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Novel method for the formation of monodisperse superheated perfluorocarbon nanodroplets as activatable ultrasound contrast agents.

ABSTRACT: Microbubble (MB) contrast agents have positively impacted the clinical ultrasound (US) community worldwide. Their use in molecular US imaging applications has been hindered by their limited distribution to the vascular space. Acoustic droplet vaporization (ADV) of nanoscale superheated perfluorocarbon nanodroplets (NDs) demonstrates potential as an extravascular contrast agent that could facilitate US-based molecular theranostic applications. However these agents are metastable and difficult to manufacture with high yields. Here, we report a new formulation technique that yields reliable, narrowly dispersed sub-300 nm decafluorobutane (DFB) or octafluoropropane (OFP)-filled phospholipid-coated NDs that are stable at body temperature, using small volume microfluidization. Final droplet concentration was high for DFB and lower for OFP (>1012vs. >1010 NDs per mL). Superheated ND stability was quantified using tunable resistive pulse sensing (TRPS) and dynamic light scattering (DLS). DFB NDs were stable for at least 2 hours at body temperature (37 °C) without spontaneous vaporization. These NDs are activatable in vitro when exposed to diagnostic US pressures delivered by a clinical system to become visible microbubbles. The DFB NDs were suficiently stable to allow their processing into functionalized NDs with anti-epithelial cell adhesion molecule (EpCAM) antibodies to target EpCAM positive cells.

SUBMITTER: de Gracia Lux C

PROVIDER: S-EPMC5801773 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Novel method for the formation of monodisperse superheated perfluorocarbon nanodroplets as activatable ultrasound contrast agents.

de Gracia Lux C C Vezeridis A M AM Lux J J Armstrong A M AM Sirsi S R SR Hoyt K K Mattrey R F RF

RSC advances 20171016 77

Microbubble (MB) contrast agents have positively impacted the clinical ultrasound (US) community worldwide. Their use in molecular US imaging applications has been hindered by their limited distribution to the vascular space. Acoustic droplet vaporization (ADV) of nanoscale superheated perfluorocarbon nanodroplets (NDs) demonstrates potential as an extravascular contrast agent that could facilitate US-based molecular theranostic applications. However these agents are metastable and difficult to ...[more]

PMID: 29430294

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Project description:Microbubbles (MBs) are optimal ultrasound contrast agents because their unique acoustic response allows for exquisite sensitivity in vivo. This unique response is derived from MBs' elasticity that allows them to oscillate differently from surrounding tissues. While the main use of MBs in the clinic is for cardiac and perfusion imaging, imparting MBs with bioresponsive properties would expand their use to detect pathophysiologic changes. This can be achieved by damping MBs' oscillations to silence their signal and rescuing it when they encounter the biomarker of interest to improve detection and specificity of diseases such as deep vein thrombosis (DVT). Here, we demonstrate that conjugating perfluorobutane-filled MBs with hyaluronic acid (HA) and cross-linking HA with biodegradable linkers eliminates harmonic signal because of increased MB stiffness and decreased oscillation. In this proof-of-concept study, we used a reversible pH-sensitive cross-linker to establish and validate this targeted and activatable pH-sensitive MB (pH-MB) platform. Conjugation of HA to MBs and targeting of pH-MBs to CD44-positive cells were validated. Harmonic signal loss due to stiffening of pH-MBs' shell was confirmed using a clinical ultrasound scanner equipped with Cadence contrast pulse sequencing. pH-MBs imaged before and after acidification increased harmonic signal fivefold. Because the cleavage of the cross-linker we used is reversible, harmonic signal was silenced again when the acidic suspension was neutralized, confirming that harmonic signal is dependent on the cross-linked HA. The rate of rise and the magnitude of harmonic signal increase could be manipulated by varying the phospholipid composition and the number of HA cross-linkers, indicating that the platform can be tuned to the desired response needed. In this study, we established the feasibility of using targeted and activatable MBs and plan to apply this platform to aid in the diagnosis and management of patients with DVT and potentially other conditions.

Project description:PurposeThis study introduces a real-time contrast-enhanced ultrasound imaging method with recently developed laser-activated nanodroplets (LANDs), a new class of phase-change nanometer-scale contrast agents that provides perceptible, sustained high-contrast with ultrasound.MethodsIn response to pulsed laser irradiation, the LANDs-, which contain liquid perfluorohexane and optical fuses-blink (vaporize and recondense). That is, they change their state from liquid nanodroplets to gas microbubbles, and then back to liquid nanodroplets. In their gaseous microbubble state, the LANDs provide high-contrast ultrasound, but the microbubbles formed in situ typically recondense in tens of milliseconds. As a result, LAND visualization by standard, real-time ultrasound is limited. However, the periodic optical triggering of LANDs allows us to observe corresponding transient, periodic changes in ultrasound contrast. This study formulates a probability function that measures how ultrasound temporal signals vary in periodicity. Then, the estimated probability is mapped onto a B-scan image to construct a LAND-localized, contrast-enhanced image. We verified our method through phantom and in vivo experiments using an ultrasound system (Vevo 2100, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) operating with a 40-MHz linear array and interfaced with a 10 Hz Nd:YAG laser (Phocus, Opotek Inc., Carlsbad, CA, USA) operating at the fundamental 1064 nm wavelength.ResultsFrom the phantom study, the results showed improvements in the contrast-to-noise ratio of our approach over conventional ultrasound ranging from 129% to 267%, with corresponding execution times of 0.10 to 0.29 s, meaning that the developed method is computationally efficient while yielding high-contrast ultrasound. Furthermore, in vivo sentinel lymph node (SLN) imaging results demonstrated that our technique could accurately identify the SLN.ConclusionsThe results indicate that our approach enables efficient and robust LAND localization in real time with substantially improved contrast, which is essential for the successful translation of this contrast agent platform to clinical settings.

Dataset Information

Novel method for the formation of monodisperse superheated perfluorocarbon nanodroplets as activatable ultrasound contrast agents.

Publications

Novel method for the formation of monodisperse superheated perfluorocarbon nanodroplets as activatable ultrasound contrast agents.

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