Size-isolation of ultrasound-mediated phase change perfluorocarbon droplets using differential centrifugation

Mercado, Karla P.; Radhakrishnan, Kirthi; Stewart, Kyle; Snider, Lindsay; Ryan, Devin; Haworth, Kevin J.

doi:10.1121/1.4946831

Cited by 19 publications

(12 citation statements)

References 16 publications

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“…For example, it is difficult to achieve efficient drug concentration in tumor sites because of their limited capacity for loading therapeutic agents, short circulation time, and large micrometer size. To address these problems, phase-change perfluorocarbon (PFC) nanodroplets have been developed 18 , 20 , 24 - 27 in which the liquid in the core of nanodroplets can vaporize to gas phase upon activation by ultrasound energy, called acoustic droplet vaporization (ADV) 28 - 30 . The stability of nanodroplets is increased, and they can accumulate in tumor tissues by passive targeting due to their nano-scaled size.…”

Section: Introductionmentioning

confidence: 99%

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

et al. 2018

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Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery.Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets).Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy.Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release.

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Section: Introductionmentioning

confidence: 99%

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

et al. 2018

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“…In cancer imaging and therapy, nanodroplets could play an important role as they are approximately 3 to 6 times smaller in diameter than microbubbles prior to vaporisation theoretically (Mercado, et al 2016, Oleksandr, et al 2013) and approximately 12 fold smaller in diameter experimentally . These nanodroplets have the potential to extravasate from the vascular endothelium to the cancerous tissue and form target-specific binding.…”

Section: Introductionmentioning

confidence: 99%

Quantification of Vaporised Targeted Nanodroplets Using High-Frame-Rate Ultrasound and Optics

Zhang

Lin

Leow

et al. 2019

Ultrasound in Medicine & Biology

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Molecular targeted nanodroplets, promising to extravasate beyond the vascular space, have great potential to improve tumor detection and characterization. High frame rate ultrasound, on the other hand, is an emerging tool for imaging at a frame rate 1-2 orders of magnitude higher than common existing ultrasound operating systems. In this study, we used high frame rate ultrasound combined with optics to study the acoustic response and size distribution of Folate Receptor (FR) -targeted versus Non-Targeted (NT)-nanodroplets in vitro with MDA-MB-231 breast cancer cells immediately after ultrasound activation. A flow velocity mapping technique, Stokes' theory, and optical microscopy were used to estimate the size of both floating and attached vaporized nanodroplets immediately after activation. It was found that the size of floating vaporized nanodroplets was on average more than 7 times larger than the size of vaporized nanodroplets attached to the cells. The results also showed that the acoustic signal of vaporized FR-nanodroplets was persistent after activation, with 70% of the acoustic signals still present 1 second after activation, compared to the vaporized NT-nanodroplets where only 40% of the acoustic signal remains. The optical microscopic images showed on average 6 times more vaporized FR-nanodroplets generated with a wider range of diameters (from 4 to 68 µm) that still attach to the cells compared to vaporized NTnanodroplets (from 1 to 7 µm) with non-specific binding after activation. It was also found that the mean size of attached vaporized FR-nanodroplets was on average about 3-fold larger than that of attached vaporized NT-nanodroplets. The study offers an improved understanding of the vaporization of the targeted nanodroplets in terms of their sizes and acoustic response in comparison with non-targeted ones, taking advantage of high-frame-rate contrast-enhanced ultrasound and optical microscopy. Such understanding would help design optimized methodology for imaging and therapeutic applications.

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“…The droplets formed using microfluidics have a narrower size distribution. The vaporization threshold and vaporization efficiency are a function of droplet diameter [5], [7], [10], [11], and narrower size distributions may provide more control over droplet vaporization.…”

Section: Discussionmentioning

confidence: 99%

“…Droplets were manufactured using high speed shaking as previously described [1], [7]. Briefly, 0.25 mL (0.425 g) of perfluoropentane (FluoroMed, Round Rock, USA) was added gravimetrically to a 2 mL serum vial.…”

Section: Methodsmentioning

confidence: 99%

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Dissolved oxygen scavenging by acoustic droplet vaporization using intravascular ultrasound

Haworth¹,

Goldstein²,

Mercado-Shekhar³

et al. 2017

2017 IEEE International Ultrasonics Symposium (IUS)

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Modification of dissolved gas content by acoustic droplet vaporization (ADV) has been proposed for several therapeutic applications. Reducing dissolved oxygen (DO) during reperfusion of ischemic tissue during coronary interventions could inhibit reactive oxygen species production and rescue myocardium. The objective of this study was to determine whether intravascular ultrasound (IVUS) can trigger ADV and reduce DO. Perfluoropentane emulsions were created using high-speed shaking and microfluidic manufacturing. High-speed shaking resulted in a polydisperse droplet distribution ranging from less than 1 micron to greater than 16 microns in diameter. Microfluidic manufacturing produced a narrower size range of droplets with diameters between 8.0 microns and 9.6 microns. The DO content of the fluids was measured before and after ADV triggered by IVUS exposure. Duplex B-mode and passive cavitation imaging was performed to assess nucleation of ADV. An increase in echogenicity indicative of ADV was observed after exposure with a clinical IVUS system. In a flow phantom, a 20% decrease in DO was measured distal to the IVUS transducer when droplets, formed via high-speed shaking, were infused. In a static fluid system, the DO content was reduced by 11% when droplets manufactured with a microfluidic chip were exposed to IVUS. These results demonstrate that a reduction of DO by ADV is feasible using a clinical IVUS system. Future studies will assess the potential therapeutic efficacy of IVUS-nucleated ADV and methods to increase the magnitude of DO scavenging.

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Size-isolation of ultrasound-mediated phase change perfluorocarbon droplets using differential centrifugation

Cited by 19 publications

References 16 publications

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

Quantification of Vaporised Targeted Nanodroplets Using High-Frame-Rate Ultrasound and Optics

Dissolved oxygen scavenging by acoustic droplet vaporization using intravascular ultrasound

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