title: Advanced cancer therapy by integrative antitumor actions via systemic administration of miR-499.
abstract: Previously, we developed tetraethylenepentamine-based polycation liposomes (TEPA-PCL) as a vector for the delivery of small RNAs. In the present research, we attempted tumor-targeted delivery of miR-499 via systemic administration and evaluated the potency of this system as a therapeutic strategy to treat cancer. Lipoplexes were formed by mixing cholesterol-grafted miR-499 (miR-499-C) with TEPA-PCL. Firstly, human umbilical endothelial cells (HUVECs) and Colon 26 NL-17 mouse carcinoma cells were transfected with these lipoplexes in vitro. The results showed that miR-499 had antiangiogenic effects on the HUVECs and suppressed the secretion of vascular endothelial growth factor (VEGF) from the Colon 26 NL-17 cells. In addition, the growth of the latter cells was inhibited by transfection with miR-499-C/TEPA-PCL. For in vivo delivery of miR-499 to tumors via systemic injection, miR-499-C/TEPA-PCL were decorated with Ala-Pro-Arg-Pro-Gly (APRPG) peptide-conjugated polyethylene glycol (PEG) to prepare APRPG-PEG-modified lipoplexes carrying miR-499 (APRPG-miR-499). APRPG-miR-499 were injected into tumor-bearing mice via a tail vein, and these lipoplexes accumulated sufficiently in both angiogenic vessels and cancer cells. In addition, the expression of miR-499-target proteins and VEGF in the tumor cells was clearly suppressed by the treatment with APRPG-miR-499. Finally, the therapeutic effect of miR-499 on tumor growth was evaluated in mice. The tumor growth was significantly inhibited by the intravenous injection of APRPG-miR-499 at such a low dose as 0.5mg/kg. These results suggest that miR-499 delivered by the present system has excellent potency to treat cancer via integrative anticancer actions.
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; University of California Irvine, Irvine 92697, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koide
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Nippon Fine Chemical Co. Ltd., 5-1-1 Umei, Takasago, Hyogo 676-0074, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Nippon Fine Chemical Co. Ltd., 5-1-1 Umei, Takasago, Hyogo 676-0074, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Life and Materials Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Dewa
authors.affiliation: Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005029:Ethylenediamines / Q000737:chemistry*; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009842:Oligopeptides / Q000737:chemistry; D014018:Tissue Distribution; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D005029:Ethylenediamines; D008081:Liposomes; C548683:MIRN499 microRNA, human; D035683:MicroRNAs; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; C490869:alanyl-prolyl-arginyl-prolyl-glycine; C467480:vascular endothelial growth factor A, mouse; C034269:tetraethylenepentamine
keywords: Antiangiogenesis; Cancer therapy; Gene delivery; Liposomes; MicroRNA; miR-499