title: Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery.
abstract: siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA-lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6-14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti-tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Mariko
authors.initials: M
authors.lastname: Matsunaga
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nakamura
authors.forename: Naoto
authors.initials: N
authors.lastname: Moriyoshi
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000400:Air Sacs / Q000098:blood supply*; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002412:Cations; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002784:Cholesterol / Q000737:chemistry; D004983:Ethanolamines / Q000737:chemistry; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D008055:Lipids / Q000737:chemistry* / Q000633:toxicity; D008081:Liposomes; D008297:Male; D051379:Mice; D009226:Myristates / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D002412:Cations; D004983:Ethanolamines; D008055:Lipids; D008081:Liposomes; D009226:Myristates; C478049:O,O'-detetradecanoyl-N-(alpha-trimethylammonioacetyl)diethanolamine chloride; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine