Perfluorocarbon emulsions

Perfluorocarbon emulsions are emulsions containing either bubbles or droplets which have perfluorocarbons inside them. Some of them are commonly used in medicine as ultrasound contrast agents, and others have been studied for use as oxygen therapeutics.

Ultrasound contrast agents

The most common use of perfluorocarbon emulsions is as ultrasound contrast agents. In this application, microscopic bubbles containing perfluorocarbon gas are injected intravenously and flow through the bloodstream.[1] An ultrasound machine then sends soundwaves through a tissue of interest, and the bubbles reflect the soundwaves to a greater extent than the surrounding tissues, thereby giving the blood greater contrast on ultrasound viewers. This can allow greater visibility of the structure of an organ of interest, or a better indication of the level of blood perfusion or blood volume in an area of interest.[2] The bubbles persist in the blood stream with half-lives of minutes before the perfluorocarbon molecules leave the bubbles and enter the surrounding fluids, before eventually passing through the lungs where they are exhaled.[3][4][5][6][7] Notable ultrasound contrast agents include Definity and Optison which are FDA approved, Sonazoid which is approved in Japan, and EchoGen which was formerly approved in Europe but never marketed.[8][9][10][11][12]

Oxygen therapeutics

Other perfluorocarbon emulsions have been tested as oxygen therapeutics. When perfluorocarbons are exposed to high concentrations of oxygen, large amounts of oxygen dissolve into the perfluorocarbons. If the perfluorocarbon/oxygen solution is then exposed to a low oxygen environment, then oxygen diffuses out of the solution.[13] Three different approaches sought to utilize this characteristic to improve oxygen delivery to tissue.

Early perfluorocarbon emulsions for oxygen delivery were developed as blood substitutes. They used large-molecule perfluorocarbons with boiling points higher than body temperature which were formed into liquid emulsion droplets. The emulsions were injected intravenously and circulated through the bloodstream, and the droplets picked up oxygen when passing through the lungs and offloaded oxygen when passing through the capillaries in other tissues.[13] The primary form of excretion of the perfluorocarbon was through the reticulo-endothelial system - the droplets would remain in the bloodstream until they were recognized by the immune system, would be taken up by phagocytes, and broken down thereby releasing the perfluorocarbon molecules which eventually pass through the lungs and be exhaled.[14] These high boiling point perfluorocarbons typically had half-lives measured in hours or days.[13][15] Relatively large doses were required, but such doses could have side effects including pneumonia.[13] Despite these challenges, Fluosol-DA was approved by the FDA and was marketed as a blood substitute in the United States from 1989 through 1994 when it was withdrawn from the market due to poor sales.[16] Perftoran was approved in the Soviet Union in 1994 and remained in limited use in Russia at least as late as 2019.[17]

The second approach to oxygen delivery tested a perfluorocarbon emulsion not as a blood substitute, but rather as a cerebrospinal fluid (CSF) substitute. In order to increase oxygen delivery to the brains of patients that had reduced blood flow due to acute ischemic stroke, artificial CSF mixed with pre-oxygenated perfluorocarbon emulsion was continuously added into the skull by a ventricular catheter while CSF was continuously removed by a lumbar catheter. Animal studies in cats with acute ischemic stroke showed very strong results, so a clinical trial in four humans was conducted. All four patients survived for 30 days to 2 years before dying of other causes. Enrollment in the trial was slow however, which caused the funding for the project to be cut.[18]

