Comparison of Single Spot and Volume Ultrasound Sonications for Efficient Nanoparticle Delivery to Glioblastoma Model in Rats
Résumé
Background, Motivation and Objective
Brain tumors therapy is limited by the Blood-Tumor Barrier (BTB) and Blood-Brain Barrier (BBB), still intact in the infiltrative areas. Low intensity Focused Ultrasound (FUS) in conjunction with microbubbles is the only method allowing the local disruption of the BTB/BBB [Hynynen et al. 2001, Zhao et al. 2015]. Proper study of the influence of acoustic
scanning parameters (duty cycle, number of focal spots) on the amount of delivered nanoparticles is not available so far. Here, we compared two acoustic strategies to enhance the molecular concentration within brain tumors. The efficacy of the two methods is evaluated on the basis of absolute concentrations of delivered MR-contrast agents (CA) and on their
rates of uptake/clearance by the tumors.
Statement of Contribution/Methods
9L tumors were implanted in both striatum of Fischer rats (n=8): one tumor was sonicated and the other one was used as a control. A MR-guided motorized FUS system [Magnin et al. 2016] was used to target only one of the two tumors. A single point sonication at the tumor core (n=3) and a sonication at 8 vertices of a 3D trajectory covering the whole tumor
volume (n=5) were compared. Frequency, duty cycle, sonication time and estimated peak negative pressure were kept constant respectively to 1.5 MHz, 3%, 120 s and 1.2 MPa. Microbubbles administration was followed by FUS application and by the intravenous injection of a Gd-based MR-CA (AGuIX). Gd uptake and clearance inside the tumors was
imaged by acquiring dynamic 3D T1-maps within 1 hour allowing to reconstruct absolute CA-maps in the whole brain [Marty et al. 2012]. Tumors were manually segmented on T2-weighted anatomical images co-registered to the CA-maps, in order to follow the CA concentration time courses in tumors.
Results/Discussion
Figure 1 shows the results obtained with 1 and 8 points sonications. With both methods, higher CA concentrations are delivered to sonicated tumors respect to the control ones. The single spot sonication appears to be more efficient, independently of the tumor size although not very efficient in large tumors (B). Choice of acoustic trajectory has a huge impact on drug delivery efficacy and needs to be optimized to each configuration. It seems to affect more the uptake rate than the clearance rate of the pharmacokinetics of tumors.