Therapeutic neovascularization by nanotechnology-mediated cell-selective delivery of pitavastatin into the vascular endothelium.
OBJECTIVE
Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.


RESULTS
In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.


CONCLUSIONS
NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.
Kubo
Mitsuki
M
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Egashira
Kensuke
K
Inoue
Takahiro
T
Koga
Jun-ichiro
J
Oda
Shinichiro
S
Chen
Ling
L
Nakano
Kaku
K
Matoba
Tetsuya
T
Kawashima
Yoshiaki
Y
Hara
Kaori
K
Tsujimoto
Hiroyuki
H
Sueishi
Katsuo
K
Tominaga
Ryuji
R
Sunagawa
Kenji
K