The unique solvent properties of fluorocarbons, such as perfluorooctyl bromide (PFOB), have established their use for oxygen delivery in ventilation therapy. The potential to extend fluorinated solvent application to drug delivery is limited by the solubility of typical hydrocarbon-based polar and nonpolar pharmaceuticals. This work examines the viability of a novel approach to the direct delivery of drugs in a fluorinated solvent through the use of fluorinated pro-drugs, or pharmaceutical agents modified with fluorinated moieties. The ability to interpret the cytotoxicity of the fluorinated prodrugs using their thermodynamic partitioning behavior is examined.

Nicotinic acid, a precursor of cofactors such as nicotinamide adenine dinucleotide (NAD), which has exhibited potential for a variety of medical applications such as for acute lung injury, was fluorinated to facilitate solubility in PFOB. Prodrugs were synthesized with fluorinated chains in the length from C₂F₃ – C₈F₁₅ and hydrocarbon chains in series CH₃ – C₆H₁₃. Partition coefficients relevant to the mechanisms of cellular uptake and incorporation of the prodrugs were determined: perfluoro (methylcyclohexane)-toluene partition coefficients, which are a standard measure of fluorophilicity and the PFOB-water partition coefficients. The fluorophilicity results indicate relatively constant partition coefficients for the lower chained fluorosurfactants, with similar results observed in the hydrocarbon nicotinates. However, a marked increase in the partitioning of higher chained fluorosurfactants into the fluorinated phase relative to the hydrocarbon phase was observed. These studies complement investigations of the cellular cytotoxicity and NAD levels of each pro-drug. Thermodynamic interpretations of the cellular uptake of fluorinated species suggests that the driving force changes as a function of the fluorinated chain length. Complementary investigations of the mechanism of prodrug incorporation in a cell, such as membrane fluidity experiments, will enable us to design prodrugs with sufficient solubility in the fluorinated phase, while maintaining their ability to transfer into the cellular matrix, and minimizing their cellular cytotoxicity.