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Delivery of Water-Soluble Drugs Using Acoustically Triggered Perfluorocarbon Double Emulsions

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ABSTRACT

Purpose

Ultrasound can be used to release a therapeutic payload encapsulated within a perfluorocarbon (PFC) emulsion via acoustic droplet vaporization (ADV), a process whereby the PFC phase is vaporized and the agent is released. ADV-generated microbubbles have been previously used to selectively occlude blood vessels in vivo. The coupling of ADV-generated drug delivery and occlusion has therapeutically synergistic potentials.

Methods

Micron-sized, water-in-PFC-in-water (W1/PFC/W2) emulsions were prepared in a two-step process using perfluoropentane (PFP) or perfluorohexane (PFH) as the PFC phase. Fluorescein or thrombin was contained in the W1 phase.

Results

Double emulsions containing fluorescein in the W1 phase displayed a 5.7±1.4-fold and 8.2±1.3-fold increase in fluorescein mass flux, as measured using a Franz diffusion cell, after ADV for the PFP and PFH emulsions, respectively. Thrombin was stably retained in four out of five double emulsions. For three out of five formulations tested, the clotting time of whole blood decreased, in a statistically significant manner (p < 0.01), when incubated with thrombin-loaded emulsions exposed to ultrasound compared to emulsions not exposed to ultrasound.

Conclusions

ADV can be used to spatially and temporally control the delivery of water-soluble compounds formulated in PFC double emulsions. Thrombin release could extend the duration of ADV-generated, microbubble occlusions.

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Abbreviations

ACT:

activated clotting time

ADV:

acoustic droplet vaporization

CPD:

citrate-phosphate-dextrose

IU:

international units

PEG:

polyethylene glycol

PFC:

perfluorocarbon

PFH:

perfluoro-n-hexane

PFP:

perfluoro-n-pentane

PRP:

pulse repetition period

US:

ultrasound

W1/PFC/W2 :

water-in-perfluorocarbon-in-water

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ACKNOWLEDGMENTS

The authors would like to thank Dr. Xia Shao (Department of Nuclear Medicine, University of Michigan, Ann Arbor, MI) for assistance with the Krytox-PEG copolymer synthesis and Dr. Kim Ives (Department of Radiology, University of Michigan, Ann Arbor, MI) for assistance in acquiring blood. The authors would also like to thank Dr. Olivier Couture (Ondes et Images, Institut Langevin, Paris, France) for useful discussions regarding reverse PFC emulsions. This work was supported in part by NIH grant 5R01EB000281.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA

    Mario L. Fabiilli, Oliver D. Kripfgans, Paul L. Carson & J. Brian Fowlkes

  2. Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA

    Mario L. Fabiilli, James A. Lee, Oliver D. Kripfgans, Paul L. Carson & J. Brian Fowlkes

  3. Applied Physics Program, University of Michigan, Ann Arbor, Michigan, USA

    Oliver D. Kripfgans

  4. 1301 Catherine Street, 3225 Medical Sciences Building I, Ann Arbor, Michigan, 48109-5667, USA

    Mario L. Fabiilli

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  1. Mario L. Fabiilli
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Correspondence to Mario L. Fabiilli.

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Fabiilli, M.L., Lee, J.A., Kripfgans, O.D. et al. Delivery of Water-Soluble Drugs Using Acoustically Triggered Perfluorocarbon Double Emulsions. Pharm Res 27, 2753–2765 (2010). https://doi.org/10.1007/s11095-010-0277-5

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