A third approach to oxygen delivery is to move perfluorocarbon molecules into positions where they can enhance the flow of oxygen through the lower parts of the oxygen cascade. While it is difficult to observe the positioning of the perfluorocarbon molecules directly, molecules positioned in the right places between red blood cells and mitochondria may reduce resistance to oxygen flow.[19][20] In cases where the oxygen tension at the mitochondria are very low, this would expose nearby red blood cells to lower oxygen tensions and cause them to offload more oxygen as described by the oxygen–hemoglobin dissociation curve. The most notable example is dodecafluoropentane emulsion (DDFPe, formerly EchoGen, now NanO2). The drug is injected intravenously then the perfluorocarbon molecules spread widely before eventually passing through the lungs whey they are evaporated and exhaled.[21][5] The drug showed very strong results in animal studies of acute ischemic stroke, heart attack and other indications.[22][23][24][25] The drug was tested in a Phase Ib/II clinical trial in 24 patients who had reduced blood flow to the brain due to acute ischemic stroke, where it was intended to increase oxygen delivery to the brain to keep the tissue alive until blood flow could be normalized. The high dose group of patients in the clinical trial had improved functional independence compared to placebo, though the number of patients tested was small and there were confounding factors including differences in stroke severity, so larger clinical trials are needed to confirm the effect.[26] Another perfluorocarbon, perfluorooctyl bromide, has been shown in animal studies to collect in tumor tissue and increase oxygenation of those tumors, potentially by improving the flow of oxygen from red blood cells.[27]

Notable perfluorocarbon emulsions

Table 1: Notable perfluorocarbon emulsions and their properties
Perfluorocarbon(s)Boiling Point (°C)Bubble or DropletScientific Name of PerfluorocarbonTrade Names of EmulsionCompanyPrimary UsesStatus
C3F8-36.7BubbleOctafluoropropane, or perflutrenDefinity, Luminity, OptisonLantheus Medical Imaging, GE HealthcareUltrasound Contrast AgentsApproved in the US and Europe[8][28][9][29]
C4F10-1.9BubblePerfluorobutaneSonazoidDaiichi SankyoUltrasound Contrast AgentApproved in Japan,[10] available in Korea, Norway, Taiwan, and China[30]
C5F1229Bubble and/or DropletDodecafluoropentane Emulsion, DDFPeNanO2, NVX-108, NVX-208, EchoGenNuvOx Pharma, Sonus PharmaceuticalsOxygen Therapeutic - Oxygen Flow Enhancer, or Ultrasound Contrast AgentPhase Ib/II complete in acute ischemic stroke[26][11][12]
C8Cl2F16115DropletPerfluorodichlorooctaneOxyfluorHemaGenOxygen Therapeutic - Blood SubstituteDiscontinued during Phase II trial[31]
C8BrF17142Bubble (when mixed with nitrogen gas), or DropletPerfluorooctyl bromideImagentAlliance PharmaceuticalsUltrasound contrast agent, contrast for MRI and CT, and Oxygen Therapeutic - Oxygen Flow EnhancerDiscontinued clinical development, continuing pre-clinical development[32][27]
C8BrF17, and C10F21Br142, 185DropletPerfluorooctyl bromide and perfluorodecylbromideOxygentAlliance PharmaceuticalsOxygen Therapeutic - Blood SubstituteDiscontinued[33]
C10H2F1864.3DropletBis-perfluorobutyletheleneoxygenated fluorocarbon nutrient emulsion (OFNE)Integra Life SciencesOxygen Therapeutic - CSF SubstituteDiscontinued[18]
C10F18, and C9F21N142DropletPerfluorodecalin and PerfluorotripropylamineFluosol, Fluosol-DAGreen Cross CorporationOxygen Therapeutic - Blood SubstituteDiscontinued[34]
C10F20148.5DropletPerfluorodeceneABL-101, OxycyteAurum Biosciences, Tenax Therapeutics, Oxygen BiotherapeuticsOxygen Therapeutic - Blood SubstitutePhase I clinical trial in acute ischemic stroke[35]
C22F41N172DropletPerftoranPerftoran, or VIDAPHORFluorO2Oxygen Therapeutic - Blood SubstituteApproved in Russia[34]

