title: Susceptibility of PTEN-positive metastatic tumors to small interfering RNA targeting the mammalian target of rapamycin.
abstract: PTEN-positive tumors are not susceptible to the treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR). Here, we determined the susceptibility of PTEN-positive cells to small interfering RNA for mTOR (si-mTOR) by using a novel liposomal delivery system. We prepared dicetyl phosphate-tetraethylenepentamine-based polycation liposomes (TEPA-PCL) decorated with polyethylene glycol (PEG) grafting Ala-Pro-Arg-Pro-Gly (APRPG), a VRGFR-1-targeting peptide. APRPG-PEG-decorated TEPA-PCL carrying si-mTOR (APRPG-TEPA-PCL/si-mTOR) had an antiproliferative effect against B16F10 murine melanoma cells (PTEN-positive) and significantly inhibited both the proliferation and tube formation of mouse 2H-11 endothelial-like cells (PTEN-positive). APRPG-TEPA-PCL/si-mTOR treatment did not induce Akt phosphorylation (Ser473) in either B16F10 or 2H-11 cells although there was strong phosphorylation of Akt in response to rapamycin treatment. Intravenous injection of APRPG-TEPA-PCL/si-mTOR significantly suppressed the tumor growth compared with rapamycin treatment in mice bearing B16F10 melanoma. These findings suggest that APRPG-TEPA-PCL/si-mTOR is useful for the treatment of PTEN-positive tumors.
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koide
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Yonenaga
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yokota
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.affiliation: Materials Science and Engineering, Nagoya Institute of Technology, Nagoya, Aichi, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Dewa
authors.affiliation: Materials Science and Engineering, Nagoya Institute of Technology, Nagoya, Aichi, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nango
authors.affiliation: Nippon Fine Chemical Co. Ltd., Takasago, Hyogo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Shizuoka, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000818:Animals; D049109:Cell Proliferation; D005029:Ethylenediamines / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D005029:Ethylenediamines; D008081:Liposomes; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; C094877:dioleoyl phosphatidylethanolamine; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C034269:tetraethylenepentamine
keywords: Angiogenesis; Mammalian target of rapamycin; PTEN; Polycation liposomes; Small interfering RNA