Therapeutic oxygen delivery by perfluorocarbon-based colloids
Graphical abstract
Introduction
Once the flagship of medically-dedicated perfluorocarbon (PFC) research, and catching most of the limelight, oxygen-carrying PFC nanoemulsions, the so-called “blood substitutes”, have so far not met expectations. No satisfactory injectable O2-delivering product has yet reached the marketplace. By contrast, another primary endeavor in medically-oriented PFC research, that is, the development of contrast-enhancing agents for diagnostic imaging, has been more successful. Several products have been licensed for use as contrast agents for ultrasound (US) imaging, as well as for ophthalmology and for in vivo cell tracking. The search for O2-delivering therapeutics has, however, not been forsaken. Further colloidal PFC products, including nanoemulsions (NEs), microbubbles (MBs) and phase-shift nanoemulsions (P-SNEs) (Scheme 1), are undergoing clinical investigations for O2 delivery, in particular for O2-dependent cancer radiotherapy, chemotherapy and photodynamic therapy. Concurrently, further PFC-based products are undergoing clinical trials for molecular imaging diagnosis of liver, breast, ovarian, prostate and colon cancers; guidance for surgical procedures; enhancement of immunotherapy; ablation of uterine fibroids; treatment of allergic asthma; treatment of smoke inhalation injury; delivery of drugs to the brain, as for management of brain tumors and neurodegenerative diseases, and assessment of treatment efficacy.
Starting with a critical assessment of a problematic Phase III trial of Oxygent (Alliance Pharmaceutical Corp., San Diego, CA), an O2-carrying PFC NE product, in cardiac surgery, this short review will present PFC-based colloids that are, or may be, used for O2 delivery. It will insist on the critical question of PFC selection and NE design and fabrication, highlight recent advances in the field and progress in our understanding of PFC behavior at fluid interfaces. After a brief reminder of the basics of PFC NE-based O2 transport and delivery, it will expose further demonstration of their capacity to deliver O2 to tissues in various circumstances. We will then discuss alternative O2-delivery options that rely on the administration of PFC-stabilized injectable MBs or on MBs generated in vivo by vaporization of P-SNEs, as well as on other colloids and scaffolds that involve PFCs or other highly fluorinated components. We will also allude to other emerging PFC-based procedures and indications that are being investigated for diagnostic, therapeutic and theranostic purposes, embracing contrast imaging, cell tracking, controlled delivery of energy and of therapeutics, including across the blood-brain barrier. Even when developed for other purposes, these products possess a definite O2 carrying capacity and the knowledge acquired in their investigation could benefit to O2 carrier development. Finally, the Prospects section will highlight some critical issues, desirable developments, and offer some opinions about the development of PFC-based O2 delivery products. The paper's organization is further detailed in the Table of Content.
Citations are leaning towards recent reviews from which numerous earlier papers can be retrieved. The italicized prefix F- conventionally signifies perfluoro. F-colloids will refer to colloids comprising highly fluorinated components. Recourse to acronyms will be minimized. Commercial PFC-based product names are in italics.
Section snippets
An inconclusive clinical trial
PFC-based oxygen carriers have suffered a serious drawback when Alliance Pharmaceutical Corp. closed its operations subsequent to a failed clinical study. The development of the most advanced PFC nanoemulsion of that time, Oxygent AF0144, a phospholipid-shelled 60% w/v F-octylbromide (C8F17Br 3) emulsion comprizing a small fraction of F-decylbromide (C10F21Br 4, 2%) for stabilization against Ostwald ripening [1,2], was interrupted in 2001 when a Phase III study in coronary artery bypass graft
The perfluorocarbon colloids at work
Intravascular administration of PFCs requires their dispersion as injectable aqueous formulations. The colloids used in nanomedicines for O2 delivery (3 The perfluorocarbon colloids at work, 4 Oxygen delivery by PFC nanoemulsions, 5 The O, 6 O) and other purposes (Section 7) consist primarily of NEs, MBs, and P-SNEs (Scheme 1). The latter involve liquid NE droplets that can be converted in vivo into gas MBs upon activation (vaporization) by heat, sound or light. Further colloids intended for
Oxygen delivery by PFC nanoemulsions
The early objective of developing PFC-based O2-delivering “blood substitutes” has not been forsaken. Further evidence of O2 delivery efficacy by means of PFC NEs has been secured. New, highly stable size-controlled NEs have been developed. The alternative option of using MBs or P-SNE-derived MBs for O2 delivery is being actively investigated. Additional indications for O2-delivering therapeutics have emerged. Potentiation of the foremost O2-dependent cancer treatment strategies, including
The O2 microbubble delivery option—a change in paradigm
An alternate option for O2 delivery relies on the direct administration of PFC-stabilized O2 micro- or nanobubbles rather than emulsion droplets. This represents a definite change in paradigm since in the former case the PFC does no longer act as a solvent for physical dissolution of O2, but as a gaseous stabilizer of an O2 microbubble. Such MBs can also be generated through vaporization of NE droplets. US exposure can prompt on-demand O2 delivery from MBs located at the disease site.
O2 delivery by further PFC-based colloids
A few recent studies that investigate O2 transport by fluorinated colloids other than PFC NEs, MBs or P-SNEs, in which O2 delivery is either a deliberate part of a theranostic strategy, or that pursue other goals, but inevitably also provide an O2 reservoir, are illustrated here. Examples of F-alkylated or F-arylated components of fluorinated polymeric micelles formed for this purpose are provided in Table 7. 1O2 production and PDT efficacy of micelles made of PEGylated copolymers bearing
Perfluorocarbon colloids can also deliver other gases, contrast, energy, drugs, genes, and have a clear vocation for theranostics
The recent years have witnessed an outburst of prospective PFC-based nanomedicines for an increasing number of indications other than O2 delivery. Objectives include increasingly sophisticated diagnostic imaging modalities, focused delivery of energy in various forms, controlled as and when required delivery of therapeutics, … and even control of urinary stress. Even when the primary goal is different, the F-colloids put to work predictably do carry, and can release a certain amount of O2.
Prospects
The past decade has witnessed an amazing surge of the number of new PFC-based O2-carrying colloids and medical indications investigated. Our knowledge of PFC colloid preparation, stabilization, physics and in vivo behavior has considerably progressed. Substantial O2 delivery efficacy data further support the capacity of PFC nanoemulsions to help relieve tissue hypoxia, potentiate O2-dependent cancer treatment, regenerate damaged tissues, preserve isolated organs, etc. In view of these data, we
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We acknowledge the European INTERREG V Program (Nanotransmed) for financial support.
References (600)
OxygentTM, a perfluorochemical-based oxygen therapeutic for surgical patients
- et al.
Perflubron emulsion (AF0144) augments harvesting of autologous blood: a phase II study in cardiac surgery
J Cardiothorac Vasc Anesth
(2002) - et al.
Clinical hemodilution
- et al.
Low hematocrit during cardiopulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery
Ann Thorac Surg
(2005) Fluorous micro- and nanophases with a biomedical perspective
Tetrahedron.
(2002)- et al.
Selected physicochemical aspects of poly- and perfluoroalkylated substances relevant to performance, environment and sustainability-part one
Chemosphere.
(2015) - et al.
Fluidization of a dipalmitoylphosphatidylcholine monolayer by fluorocarbon gases: potential use in lung surfactant therapy
Biophys J
(2006) - et al.
First quantitative assessment of the adsorption of a fluorocarbon gas on phospholipid monolayers at the air/water interface
J Colloid Interface Sci
(2021) Fluorocarbon emulsions - Designing an efficient shuttle service for the respiratory gases - the so-called “blood substitutes”
- et al.
