Limits...
Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

Fan CH, Liu HL, Ting CY, Lee YH, Huang CY, Ma YJ, Wei KC, Yen TC, Yeh CK - PLoS ONE (2014)

Bottom Line: Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening.Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS.This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.

ABSTRACT
The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

Show MeSH

Related in: MedlinePlus

Histological evaluations after BBB-opening.A: H&E-stained and B: TUNEL-stained sections after application of in-house submicron bubbles with 10-MHz FUS sonication. The dotted rectangles indicate the BBB-opening region confirmed by EB extravasation. Positive control: hemorrhage and apoptotic cells (group 4, 1.5 MPa). Scale bars: 1 mm, 1 mm, and 50 µm.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4008627&req=5

pone-0096327-g006: Histological evaluations after BBB-opening.A: H&E-stained and B: TUNEL-stained sections after application of in-house submicron bubbles with 10-MHz FUS sonication. The dotted rectangles indicate the BBB-opening region confirmed by EB extravasation. Positive control: hemorrhage and apoptotic cells (group 4, 1.5 MPa). Scale bars: 1 mm, 1 mm, and 50 µm.

Mentions: H&E staining and TUNEL assays were used to reveal the extent of erythrocyte extravasations and neuronal apoptosis, respectively. Only mild erythrocyte extravasations were found in Group 1 (Figure 6) at pressures from 2.0 to 4.5 MPa, indicating that the in-house submicron bubbles resonated at 10 MHz indeed did not produce server brain damage or cell apoptosis after FUS sonication.


Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

Fan CH, Liu HL, Ting CY, Lee YH, Huang CY, Ma YJ, Wei KC, Yen TC, Yeh CK - PLoS ONE (2014)

Histological evaluations after BBB-opening.A: H&E-stained and B: TUNEL-stained sections after application of in-house submicron bubbles with 10-MHz FUS sonication. The dotted rectangles indicate the BBB-opening region confirmed by EB extravasation. Positive control: hemorrhage and apoptotic cells (group 4, 1.5 MPa). Scale bars: 1 mm, 1 mm, and 50 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008627&req=5

pone-0096327-g006: Histological evaluations after BBB-opening.A: H&E-stained and B: TUNEL-stained sections after application of in-house submicron bubbles with 10-MHz FUS sonication. The dotted rectangles indicate the BBB-opening region confirmed by EB extravasation. Positive control: hemorrhage and apoptotic cells (group 4, 1.5 MPa). Scale bars: 1 mm, 1 mm, and 50 µm.
Mentions: H&E staining and TUNEL assays were used to reveal the extent of erythrocyte extravasations and neuronal apoptosis, respectively. Only mild erythrocyte extravasations were found in Group 1 (Figure 6) at pressures from 2.0 to 4.5 MPa, indicating that the in-house submicron bubbles resonated at 10 MHz indeed did not produce server brain damage or cell apoptosis after FUS sonication.

Bottom Line: Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening.Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS.This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.

ABSTRACT
The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

Show MeSH
Related in: MedlinePlus