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Efficiency of drug delivery enhanced by acoustic pressure during blood-brain barrier disruption induced by focused ultrasound.

Yang FY, Lee PY - Int J Nanomedicine (2012)

Bottom Line: We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation.Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS.The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan. fyyang@ym.edu.tw

ABSTRACT

Purpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood-brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters.

Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.

Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.

Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to optimize ultrasound parameters for lower sonication and reduced UCA doses, to induce BBB-D while minimizing damage to normal brain tissue.

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Related in: MedlinePlus

Experimental timeline for pulsed FUS-induced BBB disruption. EB was injected intravenously before (A), or after (B), FUS exposure.Note: Sonication was applied 15 seconds after microbubble administration to the brain.Abbreviations: BBB, blood–brain barrier; EB, Evans blue; FUS, focused ultrasound.
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f1-ijn-7-2573: Experimental timeline for pulsed FUS-induced BBB disruption. EB was injected intravenously before (A), or after (B), FUS exposure.Note: Sonication was applied 15 seconds after microbubble administration to the brain.Abbreviations: BBB, blood–brain barrier; EB, Evans blue; FUS, focused ultrasound.

Mentions: To evaluate the degree of BBB permeability, we compared two procedures for EB (100 mg/kg) injection into the rats’ femoral vein (Figure 1). The animals received EB injection about 5 minutes before or immediately after FUS exposure. In the first set of experiments, rats were sonicated with FUS in the presence of microbubbles for sonication durations of 0 to 60 seconds. In the experiments that followed, we quantified EB accumulation in rat brains after sonication for 60 seconds. In the second set of experiments, rats were injected with UCA at 300 μL/kg approximately 15 seconds prior to FUS exposure at various acoustic powers (0, 1.43, 2.86, and 4.29 W). In the third set of experiments, rats were exposed to a sonication power of 2.86 W in the presence of microbubbles at four doses (0, 150, 300, and 450 μL/kg). In the final experiment, rats received an injection of gadolinium about 5 minutes before or immediately after FUS exposure, for MRI analysis.


Efficiency of drug delivery enhanced by acoustic pressure during blood-brain barrier disruption induced by focused ultrasound.

Yang FY, Lee PY - Int J Nanomedicine (2012)

Experimental timeline for pulsed FUS-induced BBB disruption. EB was injected intravenously before (A), or after (B), FUS exposure.Note: Sonication was applied 15 seconds after microbubble administration to the brain.Abbreviations: BBB, blood–brain barrier; EB, Evans blue; FUS, focused ultrasound.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3367490&req=5

f1-ijn-7-2573: Experimental timeline for pulsed FUS-induced BBB disruption. EB was injected intravenously before (A), or after (B), FUS exposure.Note: Sonication was applied 15 seconds after microbubble administration to the brain.Abbreviations: BBB, blood–brain barrier; EB, Evans blue; FUS, focused ultrasound.
Mentions: To evaluate the degree of BBB permeability, we compared two procedures for EB (100 mg/kg) injection into the rats’ femoral vein (Figure 1). The animals received EB injection about 5 minutes before or immediately after FUS exposure. In the first set of experiments, rats were sonicated with FUS in the presence of microbubbles for sonication durations of 0 to 60 seconds. In the experiments that followed, we quantified EB accumulation in rat brains after sonication for 60 seconds. In the second set of experiments, rats were injected with UCA at 300 μL/kg approximately 15 seconds prior to FUS exposure at various acoustic powers (0, 1.43, 2.86, and 4.29 W). In the third set of experiments, rats were exposed to a sonication power of 2.86 W in the presence of microbubbles at four doses (0, 150, 300, and 450 μL/kg). In the final experiment, rats received an injection of gadolinium about 5 minutes before or immediately after FUS exposure, for MRI analysis.

Bottom Line: We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation.Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS.The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan. fyyang@ym.edu.tw

ABSTRACT

Purpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood-brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters.

Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage.

Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication.

Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to optimize ultrasound parameters for lower sonication and reduced UCA doses, to induce BBB-D while minimizing damage to normal brain tissue.

Show MeSH
Related in: MedlinePlus