title: Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection.
abstract: Small interfering ribonucleic acid (siRNA) cancer therapies administered by intravenous injection require a delivery system for transport from the bloodstream into the cytoplasm of diseased cells to perform the function of gene silencing. Here we describe nanosized polymeric micelles that deliver siRNA to solid tumors and elicit a therapeutic effect. Stable multifunctional micelle structures on the order of 45 nm in size formed by spontaneous self-assembly of block copolymers with siRNA. Block copolymers used for micelle formation were designed and synthesized to contain three main features: a siRNA binding segment containing thiols, a hydrophilic nonbinding segment, and a cell-surface binding peptide. Specifically, poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) comprising lysine amines modified with 2-iminothiolane (2IT) and the cyclo-Arg-Gly-Asp (cRGD) peptide on the PEG terminus was used. Modification of PEG-b-PLL with 2IT led to improved control of micelle formation and also increased stability in the blood compartment, while installation of the cRGD peptide improved biological activity. Incorporation of siRNA into stable micelle structures containing the cRGD peptide resulted in increased gene silencing ability, improved cell uptake, and broader subcellular distribution in vitro and also improved accumulation in both the tumor mass and tumor-associated blood vessels following intravenous injection into mice. Furthermore, stable and targeted micelles inhibited the growth of subcutaneous HeLa tumor models and demonstrated gene silencing in the tumor mass following treatment with antiangiogenic siRNAs. This new micellar nanomedicine could potentially expand the utility of siRNA-based therapies for cancer treatments that require intravenous injection.
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: R James
authors.initials: RJ
authors.lastname: Christie
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nomoto
authors.forename: Shigeto
authors.initials: S
authors.lastname: Fukushima
authors.forename: Kensuke
authors.initials: K
authors.lastname: Osada
authors.forename: Julien
authors.initials: J
authors.lastname: Halnaut
authors.forename: Frederico
authors.initials: F
authors.lastname: Pittella
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D008823:Micelles; D053769:Nanocapsules; D011108:Polymers; D034741:RNA, Small Interfering