Fluorocarbons and fluorinated amphiphiles in drug delivery and biomedical research
Introduction
This review is concerned with fluorocarbons, fluorinated amphiphiles and fluorinated colloidal systems. It will illustrate the present and potential role of these compounds and systems in drug delivery and biomedical research. Fluorinated chains confer unique properties to molecules. These properties are the foundations of new therapies based, for example, on fluorocarbons for oxygen delivery (blood substitutes) or liquid ventilation procedures that are currently in advanced human clinical trials. Therefore, the in vivo behavior of fluorocarbons has been intensively investigated. The situation is quite different where fluorinated amphiphiles are concerned. Until recently, few fluorinated surfactants had been reported that were sufficiently pure and well-defined enough to be utilized in pharmaceuticals. Information on the biological effects, pharmacology and toxicity of such surfactants is still scarce.
The dominant characteristics of fluorinated surfactants are their high surface activity and their strong tendency to self-aggregate into stable, well-organized supramolecular assemblies such as vesicles and tubules. Because of their high propensity to collect at interfaces, fluorinated surfactants can be used for the formulation of a range of multi-phase colloidal systems including direct and reverse fluorocarbon emulsions, microemulsions, gels, dispersions, aerosols, etc. Many of these colloidal systems have potential as drug delivery systems.
The scope of this review is limited to fluorocarbons and perfluoroalkylated amphiphiles that are well-defined in terms of molecular entities and for which some biological information is available. This excludes most of the fluorinated surfactants commercially available for non-medical applications, as well as monofluorinated or trifluoromethyl-substituted compounds with pharmaceutical activity, anesthetics and propellants.
Section 2 provides some background information on fluorocarbons and fluorinated surfactants, their specific structural characteristics and physicochemical properties. Section 3 discusses some biological aspects of these compounds. Section 4 focuses on fluorocarbons and fluorocarbon emulsions as oxygen-delivery systems. This section is brief, as excellent reviews have recently been published on this topic [1], [2], [3]. Section 5 discusses the potential of newly investigated fluorocarbon-based carriers for pulmonary drug delivery, including dispersions of drug microcrystallites in fluorocarbons, reverse water (or hydrocarbon)-in-fluorocarbon emulsions and microemulsions, as well as multiple emulsions. Section 6 presents various types of fluorocarbon gels for topical use. Section 7 is dedicated to vesicles and tubules made from fluorinated amphiphiles. Finally, Section 8 provides examples of use of fluorinated surfactants as tools in biomedical research, for protein extraction and 2D-crystallization, for obtaining water-in-CO2 microemulsions (a new medium for protein extraction and bioconversion), and in separation techniques.
Section snippets
Fluorocarbons
As the most electronegative of all elements, fluorine has very special properties. It has a high ionization potential and very low polarizability [4]. Yet this relatively small atom is significantly larger than hydrogen (van der Waals radius 1.47 Å vs. 1.20 Å) [5]. Consequently, perfluoroalkyl (F-alkyl) chains (CnF2n+1) are more bulky than their hydrogenated counterparts (cross sections: 30 Å2 vs. 20 Å2) [6], [7]. The average volumes of the CF2 and CF3 groups are estimated as 38 Å3 and 92 Å3,
Fluorocarbons
The biocompatibility of liquid fluorocarbons is well documented as a result of the intensive efforts that are being devoted to developing pharmaceuticals for liquid ventilation, oxygen delivery and imaging [1], [2], [3], [32], [33], [34]. Fluorocarbons intended for biomedical uses can be linear or cyclic, and may contain hydrogen, halogen, or nitrogen atoms. Although several hundreds of such compounds have been screened over the past twenty years, very few were found to meet the appropriate
Neat fluorocarbons: liquid ventilation
A neat fluorocarbon, perfluorooctyl bromide (C8F17Br, perflubron) is being investigated in Phase II/III clinical trials for the treatment of the respiratory distress syndrome, a severe condition with high mortality for which no satisfactory treatment is available yet. In this treatment, the product (LiquiVent®, Alliance Pharmaceutical Corp., San Diego, US) is instilled in the lungs of the patient [82], [83]. In comparison with ventilation with a gas, liquid ventilation eliminates the gas–liquid
Dispersions of drug microparticulates in fluorocarbons
As noted in Section 4.1., fluorocarbon liquid ventilation was shown to maintain gas exchange and acid–base status in animals and humans with respiratory dysfunction. As such patients usually also need medication, it was proposed that biologically active agents could be delivered directly during the liquid ventilation process [86]. Pulmonary administration of vasoactive drugs such as acetylcholine, epinephrine, and priscoline elicited significant systemic and pulmonary physiological responses,
Fluorocarbon gels
Gelifying fluorocarbons is quite a challenge. Fluorocarbons are extremely fluid and mobile liquids as a consequence of very weak intermolecular cohesive forces, and they do not dissolve the usual gelifying agents. Yet several types of gels have recently been produced [116].
Compartmentalized polymeric micelles
Terpolymerization of a hydrophilic monomer, acrylamide, and two polymerizable surfactant, a fluorinated (22) and a hydrogenated one (23), yielded polymerized micelles with segregated fluorinated and hydrogenated domains [134]. Such multicompartment polymeric micelles are proposed as new drug delivery systems.
Vesicles from fluorinated amphiphiles
The first examples of fluorinated bilayers and vesicles were reported by Kunitake [135] and Ringsdorf [136] for amphiphiles of types 24 and 25, respectively.
Fluorinated vesicles have since
Extraction of proteins from membrane and protein crystallization
Few studies on the use of fluorinated surfactants for protein extraction have been reported so far. Although fluorinated chains, when present in amphiphiles, induce higher surface activities than hydrogenated chains, fluorinated amphiphiles may also be qualified as less detergent toward membranes than their hydrogenated analogs. This was already illustrated by the lesser hemolytic activity of fluorinated amphiphiles. Lower protein solubilization potency was observed for compound 6 (n=10, p=4),
Conclusions and perspectives
Highly fluorinated molecular materials, fluorocarbons and fluorinated amphiphiles, constitute new promising components of emulsions, vesicles and other colloidal systems. Fluorocarbons possess a unique combination of high biological inertness, gas solubility, low surface tension, and other valuable characteristics. Fluorocarbon-in-water emulsions constitute safe, and cost-effective vehicles for in vivo oxygen delivery. Phase III clinical trials conducted on such emulsions have shown that they
Acknowledgements
The author wishes to thank Prof. J.G. Riess (MRI Institute, University of California at San Diego) for his useful advice. She also gratefully acknowledges Alliance Pharmaceutical Corp. (San Diego, CA) and the Centre National de la Recherche Scientifique for financial support.
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