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

ABSTRACT: Our group recently presented a simple strategy using the non-ionic surfactant, Pluronic, as a size control excipient to produce nanobubbles in the 100-nm range, which exhibited stability and echogenicity on par with clinically available microbubbles. The objective of the present study was to evaluate biodistribution and extravasation of the Pluronic-stabilized lipid nanobubbles compared with microbubbles in 2 experimental tumor models in mice. Standard lipid-stabilized perfluoropropane bubbles (Pluronic L10) and lipid-stabilized perfluoropropane nanobubbles were intravenously injected into mice bearing either an orthotopic mouse breast cancer (BC4 T1) or subcutaneous mouse ovarian cancer (OVCAR-3) through the tail vein to perform perfusion dynamic studies. No significant differences between the nanobubble and microbubble groups were observed in the peak enhancement of the 3 tested regions (tumor, liver and kidney). However, the decay rates of nanobubble in the tumor and kidney of BC4 T1-bearing mice, as well as in mice with OVRCAR-3 tumors were significantly slower than those of the microbubble. To quantify extravasation, fluorescently labeled bubbles were intravenously injected into mice bearing the same tumors. Histologic analysis showed that nanobubbles were retained in tumor tissue to a greater extent compared with microbubbles in both tumor models at the 3-h time point. Our results demonstrate unique nanobubble behavior compared with microbubbles and support augmented application of these agents in ultrasound molecular imaging and drug delivery beyond the tumor vasculature.

SUBMITTER: Wu H

PROVIDER: S-EPMC6689247 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Wu Hanping H Abenojar Eric C EC Perera Reshani R De Leon Al Christopher AC An Tianzhi T Exner Agata A AA

Ultrasound in medicine & biology 20190624 9

Our group recently presented a simple strategy using the non-ionic surfactant, Pluronic, as a size control excipient to produce nanobubbles in the 100-nm range, which exhibited stability and echogenicity on par with clinically available microbubbles. The objective of the present study was to evaluate biodistribution and extravasation of the Pluronic-stabilized lipid nanobubbles compared with microbubbles in 2 experimental tumor models in mice. Standard lipid-stabilized perfluoropropane bubbles ( ...[more]

PMID: 31248638

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Project description: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.

Dataset Information

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

Publications

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

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