References

  1. ↑ Linder, Johnathan; Hodovan, James; Mulvagh, Sharon; Park, Margaret; Porter, Tom; Strachan, G. Monet; Wei, Kevin (2021). "Ultrasound Enhancing Agents: Recommended Laboratory Practices from ASE" (PDF). American Society of Echocardiography. 2021 Edition: 3, 4.
  2. ↑ "The Basics". American Society of Echocardiography. Retrieved 17 November 2021.
  3. ↑ Kabalnov, A.; Bradley, J.; Flaim, S.; Klein, D.; Pelura, T.; Peters, B.; Otto, S.; Reynolds, J.; Schutt, E.; Weers, J. (1998). "Dissolution of multicomponent microbubbles in the bloodstream: 2. Experiment". Ultrasound in Medicine & Biology. 24 (5): 751–760. doi:10.1016/s0301-5629(98)00033-7. ISSN 0301-5629. PMID 9695278.
  4. ↑ Frinking, Peter; Segers, Tim; Luan, Ying; Tranquart, François (2020). "Three Decades of Ultrasound Contrast Agents: A Review of the Past, Present and Future Improvements". Ultrasound in Medicine & Biology. 46 (4): 892–908. doi:10.1016/j.ultrasmedbio.2019.12.008. ISSN 1879-291X. PMID 31941587. S2CID 210331995.
  5. 1 2 Correas, J. M.; Meuter, A. R.; Singlas, E.; Kessler, D. R.; Worah, D.; Quay, S. C. (2001). "Human pharmacokinetics of a perfluorocarbon ultrasound contrast agent evaluated with gas chromatography". Ultrasound in Medicine & Biology. 27 (4): 565–570. doi:10.1016/s0301-5629(00)00363-x. PMID 11368867.
  6. ↑ Hutter, J. C.; Luu, H. M.; Mehlhaff, P. M.; Killam, A. L.; Dittrich, H. C. (January 1999). "Physiologically based pharmacokinetic model for fluorocarbon elimination after the administration of an octafluoropropane-albumin microsphere sonographic contrast agent". Journal of Ultrasound in Medicine. 18 (1): 1–11. doi:10.7863/jum.1999.18.1.1. ISSN 0278-4297. PMID 9952073. S2CID 43828536.
  7. ↑ Landmark, Kristin Eitrem; Johansen, Per Wiik; Johnson, Judith A.; Johansen, Bjørn; Uran, Steinar; Skotland, Tore (1 March 2008). "Pharmacokinetics of Perfluorobutane Following Intravenous Bolus Injection and Continuous Infusion of Sonazoid™ in Healthy Volunteers and in Patients with Reduced Pulmonary Diffusing Capacity". Ultrasound in Medicine and Biology. 34 (3): 494–501. doi:10.1016/j.ultrasmedbio.2007.09.019. ISSN 0301-5629. PMID 18096304.
  8. 1 2 Lantheus Medical Imaging. "DEFINITY® (Perflutren Lipid Microsphere) Injectable Suspension, Revised 2011" (PDF). U.S. Food and Drug Administration. Retrieved 9 December 2021.
  9. 1 2 General Electric Company. "Optison (Perflutren Protein-Type A Microspheres Injectable Suspension, USP) Revised May 2012" (PDF). U.S. Food and Drug Administration. Retrieved 9 December 2021.
  10. 1 2 DAIICHI SANKYO COMPANY, LIMITED. "Ultrasound Contrast Agent Sonazoid® for Injection Released for Sale" (PDF). Retrieved 9 December 2021.
  11. 1 2 European Medicines Agency (17 September 2018). "Echogen (dodecafluoropentane) Product Information Section". Retrieved 9 December 2021.
  12. 1 2 European Medicines Agency. "Echogen Annex 1, Summary of Product Characteristics" (PDF). Retrieved 9 December 2021.
