The Design and Development of Improved Fluorocarbon-Based Products for use in Medicine and Biology

Abstract

Fluorocarbons and other highly fluorinated materials offer considerable potential in diagnosis and therapeutics due to their unique physical properties, chemical inertness, capacity to transport oxygen and drugs, and ability to function as contrast agents. Applications such as hemodilution and organ preservation, cancer diagnosis and chemotherapy, x-ray imaging of the lymph nodes and magnetic resonance imaging of the GI tract, cardioplegia and reperfusion, the treatment of myocardial ischemia and respiratory distress syndrome, as well as drug delivery, all obviously require different product characteristics, calling for an array of products which may range from different neat fluorocarbons to diversely formulated emulsions, or fluorinated vesicles. Substantial progress has been made in terms of emulsion efficacy and stability. Stable, ready-to-use, concentrated, though fluid, injectable emulsions have now been developed. Small doses of such emulsions were demonstrated to be highly efficient in tissue oxygenation. Commercial-scale manufacturing including heat sterilization of these emulsions have been achieved. Some of the side-effects, which generally relate to the normal response of the organism to injected particles, have been reduced, and their mechanism determined. Further efforts will undoubtedly be devoted to understanding and adjusting emulsion properties for optimal efficacy in each identified application and to maximizing benefit vs side-effect ratio. Our ability to modulate in vivo recognition, intravascular persistence and subsequent biodistribution of fluorocarbon droplets, vesicles and other particulate matter in the organism is still in its infancy. Proper control of these characteristics would further extend the potential of such products for medical uses. It is essential that no effort be spared to increase our general understanding of their physicochemical properties and in vivo "physiology".

Artifical Blood

“…These effects were attributed to the normal clearance of PFCs by the reticuloendothelial system. Opsonisation and phagocytosis of PFC droplets leads to activation of macrophages and release of prostaglandins and cytokines by the archidonic acid pathway [15,19]. Chronic or delayed side effects were characterised by inhibition of platelet aggregation with 90% weight/volume PFOB emulsion, and transient thrombocytopaenia (not below 80,000/μl).…”

Future generations of red blood cell substitutes

“…Improved conjugated haemoglobins in phase II clinical trials have been reported recently [21,22]. Still another type of oxygen carrier in phase III clinical trial is based on perfluorochemicals [23,24]. These oxygen carriers are an intermediate step between volume replacement and red blood cells.…”

Oxygen Carriers in Cardiac Surgery

“…The properties and stability of these emulsions depend on the nature and the relative proportions of the components of the emulsion, the sizes and the electric charges of the particles, the surface area available for gas exchange, the viscosity, and the intravascular half-life. 4,31,32 The mechanisms of oxygen transport and delivery by PFCs are entirely different from those of the erythrocytes (Figure 2). The oxyhemoglobin saturation curve for erythrocytes is sigmoid: a fall in oxygen partial pressure from 100 mm Hg (± 100% hemoglobin saturation ; ± 20 mL oxygen) to 35-40 mm Hg (± 75% saturation) leads to unloading of ± 25% (5 mL oxygen) of the bound oxygen.…”

“…Oxygent™ dissolves 28 mL oxygen/ 100 g at 37°C and 750 mm Hg, with a circulating half-life above nine hours for doses around 1.8 g perflubron/kg. 4,32,34 …”

“…5,6,9,32,65,66 Fluosol-DA ® has been safely administered to treat severe anemia in 401 patients in Japan, 67 with a positive but limited effect on oxygen delivery, an unsatisfactory stability and biological side effects (such as a complement activation) attributed to the surfactant. 68 In 1989, the use of Fluosol-DA ® was approved by the FDA for percutaneous transluminal coronary angioplasty (PTCA), but remained discussed; 69 the progress in PCTA technology, by avoiding ischemia, suppressed the interest for the use of Fluosol-DA ® .…”