Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors

Abstract

Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.

Focused shockwave induced blood-brain barrier opening and transfection

“…Immediately after the injection of 0.5 ml of 3% EB via the rats’ tail vein, 100 shockwave iterations were applied (intensity level 5, pulse repetition frequency (PRF) 5 Hz, N = 8). The following process was modified from a previous study 27 . The original two hour interval time for euthanization was extended to three hours.…”

“…The original two hour interval time for euthanization was extended to three hours. Three hours after the shockwave application, the rats were sacrificed and the brains were harvested for histological analysis 27 . The intensity levels for each parameter are shown in Table 1.…”

Drug Delivery Across the Blood–Brain Barrier with Focused Ultrasound and Microbubbles

“…These two molecules, which normally do not enter the brain parenchyma from the bloodstream, can potentially be used as surrogate markers for drug delivery. Although the dynamic distribution of Gd-DTPA may differ from that of Evans blue, AUC accumulation of Gd-DTPA analyzed by MRI was highly correlated with EB accumulation in the brain [26], implying that MRI AUC analysis of Gd-DTPA could predict the concentration of EB accumulating in the brain. Gd-DTPA may thus have the potential to predict the pharmacodynamics behavior and biodistribution of therapeutic agents delivered through the BBB.…”

Quantification of transient increase of the blood–brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles

“…[8][9][10][11] FUS-induced BBB disruption has been widely assessed by using magnetic resonance imaging (MRI) or post-FUS histological examination. 6,7,[12][13][14][15][16][17][18][19][20][21][22] Indirect MRI collects the images of brain slices in the presence of an MRI contrast agent such as gadolinium to access the BBB disruption in different locations of the brain. Alternatively, post-FUS histological examination relates the BBB disruption to the amount of Evans blue extravasation in the brain tissue after the dye is intravenously injected into the blood circulation before or after sonication.…”