Activity Of Hexadecylphosphocholine Research Articles

Platelet-activating factor receptor contributes to antileishmanial function of miltefosine.

Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system-dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor-deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor-deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor-deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage-T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.

Hemolytic properties of miltefosine in liposomes of various lipid compositions

The hemolytic activity of hexadecylphosphocholine (HePC) included in liposomes of phosphatidylcholine (PC), phosphatidylethanol (PET), and their mixture in various ratios has been studied. Spectroscopic data suggest that supramolecular particles containing less than 15% HePC occur as liposomes. Hemolysis at the same HePC concentration is less pronounced for liposomes (10% HePC) than for micelles (30% HePC). The inclusion of anionic phosphatidylethanol into the liposomal composition does not affect significantly the degree of hemolysis.

Controlled plasmid gene transfer to murine renal carcinoma by hexadecylphosphocholine

We report here that the anticancer drug hexadecylphosphocholine (HPC) can control plasmid DNA-mediated gene transfer to renal carcinoma following intratumoral administration. Significant improvement of gene expression levels could be achieved depending on HPC dose administered. Optimal concentration of HPC co-injected with plasmid DNA was found to be 0.2% (w/v) showing up to a 10-fold increase in reporter gene expression levels when compared to DNA administered alone. In vivo gene transfer activity of HPC was not affected by the nature of the diluent used, i.e. glucose-based or saline-based isotonic solutions. Although in vitro transfection activity of HPC formulations could not be evidenced, a liposome leakage assay revealed that HPC could significantly destabilize stable lipid membranes suggesting that a possible membrane permeation enhancer activity of HPC combined to the physical stress induced by the intratumor injection may facilitate plasmid DNA entry inside the cells resulting in increased gene expression. HPC/plasmid formulations represent new and attractive non-viral gene delivery systems with potential in cancer gene therapy and vaccination.

The role of immunomodulation on anti-tumour activity of hexadecylphosphocholine

The role of immunomodulation on anti-tumour activity of hexadecylphosphocholine

In vitro and in vivo antitumoral activity of alkylphosphonates

Hexadecylphosphocholine is a new antitumour agent with a highly selective activity in chemically induced mammary tumours. It was suggested, that hexadecylphosphocholine is a pro-drug, cleavable by phospholipases C and/or D, creating hexadecanol or hexadecylphosphate as the active principle. To test this hypothesis, the antineoplastic activity of three alkylphosphonates, cleavable either by phospholipase C or D, are compared with those of the parent compound, hexadecylphosphocholine. Cell culture experiments, in which radiolabelled alkylphosphonates were incubated with a neoplastic cell line, showed no metabolism even after 3 days of incubation. In in vivo experiments with dimethylbenzanthracene-induced rat mammary carcinomas, all three alkylphosphonates showed antineoplastic activity, although none of them reached the high activity of hexadecylphosphocholine. These results indicate that the antitumoral activity of alkylphosphocholines and alkyl lysophosphatidylcholines is due to direct toxicity and not dependent on metabolism by phospholipases C or D or related enzymes.