title: Suppression of tumor growth by systemic delivery of anti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles.
abstract: Small interfering RNAs (siRNAs) have potential applications for many diseases, such as cancer, since siRNAs can specifically silence disease-associated genes. However, effective siRNA carriers need to be developed to overcome the low siRNA stability in vivo, to form stable complexes and to facilitate intracellular uptake. In this study, to develop a carrier for systemic siRNA delivery, we prepared methoxy poly(ethylene glycol) (MPEG)/polycaprolactone (PCL) diblock copolymers conjugated with a cell-penetrating peptide, Tat, via a disulfide linkage, and evaluated their ability as an siRNA carrier. The particle size of MPEG-PCL-SS-Tat/siRNA complexes was approximately 100-200 nm. The cellular uptake ability after transfection with FAM-siRNA with MPEG-PCL-SS-Tat was significantly higher than that with FAM-siRNA only. MPEG-PCL-SS-Tat did not induce substantial cytotoxicity. Intravenous injection of MPEG-PCL-SS-Tat/anti-vascular endothelial growth factor (VEGF) siRNA (siVEGF) complexes achieved a high anti-tumor effect in tumor-bearing mice. These results suggest that MPEG-PCL-SS-Tat is a potentially effective siRNA carrier for silencing genes in vitro and in vivo.
authors.affiliation: Laboratory of Pharmaceutics and Drug Delivery, Department of Pharmaceutical Science, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. kanazawa@toyaku.ac.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Ken
authors.initials: K
authors.lastname: Sugawara
authors.forename: Ko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Shogo
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takashima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D015696:Gene Products, tat / Q000737:chemistry*; D020868:Gene Silencing; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008823:Micelles; D053758:Nanoparticles; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D012510:Sarcoma 180 / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; D008823:Micelles; D011091:Polyesters; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D011092:Polyethylene Glycols