Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Oda
Shinichiro
S
Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nagahama
Ryoji
R
Nakano
Kaku
K
Matoba
Tetsuya
T
Kubo
Mitsuki
M
Sunagawa
Kenji
K
Tominaga
Ryuji
R
Egashira
Kensuke
K
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003097:Collateral Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004558:Electric Stimulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005240:Feasibility Studies; D019417:Hindlimb Suspension; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000378:metabolism; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply*; D053758:Nanoparticles; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism; D010793:Phthalazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage* / Q000378:metabolism; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011804:Quinolines; C404768:vatalanib; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; C108475:pitavastatin; D010100:Oxygen