title: Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier.
abstract: We previously reported that of the various polyamidoamine (PAMAM) STARBURST dendrimer (generation 3, G3) (dendrimer) conjugates with cyclodextrins (CyDs), the dendrimer (G3) conjugate with α-CyD having an average degree of substitution of 2.4 (α-CDE (G3)) has the greatest potential for a novel carrier for siRNA in vitro and in vivo. To improve the siRNA transfer activity and the lack of target specificity of α-CDE (G3), we prepared folate-polyethylene glycol (PEG)-appended α-CDEs (G3) (Fol-PαCs) with various degrees of substitution of folate (DSF) and evaluated their siRNA transfer activity to folate receptor (FR)-overexpressing cancer cells in vitro and in vivo. Of the three Fol-PαCs (G3, DSF 2, 4 and 7), Fol-PαC (G3, DSF 4) had the highest siRNA transfer activity in KB cells (FR-positive). Fol-PαC (G3, DSF 4) was endocytosed into KB cells through FR. No cytotoxicity of the siRNA complex with Fol-PαC (G3, DSF 4) was observed in KB cells (FR-positive) or A549 cells (FR-negative) up to the charge ratio of 100/1 (carrier/siRNA). In addition, the siRNA complex with Fol-PαC (G3, DSF 4) showed neither interferon response nor inflammatory response. Importantly, the siRNA complex with Fol-PαC (G3, DSF 4) tended to show the in vivo RNAi effects after intratumoral injection and intravenous injection in tumor cells-bearing mice. The FITC-labeled siRNA and TRITC-labeled Fol-PαC (G3, DSF 4) were actually accumulated in tumor tissues after intravenous injection in the mice. In conclusion, the present results suggest that Fol-PαC (G3, DSF 4) could potentially be used as a FR-overexpressing cancer cell-selective siRNA delivery carrier in vitro and in vivo.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. arimah@gpo.kumamoto-u.ac.jp
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshimatsu
authors.forename: Haruna
authors.initials: H
authors.lastname: Ikeda
authors.forename: Ayumu
authors.initials: A
authors.lastname: Ohyama
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuchiya
authors.forename: Takuro
authors.initials: T
authors.lastname: Niidome
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Katayama
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Hattori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry*; D005492:Folic Acid / Q000008:administration & dosage / Q000737:chemistry*; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D007624:KB Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D047391:alpha-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D034741:RNA, Small Interfering; D047391:alpha-Cyclodextrins; D011092:Polyethylene Glycols; D007372:Interferons; D005492:Folic Acid; C032613:alpha-cyclodextrin