Fluorocarbonhydrocarbon diblockstabilized emulsions

F-octye bromide still appears to stand out as the best candidate PFC for in vivo O2 delivery. Further stability with respect to Oxygent was gained by supplementing standard phospho-lipids with mixed fluorocarbon-hydrocarbon diblock compounds, e.g. C6F13C10H21 (F6H10, 14; Figure 24.12). An involvement of the diblock molecules at the water/PFC interface, rather than only a slowing down of molecular diffusion due to lowered water solubility of the PFC phase, has been demonstrated. Evidence for such involvement includes a dramatic decrease in PFC/water interfacial tension (typically from about 24 to


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■ 1 1


Time (months)

Time (months)

Figure 24.12 Fluorocarbon-hydrocarbon diblock molecules can stabilize fluorocarbon emulsions very effectively. Stabilization with diblock C6F13C10H21 (F6H10) is more effective than with a heavy PFC of similar molecular weight, C16F34, which only reduces the solubility of the dispersed PFC phase but not the interfacial tension (from Krafft et al., 2004). Note the preservation of very small particle sizes over time when the diblock is used.

2 mN/m) between PFOB and aqueous phospholipid solutions when a diblock was added to the PFC phase; the observation that the emulsion stabilization effect of a given diblock depends on the length of the lipid's fatty acid chains; and the fact that, when the fit between lipid and diblock alkyl chain length is inadequate, a droplet coalescence mechanism sets in that actually leads to emulsion destabilization. By contrast, the stabilization effect of a heavier PFC that only reduces the solubility of the PFC phase in the aqueous phase was independent of the phos-pholipid chain length (Marie Bertilla et al., 2004). Because they are substantially lipophilic, FnHm diblocks are excreted rather rapidly. No overt toxicity was seen at doses that are about two orders of magnitude larger then that required for emulsion stabilization (Riess et al., 1994). Improved tissue oxygenation was demonstrated using an F6H10-stabilized F-octyl bromide emulsion in a rabbit model of resuscitation from acute hemorrhagic shock (Audonnet-Blaise et al., 2004). No perturbation of the hemodynamic or rheological parameters was induced, even at very large doses. Successful long-term nor-mothermic preservation of the intestine and of organ blocks has been obtained (DeRoover et al., 2001).

Phase-shift emulsions

A so-called 'phase-shift' emulsion of F-pentane 11 (boiling point 29°C) that turns into gaseous microbubbles at body temperature and was initially intended as a contrast agent for ultrasound imaging is now being investigated for O2-delivery (Lundgren et al., 2004).The fast permeating gases inside the bubble, i.e., O2 and CO2, equilibrate rapidly with the gases dissolved in the plasma and surrounding tissues, allowing O2 to be carried from the lungs to the tissues. The role of the PFC (a slowly permeating gas) is here no longer to dissolve O2, but to stabilize O2 microbubbles osmotically in vivo (Figure 24.13; van Liew and Burkard, 1997; Schutt et al., 2003).

Experimental proof of concept includes survival of normovolemic erythrocyte-depleted rats and pigs, and of pigs with potentially lethal hemorrhagic shock and with severe right-to-left shunt (Lundgren et al., 2004). Administration of the F-pentane emulsion, along with carbogen breathing, led to suppression of resistance to radiation of hypoxic cells in a rat tumor model (Koch et al., 2002).

However, withdrawal of a new drug application in the United States for use of this product as an ultrasound contrast agent may indicate that safety was not established. The mechanism for prolonged O2 delivery (at least 2 hours) also remains unclear in view of the short intravascular life of F-pentane. Indeed, diagnostic-size doses of F-pen-tane, administered in the form of an 'activated' (gas) emulsion for ultrasound imaging, were determined to have an elimination half-life of only around 2 minutes; F-pentane recovery in the expired air was almost complete after 2 hours (Correas et al., 2001). There is little doubt that stabilized O2 microbubbles can contribute to tissue oxygenation. However, emulsion formulation and stability, and in vivo bubble size control, warrant further research.

Further applications of PFC-stabilized micro-bubbles (gas emulsions) are being investigated for treatment of vascular thrombosis and site-specific drug and gene delivery (Riess, 2004; Unger et al., 2004).

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