Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles

AbstractNon-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood–brain barrier. Vector and promoter selection can provide neuronal expression in the brain, while limiting biodistribution and expression in peripheral organs. To date, the biodistribution of adeno-associated viruses (AAVs) within peripheral organs had not been quantified following intravenous injection and MRIgFUS delivery to the brain. We evaluated the quantity of viral DNA from the serotypes AAV9, AAV6, and a mosaic AAV1&2, expressing green fluorescent protein (GFP) under the neuron-specific synapsin promoter (syn). AAVs were administered intravenously during MRIgFUS targeting to the striatum and hippocampus in mice. The syn promoter led to undetectable levels of GFP expression in peripheral organs. In the liver, the biodistribution of AAV9 and AAV1&2 was 12.9- and 4.4-fold higher, respectively, compared to AAV6. The percentage of GFP-positive neurons in the FUS-targeted areas of the brain was comparable for AAV6-syn-GFP and AAV1&2-syn-GFP. In summary, MRIgFUS-mediated gene delivery with AAV6-syn-GFP had lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.

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20. An Experimental Neuropathological Study of the Effects of High-Frequency Focused Ultrasound on the Brain of Animals

Neurologia medico-chirurgica ◽

10.2176/nmc.4.159 ◽

1962 ◽

Vol 4 (0) ◽

pp. 159-159

Author(s):

Hiroshi HASEGAWA ◽

Kijuro MITSUMA ◽

Masao WATANABE ◽

Yoshiaki SUGIYAMA ◽

Keizo KAWAKAMI ◽

...

Keyword(s):

High Frequency ◽

Focused Ultrasound ◽

The Brain

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Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors

BioMed Research International ◽

10.1155/2013/627496 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 18

Author(s):

Po-Chun Chu ◽

Wen-Yen Chai ◽

Han-Yi Hsieh ◽

Jiun-Jie Wang ◽

Shiaw-Pyng Wey ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Small Molecule ◽

Focused Ultrasound ◽

Therapeutic Agents ◽

Tumor Treatment ◽

Target Region ◽

Pharmacodynamic Analysis ◽

The Brain ◽

Bbb Opening

Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.

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The Distribution of Skull Score and Skull Density Ratio in Tremor Patients for MR-Guided Focused Ultrasound Thalamotomy

Frontiers in Neuroscience ◽

10.3389/fnins.2021.612940 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kevin Wen-Kai Tsai ◽

Jui-Cheng Chen ◽

Hui-Chin Lai ◽

Wei-Chieh Chang ◽

Takaomi Taira ◽

...

Keyword(s):

Trabecular Bone ◽

Cortical Bone ◽

Focused Ultrasound ◽

Density Ratio ◽

Ct Images ◽

Image Feature ◽

Cumulative Distribution ◽

Invasive Surgical Approach ◽

Highly Correlated ◽

The Brain

ObjectiveMagnetic resonance-guided focused ultrasound (MRgFUS) is a minimum-invasive surgical approach to non-incisionally cause the thermos-coagulation inside the human brain. The skull score (SS) has already been approved as one of the most dominant factors related to a successful MRgFUS treatment. In this study, we first reveal the SS distribution of the tremor patients, and correlate the SS with the image feature from customized skull density ratio (cSDR). This correlation might give a direction to future clinical studies for improving the SS.MethodsTwo hundred and forty-six patients received a computed tomography (CT) scan of the brain, and a bone-enhanced filter was applied and reconstructed to a high spatial resolution CT images. The SS of all patients would be estimated by the MRgFUS system after importing the reconstructed CT images into the MRgFUS system. The histogram and the cumulative distribution of the SS from all the patients were calculated to show the percentage of the patients whose SS lower than 0.3 and 0.4. The same CT images of all patients were utilized to calculated the cSDR by first segmented the trabecular bone and the cortical bone from the CT images and divided the average trabecular bone intensity (aTBI) by the average cortical bone intensity (aCBI). The Pearson’s correlations between the SS and the cSDR, aTBI, and the aCBI were calculated, respectively.ResultsThere were 19.19 and 50% of the patient who had the SS lower than the empirical threshold 0.3 and 0.4, respectively. The Pearson’s correlation between the SS and the cSDR, aCBI, and the aTBI were R = 0.8145, 0.5723, and 0.8842.ConclusionHalf of the patients were eligible for the MRgFUS thalamotomy based on the SS, and nearly 20% of patients were empirically difficult to achieve a therapeutic temperature during MRgFUS. The SS and our cSDR are highly correlated, and the SS had a higher correlation with aTBI than with aCBI. This is the first report to explicitly reveal the SS population and indicate a potential way to increase the chance to achieve a therapeutic temperature for those who originally have low SS.

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MAGNETIC RESONANCE IMAGING-GUIDED FOCUSED ULTRASOUND FOR THERMAL ABLATION IN THE BRAIN

Neurosurgery ◽

10.1227/01.neu.0000245606.99946.c6 ◽

2007 ◽

Vol 60 (4) ◽

pp. 593-600 ◽

Cited By ~ 43

Author(s):

Zvi R. Cohen ◽

Jacob Zaubermann ◽

Sagi Harnof ◽

Yael Mardor ◽

Dvora Nass ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Thermal Ablation ◽

Focused Ultrasound ◽

Resonance Imaging ◽

The Brain

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Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery

Biomedicines ◽

10.3390/biomedicines8050120 ◽

2020 ◽

Vol 8 (5) ◽

pp. 120 ◽

Cited By ~ 2

Author(s):

Bakhtiar Bukari ◽

Rasika M. Samarasinghe ◽

Jinjutha Noibanchong ◽

Sarah L. Shigdar

Keyword(s):

Brain Tissue ◽

Targeted Delivery ◽

Focused Ultrasound ◽

Circulatory System ◽

Non Invasive ◽

Therapeutic Delivery ◽

Macromolecular Drugs ◽

Efficient Delivery ◽

Alternative Delivery ◽

The Brain

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies by preventing efficient delivery of macromolecular drugs to diseased brain tissue. Although current non-invasive strategies of therapeutics delivery into the brain, such as focused ultrasound and nanoparticle-mediated delivery have shown various levels of successes, they still come with risks and limitations. This review discusses the current approaches of therapeutic delivery into the brain, with a specific focus on non-invasive methods. It also discusses the potential for aptamers as alternative delivery systems and several reported aptamers with promising preliminary results.

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