  13. 1 2 3 4 Jägers, Johannes; Wrobeln, Anna; Ferenz, Katja B. (2021). "Perfluorocarbon-based oxygen carriers: from physics to physiology". Pflügers Archiv. 473 (2): 139–150. doi:10.1007/s00424-020-02482-2. ISSN 0031-6768. PMC 7607370. PMID 33141239.
  14. ↑ Flaim, Stephen F. (1 January 1994). "Pharmacokinetics and Side Effects of Perfluorocarbon-Based Blood Substitutes". Artificial Cells, Blood Substitutes, and Biotechnology. 22 (4): 1043–1054. doi:10.3109/10731199409138801. ISSN 1073-1199. PMID 7849908.
  15. ↑ Keipert, P. E.; Otto, S.; Flaim, S. F.; Weers, J. G.; Schutt, E. A.; Pelura, T. J.; Klein, D. H.; Yaksh, T. L. (1 January 1994). "Influence of Perflubron Emulsion Particle Size on Blood Half-Life and Febrile Response in Rats". Artificial Cells, Blood Substitutes, and Biotechnology. 22 (4): 1169–1174. doi:10.3109/10731199409138812. ISSN 1073-1199. PMID 7849919.
  16. ↑ Lowe, Kenneth C. (1 January 2006). "Chapter 25 - Fluosol®: The First Commercial Injectable Perfluorocarbon Oxygen Carrier". Blood Substitutes. Academic Press. pp. 276–287. ISBN 978-0-12-759760-7.
  17. ↑ Latson, Gary W. (October 2019). "Perftoran (Vidaphor)-Introduction to Western Medicine". Shock (Augusta, Ga.). 52 (1S Suppl 1): 65–69. doi:10.1097/SHK.0000000000001063. ISSN 1540-0514. PMID 29189604. S2CID 20476896.
  18. 1 2 Bell, Rodney D.; Powers, Barbara L.; Brock, David; Provencio, J. Javier; Flanders, Adam; Benetiz, Ronald; Rosenwasser, Robert; Strause, Jamie; Frazer, Glenn; Kramer, Michael S.; Hesson, David; Barnitz, James; Osterholm, J. L. (2006). "Ventriculo-lumbar perfusion in acute ischemic stroke". Neurocritical Care. 5 (1): 21–29. doi:10.1385/NCC:5:1:21. ISSN 1541-6933. PMID 16960290. S2CID 12607331.
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  20. ↑ Spiess, Bruce D. (April 2009). "Perfluorocarbon emulsions as a promising technology: a review of tissue and vascular gas dynamics". Journal of Applied Physiology. 106 (4): 1444–1452. doi:10.1152/japplphysiol.90995.2008. ISSN 8750-7587. PMID 19179651.
  21. ↑ Arthur, Christine; Song, Lin; Culp, William; Brown, Aliza; Borrelli, Michael; Skinner, Robert; Hendrickson, Howard (2017). "Tissue Concentration of Dodecafluoropentane (DDFP) Following Repeated IV Administration in the New Zealand White Rabbit". The AAPS Journal. 19 (2): 520–526. doi:10.1208/s12248-016-0013-0. ISSN 1550-7416. PMID 28028728. S2CID 25123531.
  22. ↑ Culp, William C.; Woods, Sean D.; Skinner, Robert D.; Brown, Aliza T.; Lowery, John D.; Johnson, Jennifer L. H.; Unger, Evan C.; Hennings, Leah J.; Borrelli, Michael J.; Roberson, Paula K. (2012). "Dodecafluoropentane Emulsion Decreases Infarct Volume in a Rabbit Ischemic Stroke Model". Journal of Vascular and Interventional Radiology. 23 (1): 116–121. doi:10.1016/j.jvir.2011.10.001. ISSN 1051-0443. PMC 3253225. PMID 22079515.
  23. ↑ Woods, S. D.; Skinner, R. D.; Ricca, A. M.; Brown, A. T.; Lowery, J. D.; Borrelli, M. J.; Lay, J. O.; Culp, W. C. (1 October 2013). "Progress in Dodecafluoropentane Emulsion as a Neuroprotective Agent in a Rabbit Stroke Model". Molecular Neurobiology. 48 (2): 363–367. doi:10.1007/s12035-013-8495-6. ISSN 1559-1182. PMC 3787698. PMID 23813100.