Dissolution of multicomponent microbubbles in the blood stream: 1 Theory
Ultrasound Med Biol
(1998)
The solubility of oxygen in highly fluorinated liquids
J Fluorine Chem
Human pharmacokinetics of a perfluorocarbon ultrasound contrast agent evaluated with gas chromatography
Ultrasound Med Biol
Growth and dissolution of an encapsulated contrast microbubble: effects of encapsulation permeability
Ultrasound Med Biol
Albumin-derived perfluorocarbon-based artificial oxygen carriers: a physico-chemical characterization and first in vivo evaluation of biocompatibility
Eur J Pharm Biopharm
Preparation and in vitro characterization of chitosan nanobubbles as theranostic agents
Colloids Surf B Biointerfaces
Fluorinated-functionalized hyaluronic acid nanoparticles for enhanced photodynamic therapy of ocular choroidal melanoma by ameliorating hypoxia
Carbohydr Polym
Microbubble formulations: synthesis, stability, modeling and biomedical applications
Ultrasound Med Biol
Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue
Int J Pharm
Carbohydrate- and related polyol-derived fluorosurfactants - An update
Carbohydr Res
On the acoustic properties of vaporized submicron perfluorocarbon droplets
Ultrasound Med Biol
Time and frequency characteristics of cavitation activity enhanced by flowing phase-shift nanodroplets and lipid-shelled microbubbles during focused ultrasound exposures
Ultrasound Med Biol
Highly fluorinated amphiphiles and colloidal systems, and their applications in the biomedical field - a contribution
Biochimie.
Emulsions of fluorinated oils stabilised by fluorinated silica nanoparticles
Colloids Surf A: Physicochem Eng Aspects
Per- and polyfluorinated substances (PFASs): environmental challenges
Curr Opin Colloid Interface Sci
Microbubbles in ultrasound-triggered drug and gene delivery
Adv Drug Deliv Rev
Fluorous materials in microbubble engineering science and technology - design and development of new bubble preparation and sizing technologies
J Fluorine Chem
Oxygen carriers (“blood substitutes”) – raison d’être, chemistry, and some physiology
Chem Rev
Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery
Artif Cells Blood Substit Immobil Biotechnol
Use of perflubron emulsion to decrease allogeneic blood transfusion in high-blood-loss non-cardiac surgery: results of a European phase 3 study
Anesthesiology.
An overview of two human trials of perfluorocarbon emulsions in noncardiac surgery
Shock.
Perfluorocarbon-based oxygen delivery
Artif Cells Blood Substit Immobil Biotechnol
The concept of augmented acute normovolemic hemodilution: using a perfluorochemical-based intravenous oxygen carrier to decrease allogeneic blood transfusion in elective surgery
Transf Alt Transf Med
Does acute normovolemic hemodilution reduce perioperative allogeneic transfusion? A meta-analysis. The international study of perioperative transfusion
Anesth Analg
Hemodilution during cardiopulmonary bypass increases cerebral infarct volume after middle cerebral artery occlusion in rats
Anesth Analg
Effects of extreme hemodilution during cardiac surgery on cognitive function in the elderly
Anesthesiology.
Perfluorocarbons: knowledge gained from clinical trials
Shock.
Clinical trials in cardiac surgery
Fluorine chemistry at the Millenium. Fascinated by fluorine
19F magnetic resonance imaging (MRI): from design of materials to clinical applications
Chem Rev
Perfluorocarbons and perfluorocarbon emulsions for pulmonary indications
Fluorine compounds, organic
Chemistry, physical chemistry and uses of molecular fluorocarbon-hydrocarbon diblocks, triblocks and related compounds - unique apolar components for self-assembled colloid and interface engineering
Chem Rev
Recruitment and immobilisation of a fluorinated biomarker across an interfacial phospholipid film using a fluorocarbon gas
Angew Chem Int Ed
Multicore liquid perfluorocarbon-loaded multimodal nanoparticles for stable ultrasound and 19F MRI applied to in vivo cell tracking
Adv Funct Mater
Adsorption process for phospholipids of different chain lengths at a fluorocarbon/water interface studied by Du Noüy ring and spinning drop
Colloid Polym Sci
A nonpolar, nonamphiphilic molecule can accelerate adsorption of phospholipids and lower their surface tension at the air/water interface
ChemPhysChem.
Counteracting the inhibitory effect of proteins towards lung surfactant substitutes: a fluorocarbon gas helps displace albumin at the air/water interface
Chem Commun
Fluorocarbon exposure mode markedly affects phospholipid monolayer behavior at the gas/liquid interface: impact on size and stability of microbubbles
Langmuir.
Overcoming inactivation of the lung surfactant by serum proteins: a potential role for fluorocarbons?
Soft Matter
Modeling of the effect of fluorocarbon gases on the properties of phospholipid monolayers and the adsorption dynamics of their aqueous solutions or dispersions
Colloid Polym Sci
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