An advanced focused ultrasound protocol improves the blood-brain barrier permeability and doxorubicin delivery into the rat brain

Jung, Byeongjin; Huh, Hyungkyu; Lee, Eun-Hee; Han, Mun; Park, Ju‐Young

doi:10.1016/j.jconrel.2019.10.044

Cited by 17 publications

(15 citation statements)

References 60 publications

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“…Thus, by applying different acoustic pressures, the two target areas showed comparable degrees of BBBD, comparable patterns of DTI parameters, and histological results. Since the FUS parameter in group-0.65 MPa has been widely used in the rat brain to safely disrupt the BBB and deliver therapeutics in several previous studies ( Kinoshita et al, 2006b ; Cho et al, 2016 ; Jung et al, 2019 ), we selected the FUS parameter to determine whether water transport could be facilitated in the BBBD brain area. We additionally applied higher sonication conditions in group-0.80 MPa to evaluate the effect of the magnitude of BBB opening on local water dynamics.…”

Section: Discussionmentioning

confidence: 99%

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

et al. 2021

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Interstitial solutes can be removed by various overlapping clearance systems, including blood–brain barrier (BBB) transport and glymphatic clearance. Recently, focused ultrasound (FUS)-induced BBB disruption (BBBD) has been applied to visualize glymphatic transport. Despite evidence that FUS–BBBD might facilitate glymphatic transport, the nature of fluid movement within the sonication region is yet to be determined. In this study, we sought to determine whether FUS–BBBD may facilitate the local movement of water molecules. Two different FUS conditions (0.60–0.65 MPa and 0.75–0.80 MPa) were used to induce BBBD in the caudate-putamen and thalamus regions of healthy Sprague–Dawley rats. The water diffusion caused by FUS–BBBD was analyzed using the apparent diffusion coefficient (ADC), axial diffusivity, radial diffusivity (RD), and fractional anisotropy, obtained at 5 min, 24 and 48 h, as well as the water channel expression of aquaporin-4 (AQP-4) immunostaining at 48 h after FUS-induced BBBD. In addition, hematoxylin and eosin histopathology and Fluoro-Jade C (FJC) immunostaining were performed to analyze brain damage. The signal changes in ADC and RD in the sonication groups showed significant and transient reduction at 5 min, with subsequent increases at 24 and 48 h after FUS-induced BBBD. When we applied higher sonication conditions, the ADC and RD showed enhancement until 48 h, and became comparable to contralateral values at 72 h. AQP-4 expression was upregulated after FUS-induced BBBD in both sonication conditions at 48 h. The results of this study provide preliminary evidence on how mechanical forces from FUS alter water dynamics through diffusion tensor imaging (DTI) measures and AQP4 expression.

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Section: Discussionmentioning

confidence: 99%

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

et al. 2021

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“…The local concentration of DOX delivered to the sonication target was linearly correlated with the MRI signal enhancement and the BBB permeability K trans 14,28 . In addition, several attempts were made to enhance the local delivery of the chemotherapeutic agents by using multiple sonications 29 or additional sonication without microbubbles before the main sonication 27 and resulted in 26.08% (double sonication) and 75% (triple sonication) of DOX delivery increment. When compared to these attempts, a 33.1% difference in K trans induced by the target's characteristic reported in this study cannot be neglected as the following outcomes of the chemotherapeutic treatment may vary due to the DOX delivery difference 30 .…”

Section: Discussionmentioning

confidence: 99%

“…1 f. In the previous study 14 , Cp and Th regions also had different MRI signal enhancement and leakage of trypan blue when sonicated under the same acoustic pressure, which indicates a difference in the level of BBB disruption. Considering these local differences, several previous pre-clinical studies 13 , 27 used a higher level of acoustic power at Cp to achieve a similar level of BBB disruption, which resulted in a similar (around twofold) increase of chemotherapeutic substance DOX delivery compared to the contralateral hemisphere of both Cp and Th . The local concentration of DOX delivered to the sonication target was linearly correlated with the MRI signal enhancement and the BBB permeability K trans 14 , 28 .…”

Section: Discussionmentioning

confidence: 99%

“…A 2D rapid-acquisition with relaxation enhancement (RARE) T 1 -weighted pulse sequence (echo time; TE = 6.5 ms, repetition time; TR = 1500 ms, field of view; FOV = 40 × 40 mm 2 , matrix size = 256 × 256, bandwidth = 100,000 Hz, RARE factor = 4 and slice thickness = 1.5 mm) in coronal view was used to detect the local BBB disruption. A 2D RARE T 2 -weighted pulse sequence (echo time; TE = 33 ms, repetition time; TR = 2500 ms field of view; FOV = 40 × 40 mm 2 , matrix size = 256 × 256, bandwidth = 36,765 Hz, RARE factor = 8 and slice thickness = 1.5 mm) in coronal view was used to guide the sonication procedure, similar to previous studies 13,27,28,36 .…”

Section: Animals All Experiments Were Conducted Following Proceduresmentioning

confidence: 99%

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A local difference in blood–brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound

Huh

Park

Seo

et al. 2020

Sci Rep

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A blood–brain barrier (BBB) opening induced by focused ultrasound (FUS) has been widely studied as an effective way of treating brain diseases. We investigate the effect of ultrasound’s incidence angle at caudate putamen (Cp) and thalamus (Th) of the rat brain by inducing the same power of focused ultrasound that corresponds to the acoustic pressure of 0.65 MPa in free field. The BBB permeability (Ktrans) was quantitatively evaluated with dynamic contrast-enhanced magnetic resonance imaging. The group averaged (n = 11) maximum Ktrans at Cp (0.021 ± 0.012 min−1) was 1.39 times smaller than the Ktrans of Th (0.029 ± 0.01 min−1) with p = 0.00343. The group averaged (n = 6) ultrasound’s incidence angles measured using the computed tomography image of rat skulls were compared with the maximum Ktrans and showed a negatively linear relation R2 = 0.7972). The maximum acoustic pressure computed from the acoustic simulation showed higher average acoustic pressures at Th (0.37 ± 0.02 MPa) compared to pressures at Cp (0.32 ± 0.01 MPa) with p = 0.138 × 10−11. More red blood cell were observed at the Th region compared to the Cp region in the tissue staining. These results indicate that localized characteristics of the sonication target within the subject should be considered for safer and more efficient BBB disruption induced by FUS.

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“…To date, the treatment of brain diseases is still an important topic all over the world 26 . Owing to the existence of the blood‒brain barrier (BBB) 27 , it is difficult for medicines to penetrate or bypass the BBB by the traditional peripheral administration methods 28 , and it is hard to reach an effective therapeutic concentration in the central nervous system (CNS) 29 .…”

Section: Introductionmentioning

confidence: 99%

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Pang

Zhu

et al. 2021

Acta Pharmaceutica Sinica B

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Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor- α caused by PTSD. Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1A receptor. Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration, as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs. Overall, nasal CBD TSGs are safe and effective and have controlled release. There are a novel promising option for the clinical treatment of PTSD.

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An advanced focused ultrasound protocol improves the blood-brain barrier permeability and doxorubicin delivery into the rat brain

Cited by 17 publications

References 60 publications

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

A local difference in blood–brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

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