Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

Abstract

This study explores perfluorooctyl bromide (PFOB) as a potential vehicle for the pulmonary delivery of a series of prodrugs of nicotinic acid using cell culture studies. The prodrugs investigated have PFOB-water (log K p = 0.78 to > 2.2), perfluoromethylcyclohexane-toluene (log K p = −2.62 to 0.13) and octanol-water (log K p = 0.90 to 10.2) partition coefficients spanning several orders of magnitude. In confluent NCI-358 human lung cancer cells, the toxicity of prodrugs administered in culture medium or PFOB depends on the medium of administration, with EC20's above 8 mM and 2.5 mM for culture medium and PFOB, respectively. Short-chain nicotinates administered both in PFOB and medium increase cellular NAD/NADP levels at 1 mM nicotinate concentrations. Long-chain nicotinates, which could not be administered in medium due to their poor aqueous solubility, increased NAD/NADP levels if administered in PFOB at concentrations ≥ 10 mM. These findings suggest that even highly lipophilic prodrugs can partition out of the PFOB phase into cells, where nicotinic acid is released and converted to NAD. Thus, PFOB may be a novel and biocompatible vehicle for the delivery of lipophilic prodrugs of nicotinic acid and other drugs directly to the lung of laboratory animals and humans.

Synthesis and Evaluation of Water‐Soluble Fluorinated Dendritic Block‐Copolymer Nanoparticles as a 19F‐MRI Contrast Agent

“…They showed two resonance peaks at -124 and -138 ppm attributed to -CH 2 CF 2 and -CF 2 CF 2 H, respectively. [6,21] This chemical shift was unchanged even after the block polymerization of CMB, indicating that PTFPMA does not interact with PCMB. The signal intensity observed in MRI depends largely on the longitudinal relaxation rate, 1/T 1 , and the transverse rate, 1/T 2 , and tends to increase with the increase in 1/T 1 and the decrease in 1/T 2 .…”

Highly fluorinated amphiphilic molecules and self-assemblies with biomedical potential

“…Nicotinic acid ester prodrugs fitted with F-alkyl chains have been synthesized and their cytotoxicity evaluated [26]. These F-amphiphiles may serve for pulmonary drug delivery using F-octyl bromide as a vehicle.…”

Semi-fluorinated alkanes as carriers for drug targeting in acute respiratory failure

“…This lack of effectiveness is probably caused by a different partitioning of α-tocopherol out of the SFA phase into blood. As proposed by Lehmler and coworkers [20], the octanol-water partition coefficient (logK OW ) may be used to explain the uptake of drugs administered to the lung using perfluorocarbons or, as in the present study, SFAs. Thus, the drastic difference in the logK OW most likely explains why ibuprofen (logK OW = 3.7) but not tocopherol (logK OW = 11.9) could be delivered successfully using SFA-PLV.…”

“…Some previously performed trials have evaluated perfluorocarbons for intrapulmonary drug delivery of antibiotics [21][22][23][24][25], anesthetics [26], vasoactive substances [27][28][29], for the installation of several prodrugs [20], gene transfer [30], and antioxidant enzymes [31]. In most of these studies effectiveness of intrapulmonary drug delivery is limited due to a low drug solubility, thereby causing inhomogeneous distribution of the agent in the lungs.…”