pitavastatin and vatalanib

We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals.. Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle.. Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects.. The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cells, Cultured; Chronic Disease; Collateral Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Electric Stimulation; Endothelial Cells; Feasibility Studies; Hindlimb Suspension; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Injections, Intramuscular; Ischemia; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Nanoparticles; Neovascularization, Physiologic; Oxygen; Phthalazines; Protein Kinase Inhibitors; Pyridines; Quinolines; Rabbits; Regional Blood Flow; Time Factors; Vascular Endothelial Growth Factor Receptor-1