  24. ↑ Culp, W. C.; Brown, A. T.; Lowery, J. D.; Arthur, M. C.; Roberson, P. K.; Skinner, R. D. (October 2015). "Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model". Molecular Neurobiology. 52 (2): 979–984. doi:10.1007/s12035-015-9243-x. ISSN 1559-1182. PMC 4998836. PMID 26055229.
  25. ↑ Liu, Zhonglin; Barber, Christy; Gupta, Akash; Wan, Li; Won, Young-Wook; Furenlid, Lars R.; Chen, Qin; Desai, Ankit A.; Zhao, Ming; Bull, David A.; Unger, Evan C.; Martin, Diego R. (March 2019). "Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction". Nuclear Medicine and Biology. 70: 67–77. doi:10.1016/j.nucmedbio.2019.01.004. ISSN 1872-9614. PMC 6778684. PMID 30772168.
  26. 1 2 Culp, William C.; Onteddu, Sanjeeva S.; Brown, Aliza; Nalleballe, Krishna; Sharma, Rohan; Skinner, Robert D.; Witt, Taylor; Roberson, Paula K.; Marsh, James D. (August 2019). "Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial". Journal of Vascular and Interventional Radiology. 30 (8): 1244–1250.e1. doi:10.1016/j.jvir.2019.04.020. ISSN 1535-7732. PMID 31349978. S2CID 198933339.
  27. 1 2 Xiang, Yun; Bernards, Nicholas; Hoang, Bryan; Zheng, Jinzi; Matsuura, Naomi (11 March 2019). "Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing". Nanotheranostics. 3 (2): 135–144. doi:10.7150/ntno.29908. ISSN 2206-7418. PMC 6470341. PMID 31008022.
  28. ↑ "Luminity". Luminity. European Medicines Agency. 17 September 2018. Retrieved 25 January 2022.
  29. ↑ "Optison". European Medicines Agency. 17 September 2018.
  30. ↑ Lee, Jae Young; Minami, Yasunori; Choi, Byung Ihn; Lee, Won Jae; Chou, Yi-Hong; Jeong, Woo Kyoung; Park, Mi-Suk; Kudo, Nobuki; Lee, Min Woo; Kamata, Ken; Iijima, Hiroko; Kim, So Yeon; Numata, Kazushi; Sugimoto, Katsutoshi; Maruyama, Hitoshi; Sumino, Yasukiyo; Ogawa, Chikara; Kitano, Masayuki; Joo, Ijin; Arita, Junichi; Liang, Ja-Der; Lin, Hsi-Ming; Nolsoe, Christian; Gilja, Odd Helge; Kudo, Masatoshi (2020). "The AFSUMB Consensus Statements and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound using Sonazoid". Ultrasonography. 39 (3): 191–220. doi:10.14366/usg.20057. ISSN 2288-5919. PMC 7315291. PMID 32447876.
  31. ↑ Shaw, Robert F.; Richard, Thomas J. (1 January 2006). "Chapter 27 - Rational Development of Oxyfluor™". Blood Substitutes. Academic Press. pp. 298–311. ISBN 978-0-12-759760-7.
  32. ↑ Cheng, Kenneth T. (2004). "Perflexane-Lipid Microspheres". Molecular Imaging and Contrast Agent Database. PMID 20641960.
  33. ↑ "Alliance Pharmaceutical Corp. Updates Oxygent Clinical Development Plan". www.pharmaceuticalonline.com. Retrieved 25 January 2022.
  34. 1 2 Khan, Fahad; Singh, Kunwar; Friedman, Mark T. (2020). "Artificial Blood: The History and Current Perspectives of Blood Substitutes". Discoveries. 8 (1): e104. doi:10.15190/d.2020.1. ISSN 2359-7232. PMC 7086064. PMID 32309621.
  35. ↑ "Perfluorocarbon (ABL-101) Oxygenation for Stroke: Trial With GOLD (Glasgow Oxygen Level Dependent Technology) Imaging Theranostic (POST-IT)". ClinicalTrials.gov. Retrieved 25 January 2022.
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