3-5-dipentadecyloxybenzamidine-hydrochloride and Disease-Models--Animal

TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids.. Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03).. TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

Topics: Angioplasty, Balloon; Animals; Anti-Inflammatory Agents; Atherosclerosis; Benzamidines; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical; Chemokines; Constriction, Pathologic; Disease Models, Animal; Fatty Acids; Feasibility Studies; Humans; Iliac Artery; Immunohistochemistry; Injections, Intravenous; Liposomes; Metals; Microscopy, Confocal; Muscle, Smooth, Vascular; Nanoparticles; Prednisolone; Prosthesis Design; Rabbits; Secondary Prevention; Stents; Time Factors

Topics: Angioplasty, Balloon; Animals; Anti-Inflammatory Agents; Atherosclerosis; Benzamidines; Cell Proliferation; Constriction, Pathologic; Disease Models, Animal; Fatty Acids; Humans; Iliac Artery; Injections, Intravenous; Liposomes; Metals; Muscle, Smooth, Vascular; Nanoparticles; Prednisolone; Prosthesis Design; Secondary Prevention; Stents

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