Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine

Abstract

The interaction of four long-chain nicotinates, compounds that are of interest as potential chemopreventive agents, with dipalmitoylphosphatidylcholine (DPPC) was investigated in monolayers at the air-water interface and in fully hydrated bilayers. For the monolayer studies, the compression isotherms of mixtures of the respective nicotinate with DPPC were recorded at various compositions on a hydrochloric acid subphase (pH 1.9-2.1, 37 ؎ 2 ؇ C). The headgroup of the nicotinates (24-29 Å 2 /molecule) is larger than that of the hydrophobic tail (20 Å 2 /molecule). The pure nicotinates exhibit a temperature-and chain lengthdependent transition from an expanded to a condensed phase. Analysis of the concentration dependence of the average molecular area at constant film pressure and the concentration dependence of the breakpoint of the phase transition from the expanded to the condensed state suggests that all four DPPC-nicotinate mixtures are partially miscible at the air-water interface. Although a complex phase behavior with several phase transitions was observed, differential scanning calorimetry studies of the four mixtures are also indicative of the partial miscibility of DPPC and the respective nicotinate.Overall, the complex phase behavior most likely results from the head-tail mismatch of the nicotinates and the geometric packing constraints in the twocomponent lipid bilayer. Nicotinic acid and its alkyl esters are of considerable biological and pharmacological importance. Besides being the precursor of cofactors to many vital enzymes, nicotinic acid is a drug possessing vasodilating and fibrinolytic properties. Nicotinic acid itself has been proven beneficial against bleomycin-and cyclophosphamide-induced lung injury in animal models (1-5). Dietary supplements of nicotinic acid and dermatologic formulations of its longchain esters are under investigation for the prevention and treatment of skin carcinogenesis (6). Therefore, nicotinic acid esters may be useful as a chemopreventive agent for the prevention of lung cancer.Currently, there is significant interest in the pulmonary administration of several chemopreventive agents, such as steroids and retinoids, directly to the lung because of reduced systemic toxicity (7-11). This route of administration may also be advantageous for the administration of nicotinic acid esters, by using either an aerosol or a perfluorocarbon vehicle (12, 13). Although the interaction of various chemopreventive agents, especially retinoids, with phospholipids has been investigated (14, 15), there is no current knowledge about the factors that determine the interaction (i.e., phase behavior) of nicotinates with biological lipids such as the phospholipids present in pulmonary surfactant. A better understanding of these interactions, however, is a prerequisite for the rational design of nicotinates for pulmonary administration, especially using a perfluorocarbon-based drug delivery system (12, 13). The aim of this study is to understand which molecular characteristics influe...

Interaction of a partially fluorinated long-chain nicotinate with dipalmitoylphosphatidylcholine

“…Calculated amounts of DPPC and nicotinate were dissolved in chloroform-methanol (3:1, v/v) at the appropriate mole fractions (16,17,26,27). The solvent was removed under a stream of nitrogen, and the mixtures were further dried under vacuum for at least 3 h. The samples (either mixtures of phospholipids and nicotinate or pure phospholipid) were hydrated in an excess of water (three times by weight).…”

“…The starting material for its synthesis, 11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluorohexadecan-1-ol, was synthesized using the methodology described previously (23). F-NA18 and its hydrocarbon analog, NA18, were synthesized from nicotinic acid and the corresponding alcohol according to literature procedures (8,16,24). In short, 1.1 equivalent of nicotinic acid was reacted with 1.0 equivalent of the corresponding alcohol in anhydrous dichloromethane using dicyclohexylcarbodiimide as a coupling reagent and dimethylaminopyridine as a catalyst.…”

“…All experiments were carried out in triplicate. Onset, maximum, and offset temperatures, as well as peak width of the pretransition and the main phase transition, were determined for the second run using Universal Analysis NT software (16,17,22,23,26).…”

“…This method allows the investigation of lipid mixtures and their miscibility at the air-water interface. DSC, on the other hand, is a straightforward tool to investigate the effect of the incorporation of organic compounds (e.g., nicotinates) into organic bilayers (16,17). This technique allows the study of the effect of an interacting solute compound on the main lipid phase transition in a fully hydrated phospholipid bilayer membrane (20,21).…”

“…Studies of the phase behavior of long-chain nicotinates have shown partial miscibility with dipalmitoylphosphatidylcholine (DPPC) (16). Most notably, longer chain nicotinates, such as heptadecyl and octadecyl nicotinates, display a highly complex phase behavior with DPPC, which can be attributed to the headtail mismatch that results from the larger cross-sectional area of the nicotinic acid head group [ ‫ف‬ 26 square angstroms (Å 2 )/molecule] versus the hydrophobic tail ( ‫ف‬ 20 Å 2 /molecule).…”