system. 2 ul/kg of Definity microbubbles are injected simultaneously with the start of the sonication. Axial CT scans as well as the DCE-CT perfusion maps were used to target the tumor. DCE-CT (80 kVp, 250 mA, axial slice thickness = 1.25 mm) was performed using a two phase protocol: 1st phase consisting of continuous 0.5 s rotations for 30 s, and a 2nd phase of 0.5 s rotations at 14.5 s intervals for 150s. 2.5 ml/kg of iodinated contrast agent was injected over 5 seconds simultaneous to the start of each DCE-CT scan. Proprietary CT Perfusion software was used to compute permeability surface area product (PS), cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps using a standard small molecule contrast agent (Isovue ~ 760 Da) that is able to diffuse across the BTB. The BTB PS was also evaluated using a much larger contrast agent (eXia ~ 65,000 Da) that mimics the delivery of agents such as monoclonal antibodies.
Canadian Institute for Health Research, Canada Foundation for Innovation, Federal Development Canada Agency, Ontario Brain Institute
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