Time-intensity-curve Analysis and Tumor Extravasation of Nanobubble Ultrasound Contrast Agents

Wu, Han-Ping; Abenojar, Eric; Perera, Reshani; Leon, Al C. de; An, Tianzhi; Exner, Agata A.

doi:10.1016/j.ultrasmedbio.2019.05.025

Cited by 68 publications

(66 citation statements)

References 36 publications

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“…Several researchers have investigated the acoustic character and pharmacokinetics of NBs, suggesting possible involvement of EPR effect (Tong et al, 2013;Wu et al, 2013;Cavalli et al, 2015;Du et al, 2018). Furthermore, it has recently been reported that the timeintensity-curve of extravasated NBs can be detected in tumors (Wu et al, 2019). Histologic analysis showed that NBs were retained in tumor tissue to a greater extent compared with MBs.…”

Section: Discussionmentioning

confidence: 99%

Nanobubble Mediated Gene Delivery in Conjunction With a Hand-Held Ultrasound Scanner

et al. 2020

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Recent research has revealed that nanobubbles (NBs) can be an effective tool for gene transfection in conjunction with therapeutic ultrasound (US). However, an approach to apply commercially available hand-held diagnostic US scanners for this purpose has not been evaluated as of now. In the present study, we first compared in vitro, the efficiency of gene transfer (pCMV-Luciferase) with lipid-based and albumin-based NBs irradiated by therapeutic US (1MHz, 5.0 W/cm 2) in oral squamous carcinoma cell line HSC-2. Secondly, we similarly examined if gene transfer in mice is possible using a clinical hand-held US scanner (2.3MHz, MI 1.0). Results showed that lipid-based NBs induced more gene transfection compared to albumin-based NBs, in vitro. Furthermore, significant gene transfer was also obtained in mice liver with lipid-based NBs. Sub-micro sized bubbles proved to be a powerful gene transfer reagent in combination with conventional hand-held ultrasonic diagnostic device.

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Section: Discussionmentioning

confidence: 99%

Nanobubble Mediated Gene Delivery in Conjunction With a Hand-Held Ultrasound Scanner

et al. 2020

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“…While MBs are restricted to the blood stream, smaller sub-micron sized nanobubbles (NBs) are capable of extravasating through the hyper-permeable microvasculature of injured tissue. This includes accumulation of~100-300 nm diameter NBs within tumors as a result of increased tumor vascular permeability [23][24][25] . Such NBs are echogenic at clinically relevant ultrasound frequencies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), allowing regions of high permeability microvasculature to be imaged non-invasively and in real time.…”

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confidence: 99%

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes

et al. 2020

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In type1 diabetes (T1D) autoreactive T-cells infiltrate the islets of Langerhans, depleting insulin-secreting β-cells (insulitis). Insulitis arises during an asymptomatic phase, prior to clinical diagnosis of T1D. Methods to diagnose insulitis and β-cell mass changes during this asymptomatic phase are limited, precluding early therapeutic intervention. During T1D the islet microvasculature increases permeability, allowing nanoparticles to access the microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide acoustic backscatter in vasculature. Here, we report that sub-micron sized 'nanobubble' ultrasound contrast agents can be used to measure increased islet microvasculature permeability and indicate asymptomatic T1D. Through CEUS and histological analysis, preclinical models of T1D show accumulation of nanobubbles specifically within pancreatic islets, correlating with insulitis. Importantly, accumulation is detected early in disease progression and decreases with successful therapeutic intervention. Thus, sub-micron sized nanobubble ultrasound contrast agents provide a predicative marker for disease progression and therapeutic reversal early in asymptomatic T1D.

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“…In addition, because of their 1-10 µm diameter, the microbubbles remain in the vasculature, and, thus, have limited applications. Recently, significant effort has been devoted to developing new generations of more stable bubbles in an expanded range of sizes, including in the nanoscale [5][6][7]. Stable sub-micron or nanobubbles extend bubble circulation time and have been shown to localize beyond the tumor vasculature via the enhanced permeability effect (EPR) [8,9], hence offering many new potential ultrasound contrast agent (UCA) applications for tumor imaging and therapy.…”

Section: Introductionmentioning

confidence: 99%

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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Time-intensity-curve Analysis and Tumor Extravasation of Nanobubble Ultrasound Contrast Agents

Cited by 68 publications

References 36 publications

Nanobubble Mediated Gene Delivery in Conjunction With a Hand-Held Ultrasound Scanner

Nanobubble Mediated Gene Delivery in Conjunction With a Hand-Held Ultrasound Scanner

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes

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

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