Fluorocarbons and fluorinated amphiphiles in drug delivery and biomedical research

https://doi.org/10.1016/S0169-409X(01)00107-7Get rights and content

Abstract

The specific properties of fluorocarbons, exceptional chemical and biological inertness, high gas-dissolving capacity, low surface tension, excellent spreading characteristics and high fluidity, have triggered numerous applications of these compounds in oxygen delivery. An injectable emulsion of fluorocarbon-in-water destined to deliver oxygen to tissues at risk of hypoxia has now completed Phase III clinical trials in Europe. A neat fluorocarbon is currently investigated in Phase II for treatment of acute respiratory failure by liquid ventilation. Fluorinated lipids and fluorinated surfactants can be used to elaborate and stabilize various colloidal systems, including different types of emulsions, vesicles and tubules, that also show promise for controlled release drug delivery.

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.

References (170)

  • M El Ghoul et al.

    Non-ionic surfactants derived from lactose: the N-(2-(F-alkyl)ethyl)-lactosamines and -lactobionamides

    J. Fluorine Chem.

    (1992)
  • J.G Riess et al.

    Carbohydrate- and related polyol-derived fluorosurfactants – an update

    Carbohydr. Res.

    (2000)
  • I Rico-Lattes et al.

    Synthesis of new sugar-based surfactants having biological applications: key role of their self-association

    Colloids Surf.

    (1997)
  • R Hirschl et al.

    Liquid ventilation in adults, children, and full-term neonates

    Lancet

    (1995)
  • K.M Kent et al.

    Reduction of myocardial ischemia during percutaneous transluminal coronary angioplasty with oxygenated Fluosol

    Am. J. Cardiol.

    (1990)
  • A Robert et al.

    Solubilization of water in binary mixtures of fluorocarbons and nonionic fluorinated surfactants: existence of domains of reverse microemulsions

    J. Colloid Interf. Sci.

    (1984)
  • A Chittofrati et al.

    Perfluoropolyether microemulsions: conductivity behavior of three-component W/O systems

    Colloids Surf.

    (1992)
  • K.-V Schubert et al.

    Microemulsifying fluorinated oils with mixtures of fluorinated and hydrogenated surfactants

    Colloids Surf.

    (1994)
  • W.L Holman et al.

    Tissue oxygenation with graded dissolved oxygen delivery during cardiopulmonary bypass

    J. Thorac. Cardiovasc. Surg.

    (1995)
  • J.G Riess et al.

    Update on perfluorocarbon-based oxygen delivery systems

  • J.G Riess

    Fluorocarbon-based oxygen delivery: basic principles and product development

  • K.K Tremper et al.

    Blood use and non-blood use: designing blood substitutes

  • E Kissa

    Fluorinated surfactants, synthesis, properties, applications

  • A Bondi

    Van der Waals volumes and radii

    J. Phys. Chem.

    (1964)
  • G.J.T Tiddy

    Concentrated surfactant systems

  • M.J Rosen

    Surfactants and Interfacial Phenomena

    (1978)
  • C Tanford

    The Hydrophobic Effect: Formation of Micelles and Biological Membranes

    (1980)
  • H Hoffmann et al.

    Small angle neutron scattering measurements on micellar solutions of perfluor detergents

    Colloid Polym. Sci.

    (1983)
  • D.F Eaton et al.

    Are fluorocarbon chains ‘stiffer’ than hydrocarbon chains? Dynamics of end-to-end cyclization in a C8F16 segment monitored by fluorescence

    J. Am. Chem. Soc.

    (1990)
  • D.W.R Gruen

    A model for the chains in amphiphilic aggregates. 2. Thermodynamic and experimental comparisons for aggregates of different shape and size

    J. Phys. Chem.

    (1985)
  • P.J Flory

    Statistical Mechanics of Chain Molecules

    (1969)
  • H.A Rigby et al.

    A room-temperature transition in polytetrafluoroethylene

    Nature

    (1949)
  • G.T Furukawa et al.

    Calorimetric properties of polytetrafluoroethylene (Teflon)

    J. Res. Natl. Bureau Stand.

    (1952)
  • B.E Smart

    Fluorocarbons

  • J.G Riess

    Perfluorochemical emulsions for intravascular use: principles, materials and methods

  • T.M Reed

    Physical chemistry of fluorocarbons

  • J.G Riess

    Fluorocarbon emulsions – designing an efficient shuttle service for the respiratory gases – the so-called ‘blood substitutes’

  • J.G Riess et al.

    Fluorocarbons and fluorosurfactants for in vivo oxygen transport (blood substitutes), imaging and drug delivery

    Mat. Res. Soc. Bull.

    (1999)
  • P Mukerjee et al.

    Adsorption of fluorocarbon and hydrocarbon surfactants to air–water, hexane–water, and perfluorohexane–water interfaces. Relative affinities and fluorocarbon–hydrocarbon nonideality effects

    J. Phys. Chem.

    (1981)
  • J Schneider et al.

    Structural studies of polymers with hydrophilic spacer groups. II. Infrared spectroscopy of Langmuir–Blodgett multilayers of polymers with fluorocarbon side chains at ambient and elevated temperatures

    Macromolecules

    (1989)
  • K Shinoda et al.

    The physiochemical properties of aqueous solutions of fluorinated surfactants

    J. Phys. Chem.

    (1972)
  • J.C Ravey et al.

    Comparative study of fluorinated and hydrogenated nonionic surfactants. I. Surface activity properties and critical concentrations

    Prog. Colloid. Polym. Sci.

    (1988)
  • V.M Sadtler et al.

    Micellization and adsorption of fluorinated amphiphiles: Questioning the 1 CF2∼1.5 CH2 rule

    Chem. Eur. J.

    (1998)
  • B.M Fung et al.

    Unusual micellar properties of a new class of fluorinated nonionic surfactants

    J. Phys. Chem.

    (1988)
  • W Guo et al.

    Micelles and aggregates of fluorinated surfactants

    J. Phys. Chem.

    (1991)
  • M.P Turberg et al.

    Semifluorinated hydrocarbons: primitive surfactant molecules

    J. Am. Chem. Soc.

    (1988)
  • N.S Faithfull

    The role of perfluorochemicals in surgery and the ITU

  • J.G Riess

    Fluorocarbon-based in vivo oxygen transport and delivery systems

    Vox Sang.

    (1991)
  • M.P Krafft et al.

    The design and engineering of oxygen-delivering fluorocarbon emulsions

  • J.G Riess

    Reassessment of criteria for the selection of perfluorochemicals for second-generation blood substitutes: Analysis of structure/property relationships

    Artif. Organs

    (1984)
  • Cited by (501)

    • Supramolecular gels from bolaamphiphilic molecules

      2024, Journal of Molecular Liquids
    View all citing articles on Scopus
    View full text