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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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Relationship between EB extravasation and sonication power after microbubble and FUS treatment, following and followed by, EB injection at the UCA dose of 300 μL/kg. EB extravasation as a function of the acoustic power in the presence of microbubbles.Notes: *Significant difference compared to the contralateral nonsonicated hemisphere; #Significant difference between two sonicated groups. (* and #, P < 0.05).Abbreviations: EB, Evans blue; FUS, focused ultrasound; MB, microbubble; UCA, ultrasound contrast agent.
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f3-ijn-7-2573: Relationship between EB extravasation and sonication power after microbubble and FUS treatment, following and followed by, EB injection at the UCA dose of 300 μL/kg. EB extravasation as a function of the acoustic power in the presence of microbubbles.Notes: *Significant difference compared to the contralateral nonsonicated hemisphere; #Significant difference between two sonicated groups. (* and #, P < 0.05).Abbreviations: EB, Evans blue; FUS, focused ultrasound; MB, microbubble; UCA, ultrasound contrast agent.

Mentions: Figure 3 shows the mean extravasation of EB per unit mass of brain tissue from the sonicated site for four sonication powers, for the same dose of UCA. The degree of EB extravasation increased with acoustic power. Additionally, the amount of EB extravasation was greater in the group injected before sonication than it was in the group receiving EB after sonication; this difference was particularly evident for the lowest sonication power of 1.43 W (P < 0.05). Figure 4 shows that the amount of EB extravasated from sonicated brains increased with increasing UCA dose from 0 to 450 μL/kg at 2.86 W sonication power. Moreover, these concentrations were greater in the group receiving EB injection before sonication than they were in the group that received EB administration after sonication, particularly for the highest UCA dose of 450 μL/kg (P < 0.01). Importantly, however, the EB extravasation was significantly greater in brains with the EB injection followed by sonication for UCA at 300 μL/kg than it was for brains with EB administration following sonication for UCA at 450 μL/kg (P < 0.05). In contrast to EB concentration values for the sonicated brains, only insignificant differences were found for the values of control brains at the various acoustic powers and UCA doses.


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)

Relationship between EB extravasation and sonication power after microbubble and FUS treatment, following and followed by, EB injection at the UCA dose of 300 μL/kg. EB extravasation as a function of the acoustic power in the presence of microbubbles.Notes: *Significant difference compared to the contralateral nonsonicated hemisphere; #Significant difference between two sonicated groups. (* and #, P < 0.05).Abbreviations: EB, Evans blue; FUS, focused ultrasound; MB, microbubble; UCA, ultrasound contrast agent.
© Copyright Policy
Related In: Results  -  Collection

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

f3-ijn-7-2573: Relationship between EB extravasation and sonication power after microbubble and FUS treatment, following and followed by, EB injection at the UCA dose of 300 μL/kg. EB extravasation as a function of the acoustic power in the presence of microbubbles.Notes: *Significant difference compared to the contralateral nonsonicated hemisphere; #Significant difference between two sonicated groups. (* and #, P < 0.05).Abbreviations: EB, Evans blue; FUS, focused ultrasound; MB, microbubble; UCA, ultrasound contrast agent.
Mentions: Figure 3 shows the mean extravasation of EB per unit mass of brain tissue from the sonicated site for four sonication powers, for the same dose of UCA. The degree of EB extravasation increased with acoustic power. Additionally, the amount of EB extravasation was greater in the group injected before sonication than it was in the group receiving EB after sonication; this difference was particularly evident for the lowest sonication power of 1.43 W (P < 0.05). Figure 4 shows that the amount of EB extravasated from sonicated brains increased with increasing UCA dose from 0 to 450 μL/kg at 2.86 W sonication power. Moreover, these concentrations were greater in the group receiving EB injection before sonication than they were in the group that received EB administration after sonication, particularly for the highest UCA dose of 450 μL/kg (P < 0.01). Importantly, however, the EB extravasation was significantly greater in brains with the EB injection followed by sonication for UCA at 300 μL/kg than it was for brains with EB administration following sonication for UCA at 450 μL/kg (P < 0.05). In contrast to EB concentration values for the sonicated brains, only insignificant differences were found for the values of control brains at the various acoustic powers and UCA doses.

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