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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:796.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium

Mitsuki Kubo; Kensuke Egashira; Takahiro Inoue; Jun-ichiro Koga; Shinichiro Oda; Ling Chen; Kaku Nakano; Tetsuya Matoba; Yoshiaki Kawashima; Kaori Hara; Hiroyuki Tsujimoto; Katsuo Sueishi; Ryuji Tominaga; Kenji Sunagawa

From the Department of Cardiovascular Medicine (M.K., K.E., T.I., J.K., L.C., K.N., T.K., K. Sunagawa), Surgery (S.O., R.T.), and Pathology (K. Sueishi), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the School of Pharmaceutical Science (Y.K.), Aichi Gakuin University, Aichi, Japan; and Hosokawa Powder Technology Research Institute (K.H., H.T.), Osaka, Japan.

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

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.

Methods and 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.

We tested the hypothesis that selective nanoparticle (NP)-mediated delivery of pitavastatin to endothelial cells can be an integrative approach to enhance therapeutic neovascularization. We used a murine model of hindlimb ischemia and showed that polymeric NP-mediated delivery of pitavastatin is useful for increasing therapeutic neovascularization.

Key Words: nanotechnology • drug delivery system • statin • therapeutic neovascularization