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Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets.

ABSTRACT: Perfluorocarbon nanodroplets (PFCnDs) are phase-change contrast agents that have the potential to enable extravascular contrast-enhanced ultrasound and photoacoustic (US/PA) imaging. Producing consistently small, monodisperse PFCnDs remains a challenge without resorting to technically challenging methods. We investigated the impact of variable shell composition on PFCnD size and US/PA image properties. Our results suggest that increasing the molar percentage of PEGylated lipid reduces the size and size variance of PFCnDs. Furthermore, our imaging studies revealed that nanodroplets with more PEGylated lipids produce increased US/PA signal compared with those with the standard formulation. Finally, we highlight the ability of this approach to facilitate US/PA imaging in a murine model of breast cancer. These data indicate that, through a facile synthesis process, it is possible to produce monodisperse, small-sized PFCnDs. Novel in their simplicity, these methods may promote the use of PFCnDs among a broader user base to study a variety of extravascular phenomena.

SUBMITTER: Yarmoska SK

PROVIDER: S-EPMC6491255 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets.

Yarmoska Steven K SK Yoon Heechul H Emelianov Stanislav Y SY

Ultrasound in medicine & biology 20190408 6

Perfluorocarbon nanodroplets (PFCnDs) are phase-change contrast agents that have the potential to enable extravascular contrast-enhanced ultrasound and photoacoustic (US/PA) imaging. Producing consistently small, monodisperse PFCnDs remains a challenge without resorting to technically challenging methods. We investigated the impact of variable shell composition on PFCnD size and US/PA image properties. Our results suggest that increasing the molar percentage of PEGylated lipid reduces the size a ...[more]

PMID: 30975536

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Project description:Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used in vivo as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and 19F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated in situ by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing. Methods: Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF3(CF2)7Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n?3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [18F]FAZA (n? 3 per group). Results: Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. In vivo PET imaging with [18F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone. Conclusion: Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents.

Project description:Liquid perfluorocarbon nanodroplets (NDs) are an attractive alternative to microbubbles (MBs) for ultrasound-mediated therapeutic and diagnostic applications. ND size and size distribution have a strong influence on their behaviour in vivo, including extravasation efficiency, circulation time, and response to ultrasound stimulation. Thus, it is desirable to identify ways to tailor the ND size and size distribution during manufacturing. In this study phospholipid-coated NDs, comprising a perfluoro-n-pentane (PFP) core stabilised by a DSPC/PEG40s (1,2-distearoyl-sn-glycero-3-phosphocholine and polyoxyethylene(40)stearate, 9:1 molar ratio) shell, were produced in phosphate-buffered saline (PBS) by sonication. The effect of the following production-related parameters on ND size was investigated: PFP concentration, power and duration of sonication, and incorporation of a lipophilic fluorescent dye. ND stability was also assessed at both 4 °C and 37 °C. When a sonication pulse of 6 s and 15% duty cycle was employed, increasing the volumetric concentration of PFP from 5% to 15% v/v in PBS resulted in an increase in ND diameter from 215.8 ± 16.8 nm to 408.9 ± 171.2 nm. An increase in the intensity of sonication from 48 to 72 W (with 10% PFP v/v in PBS) led to a decrease in ND size from 354.6 ± 127.2 nm to 315.0 ± 100.5 nm. Increasing the sonication time from 20 s to 40 s (using a pulsed sonication with 30% duty cycle) did not result in a significant change in ND size (in the range 278-314 nm); however, when it was increased to 60 s, the average ND diameter reduced to 249.7 ± 9.7 nm, which also presented a significantly lower standard deviation compared to the other experimental conditions investigated (i.e., 9.7 nm vs. > 49.4 nm). The addition of the fluorescent dye DiI at different molar ratios did not affect the ND size distribution. NDs were stable at 4 °C for up to 6 days and at 37 °C for up to 110 min; however, some evidence of ND-to-MB phase transition was observed after 40 min at 37 °C. Finally, phase transition of NDs into MBs was demonstrated using a tissue-mimicking flow phantom under therapeutic ultrasound exposure conditions (ultrasound frequency: 0.5 MHz, acoustic pressure: 2-4 MPa, and pulse repetition frequency: 100 Hz).

Dataset Information

Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets.

Publications

Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets.

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