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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

Hematoxylin and eosin staining of transverse brain sections sonicated at 2.86 W with UCA doses of (A–C) 300 μL/kg and (D–F) 450 μL/kg.Notes: The affected brain structures include the hypothalamus, thalamus, and hippocampus. Local displacement and increased extravasation of red blood cells were more obvious in specimens treated at the greater UCA dosage of 450 μL/kg than in specimens treated with UCA doses of 300 μL/kg.Abbreviation: UCA, ultrasound contrast agent.
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f7-ijn-7-2573: Hematoxylin and eosin staining of transverse brain sections sonicated at 2.86 W with UCA doses of (A–C) 300 μL/kg and (D–F) 450 μL/kg.Notes: The affected brain structures include the hypothalamus, thalamus, and hippocampus. Local displacement and increased extravasation of red blood cells were more obvious in specimens treated at the greater UCA dosage of 450 μL/kg than in specimens treated with UCA doses of 300 μL/kg.Abbreviation: UCA, ultrasound contrast agent.

Mentions: Figure 7 shows representative H&E-stained sections for UCA treatments at 300 and 450 μL/kg at sonication power of 2.86 W. The corresponding TUNEL-stained sections were prepared for histopathologic examination and apoptotic evaluation (Figure 8). Red blood cells were present in sonicated brain tissue in and around the focal region, and were more severe for the higher dose (450 μL/kg) samples. This observation is consistent with the finding that more apoptotic cells were present in sonicated UCA 450 μL/kg samples than they were in UCA 300 μL/kg samples. Figure 9 indicates that there were significant differences between these two groups.


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)

Hematoxylin and eosin staining of transverse brain sections sonicated at 2.86 W with UCA doses of (A–C) 300 μL/kg and (D–F) 450 μL/kg.Notes: The affected brain structures include the hypothalamus, thalamus, and hippocampus. Local displacement and increased extravasation of red blood cells were more obvious in specimens treated at the greater UCA dosage of 450 μL/kg than in specimens treated with UCA doses of 300 μL/kg.Abbreviation: UCA, ultrasound contrast agent.
© Copyright Policy
Related In: Results  -  Collection

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

f7-ijn-7-2573: Hematoxylin and eosin staining of transverse brain sections sonicated at 2.86 W with UCA doses of (A–C) 300 μL/kg and (D–F) 450 μL/kg.Notes: The affected brain structures include the hypothalamus, thalamus, and hippocampus. Local displacement and increased extravasation of red blood cells were more obvious in specimens treated at the greater UCA dosage of 450 μL/kg than in specimens treated with UCA doses of 300 μL/kg.Abbreviation: UCA, ultrasound contrast agent.
Mentions: Figure 7 shows representative H&E-stained sections for UCA treatments at 300 and 450 μL/kg at sonication power of 2.86 W. The corresponding TUNEL-stained sections were prepared for histopathologic examination and apoptotic evaluation (Figure 8). Red blood cells were present in sonicated brain tissue in and around the focal region, and were more severe for the higher dose (450 μL/kg) samples. This observation is consistent with the finding that more apoptotic cells were present in sonicated UCA 450 μL/kg samples than they were in UCA 300 μL/kg samples. Figure 9 indicates that there were significant differences between these two groups.

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