Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control

Bing, Chenchen; Hong, Yu; Hernandez, Christopher; Rich, Megan; Cheng, Bingbing; Munaweera, Imalka; Szczepanski, Debra; Xi, Yin; Bolding, Mark; Exner, Agata A.; Chopra, Rajiv

doi:10.1038/s41598-018-26330-7

Cited by 78 publications

(92 citation statements)

References 58 publications

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“…A similar dependence on microbubble gas volume and not on size or size distribution was observed for blood brain barrier (BBB) opening using focused ultrasound [27]. Nanobubbles with similar gas volumes to commercially available micron-sized UCAs, Definity and Optison, were shown to be more reliable for BBB opening, which could be a result of its smaller size and larger number of bubbles present [28]. A recent report by our group showed that at similar gas volumes, nanobubbles are less affected by changes in gas volume concentration compared to microbubbles [25].…”

Section: Introductionmentioning

confidence: 70%

“…Bubble gas volume is typically estimated theoretically by assuming a bubble sphere, calculating its volume, and subtracting the bubble shell volume accordingly [26][27][28]. For a phospholipid bubble, the theoretical amount of gas is typically quantified by taking into account that the thickness of the bubble shell is 2.5 nm (typical lipid bilayer thickness is 5 nm and a bubble shell is a lipid monolayer) [29].…”

Section: Introductionmentioning

confidence: 99%

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Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents

et al. 2020

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The amount of gas in ultrasound contrast agents is related to their acoustic activity. Because of this relationship, gas volume has been used as a key variable in normalizing the in vitro and in vivo acoustic behavior of lipid shell-stabilized bubbles with different sizes and shell components. Despite its importance, bubble gas volume has typically only been theoretically calculated based on bubble size and concentration that is typically measured using the Coulter counter for microbubbles and nanoparticle tracking analysis (NTA) for nanoscale bubbles. However, while these methods have been validated for the analysis of liquid or solid particles, their application in bubble analysis has not been rigorously studied. We have previously shown that resonant mass measurement (RMM) may be a better-suited technique for sub-micron bubble analysis, as it can measure both buoyant and non-buoyant particle size and concentration. Here, we provide validation of RMM bubble analysis by using headspace gas chromatography/mass spectrometry (GC/MS) to experimentally measure the gas volume of the bubble samples. This measurement was then used as ground truth to test the accuracy of theoretical gas volume predictions based on RMM, NTA (for nanobubbles), and Coulter counter (for microbubbles) measurements. The results show that the headspace GC/MS gas volume measurements agreed well with the theoretical predictions for the RMM of nanobubbles but not NTA. For nanobubbles, the theoretical gas volume using RMM was 10% lower than the experimental GC/MS measurements; meanwhile, using NTA resulted in an 82% lower predicted gas volume. For microbubbles, the experimental gas volume from the GC/MS measurements was 27% lower compared to RMM and 72% less compared to the Coulter counter results. This study demonstrates that the gas volume of nanobubbles and microbubbles can be reliably measured using headspace GC/MS to validate bubble size measurement techniques. We also conclude that the accuracy of theoretical predictions is highly dependent on proper size and concentration measurements.

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Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents

et al. 2020

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“…Nanobubbles were synthesized using previously published protocols 25,45 . Briefly, unlabeled NBs were made dissolving a lipid mixture of DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DPPA (1,2-dipalmitoyl-sn-glycero-3-phosphate), DPPE (1,2dipalmitoyl-sn-glycero-3-phosphoethanolamine) (Avanti Polar Lipids, Pelham, AL), and mPEG-DSPE (1,2-distearoyl-phosphatidylethanol-amine-methyl-poly ethylene glycol conjugate-2000) (Laysan Lipids, Arab, AL) in chloroform in a 4:1:1:1 mass ratio.…”

Section: Nanobubble Synthesis and Characterizationmentioning

confidence: 99%

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

Ramirez

Abenojar

Hernandez

et al. 2019

Preprint

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Type 1 diabetes (T1D) is characterized by the infiltration of autoreactive T-cells into the islet of Langerhans, and depletion of insulin-secreting β-cells. This immune cell infiltration (insulitis) first occurs during an asymptomatic phase of T1D that can take place many years prior to clinical diagnosis. Methods to diagnose insulitis and changes in β-cell mass during this asymptomatic phase are limited, thus precluding early therapeutic intervention. While therapeutic treatments can delay T1D progression, treatment efficacy is limited and widely varying, and a method to track this efficacy is also lacking. During T1D progression, the islet microvasculature increases permeability as a result of insulitis, in both mouse models of T1D and humans with T1D. This increased permeability can allow nanoparticles, such as contrast agents for diagnostic imaging, to access the islet microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide high acoustic backscatter in vasculature and tissue and is clinically approved. A novel, sub-micron sized 'nanobubble' (NB) ultrasound contrast agent has been developed and shown to extravasate and accumulate in tumors, where microvascular permeability is high. To test whether CEUS can be used to measure increased islet microvasculature permeability and indicate the asymptomatic phase of T1D, we applied CEUS measurements with NBs in pre-clinical T1D models. NOD mice and mice receiving an adoptive-transfer of diabetogenic splenocytes showed accumulation of NBs specifically within the pancreatic islets, and only in the presence of insulitis. This accumulation was measured by both ultrasound contrast and histological analysis, and accumulation only occurred for sub-micron sized bubbles. Importantly, accumulation was detected as early as 4w in NOD mice. Thus, CEUS with sub-micron sized NB contrast agent may provide a predicative marker for disease progression early in asymptomatic T1D, as well as monitoring of disease prevention or reversal.

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“…Therefore, modalities that increase the BBB amenability for the cure of CNS ailments are highly valued. For instance, the focused ultrasound has been reported to open the BBB via micro/nanobubbles formation (Bing, Hong et al 2018, Wu, Aurup et al 2018) and allow maximum drug accumulation in the brain. Recently, Liu et al employed focused ultrasound to reversibly break the BBB and enhance the TMZ localization in GBM from 6.98 to 19 ng/mg (Liu, Huang et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Ultrasound Activated Nano TiO2 Loaded With Temozolomide Paves the Way for Resection of Chemo-resistant Glioblastoma Multiforme

Rehman

Rauf

Shaikh³

et al. 2020

Preprint

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Background Glioblastoma Multiforme (GBM) is one the most daunting issue to modern therapeutics, with a higher mortality rate post-diagnosis. Temozolomide (TMZ) is the only available treatment; however, the frequent resistance leaves the oncologists at the dead end. Therefore, new approaches to circumvent the GBM are highly desired. In this contribution, we have employed TiO2 nanosticks loaded with TMZ as nanomedicine for TMZ resistant GBM resection. Results The ultrasonication triple action effect could highly facilitate the tumor ablation by enhancing the TiO2 nanosticks traversing across BBB, releasing the TMZ payload from TiO2 nanosticks and Reactive Oxygen Species (ROS) generation from TiO2 nanosticks within GBM milieu. The tumor ablation was confirmed by MTT and Annexin(v)-PI assays, apoptotic proteins expression via western blot and ROS level detection in vitro, whereas tumor volume, weight, survival rate, and relative photon flux in the xenograft and orthoptic TMZ resistant GBM murine models as in vivo. Conclusion We found this nanomedicine-based ultrasound modality highly efficient in GBM treatment and is of future clinical application value due to employment of already FDA approved techniques and nanomedicine.

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Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control

Cited by 78 publications

References 58 publications

Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents

Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

Ultrasound Activated Nano TiO2 Loaded With Temozolomide Paves the Way for Resection of Chemo-resistant Glioblastoma Multiforme

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