Figure 1.
Conceptual diagrams of focused ultrasound induced blood-brain barrier opening to enhance chemotherapeutic agent delivery for brain tumor treatment.
(a) Focused ultrasound is used to transcranially steer the exposure to the targeted brain tumor region; (b) focused ultrasound induces a local and reversible increase in BBB permeability of tight junctions in cerebral vessels and capillaries in the tumor core/ peripheral region. EC = endothelial cell, N = neuron, P = pericytes, A = astrocyte, D = chemotherapeutic agent, MB = microbubble.
Figure 2.
Time course for animal experiments and longitudinal MRI follow-up in experimental group 3.
Figure 3.
Representative Evans Blue dye stained Brain sections and calibrations after inducing FUS-BBB opening.
(a, b) brain sections viewed from the top and in corresponding brain sections. Bar = 5 mm. (c) Calibration of Evans Blue dye concentration using its correlation with ELISA light absorption (r2 = 0.9992). (d) Evans Blue quantification of experimental group 1 animals. FUS-BBB opening reached a 3.8-fold increase in EB concentration in normal rats (p<0.001) and a 2.1-fold increase in tumor rats (p = 0.09).
Figure 4.
Representative MR images before (upper panel) and after (lower panel) conducting FUS BBB-opening in rat brain tumors.
(a, e) T1-weighted images; (b, f) Gd-DTPA contrast-enhanced T1-weighted images; (c, g) subtracted after and before Gd-DTPA injection T1 images; (d, h) T2-weighted images.
Figure 5.
In-vivo TMZ concentration measurement.
(a) Measured TMZ concentrations (in µg/ µL) in cerebrospinal fluid (CSF) and blood plasma in animals treated with TMZ only (TMZ; n = 4) or combined TMZ with FUS-BBB opening (TMZ+FUS; n = 6). (b) Corresponding CSF/Plasma ratios (in %) determined from (a) (p = 0.06).
Figure 6.
Representative T2-weighted MR images to monitor brain tumor progression at day 10 and 17 in experimental group 3.
(a) sham control; (b) low dose TMZ oral delivery; (c) median dose TMZ oral delivery; (d) high median dose TMZ oral delivery; (e, f) median dose TMZ integrated with FUS-BBB opening procedures.
Figure 7.
Tumor progression observation among groups.
(a) Tumor volume (in mm3) between day 10 and 17 in experimental group 3; (b) Ratio of the tumor volume between day 17 and day 10 determined from (a).
Figure 8.
Kaplan–Meier plot demonstrating animal survival in experimental group 3.
Table 1.
Efficacy of various treatment protocols of induced brain tumors in rats.
Figure 9.
Hematoxylin and eosin (H&E) stained sections of rat brains.
Tissues were collected for analysis from the TMZ-delivery alone ((a) – (c); brain samples obtained immediately after animal died) or combined TMZ/FUS exposure animals ((d) – (f): brain samples obtained after day 90). (a) and (d): whole brain section; (b) and (e): 4 ×;(c) and (f): 10 ×.