title: Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia.
abstract: OBJECTIVE
  Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model.
  
  
  RESULTS
  In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP.
  
  
  CONCLUSIONS
  NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagahama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Kaku
authors.initials: K
authors.lastname: Nakano
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D019344:Lactic Acid; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D053758:Nanoparticles; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation; D000077205:Pioglitazone; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D016220:Fibroblast Growth Factor 1; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D052250:Nitric Oxide Synthase Type III; D000077205:Pioglitazone