Perfluorooctyl bromide (PFOB) has been clinically studied as a respiratory medium for liquid ventilation. This respiratory support technique employs PFOB as a vehicle for the transport of oxygen to the lung. PFOB is also envisioned as a pulmonary drug delivery vehicle that allows (a) direct delivery of a drug to the lung in high concentrations at the injured lung parenchyma, (b) equal distribution within the lung, and (c) limited systemic distribution (which reduces systemic toxicity). Unfortunately, typical drug molecules are insoluble in PFOB, which currently limits its usefulness as drug delivery vehicle. To overcome the solubility problem, we have synthesized a series of model prodrugs of nicotinic acids. These prodrugs show a high solubility in PFOB and are also water soluble, readily hydrolyzed in the presence of esterases and show little cytotoxicity. Our working hypothesis is that, because of these properties, prodrugs, for example prodrugs of nicotinic acid, can be successfully delivered to the lung where they will partition into the lung tissue, thus achieving higher tissue levels compared to conventional drug delivery approaches. The parent drug will be released by chemical or enzymatic degradation within the tissue. Herein we propose to (i) investigate and model the partition behavior of nicotinic acid prodrugs relevant to cellular uptake using a linear free energy relationship (LFER), (ii) study the transport of nicotinic acid prodrugs in a cell culture model of the perfluorocarbon (PFOB)-tissue interface, and (iii) evaluate the drug delivery system in vivo by investigating the uptake and distribution of C-14 labeled prodrugs after administration with PFOB in male rats. This proposal brings together a multidisciplinary research team of chemists, cell/molecular biologists and chemical engineers. Our approach of employing a linear free energy relationship (LFER) to assess the partition behavior at the PFOB tissue interface in combination with cell culture and animal studies will allow us to better understand and predict the parameters relevant for the release of drugs from a PFOB-based drug formulation. These findings will allow us to design (pro-)drugs suitable for pulmonary administration using PFOB as vehicle, thus providing a novel and superior method for the targeted administration of drugs to the injured sites of the lung.
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