3-5-dipentadecyloxybenzamidine-hydrochloride and Glomerulonephritis

Newly designed polyethylene glycol (PEG)-modified cationic liposomes, containing a novel cationic lipid TRX-20 (3,5-dipentadecyloxybenzamidine hydrochloride), bind specifically to cultured human mesangial cells, and not to endothelial cells. In this study, we investigated targeting the delivery of PEG-modified liposomes containing TRX-20 (TRX-liposomes) to mesangial cells and evaluated their pharmacokinetic behavior in a rat experimental glomerulonephritis model, using prednisolone phosphate (PSLP) as a model drug.. TRX-liposomes were injected intravenously into experimental glomerulonephritic rats and normal rats to compare its pharmacokinetic behavior with that of non-cationic liposomes (PEG-liposomes). Rhodamine-labeled liposomes were used to evaluate the accumulation in inflamed kidneys. Pharmacological effects of three formulations of PSLP (i.e., a single injection of two liposomal formulations and daily injections of PSLP in saline solution) were estimated in terms of suppressing glomerular cell proliferation in the rat nephritis model.. TRX-liposomes markedly accumulated in the glomeruli of inflamed kidneys, but did not accumulate in the glomeruli of normal kidneys. Although the PEG-liposomes also accumulated in the glomeruli of the inflamed kidneys, their pharmacological behavior was quite different from that of the TRX-liposomes, which were internalized by the target cells. In a comparison among the three formulations of PSLP, the dose of TRX-liposomes required for significant suppression of glomerular cell proliferation was much less (dose of 0.032 mg/kg and above) than that required for the same effect by the PSLP saline solution (3.2 mg/kg daily; 12.8 mg/kg total) and PEG-liposomes (0.32 mg/kg). Interestingly, significant suppression of mesangial cell activation, as assessed by the expression of alpha-smooth muscle actin, was observed in nephritic rats treated with TRX-liposomes, but not in the other two treatment groups.. The pharmaceutical properties of TRX-liposomes due to their preferential binding to mesangial cells and long circulation time make this a likely candidate system for targeted drug delivery to the inflamed glomeruli of glomerulonephritis.

Topics: Animals; Benzamidines; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Drug Delivery Systems; Drug Evaluation, Preclinical; Fatty Acids; Glomerulonephritis; Injections, Intravenous; Liposomes; Male; Mesangial Cells; Microscopy, Fluorescence; Molecular Structure; Prednisolone; Rats; Rats, Sprague-Dawley; Tissue Distribution