Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier

Hidetoshi Arima, Ayumi Yoshimatsu, Haruna Ikeda, Ayumu Ohyama, Keiichi Motoyama, Taishi Higashi, Akira Tsuchiya, Takuro Niidome, Yoshiki Katayama, Kenjiro Hattori, Tomoko Takeuchi

研究成果: ジャーナルへの寄稿記事

66 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)2591-2604
ページ数14
ジャーナルMolecular pharmaceutics
9
発行部数9
DOI
出版物ステータス出版済み - 9 4 2012

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Dendrimers
Cyclodextrins
Folic Acid
Small Interfering RNA
Neoplasms
KB Cells
Intravenous Injections
Fluorescein-5-isothiocyanate
RNA Interference
Endocytosis

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

これを引用

Arima, H., Yoshimatsu, A., Ikeda, H., Ohyama, A., Motoyama, K., Higashi, T., ... Takeuchi, T. (2012). Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier. Molecular pharmaceutics, 9(9), 2591-2604. https://doi.org/10.1021/mp300188f

Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier. / Arima, Hidetoshi; Yoshimatsu, Ayumi; Ikeda, Haruna; Ohyama, Ayumu; Motoyama, Keiichi; Higashi, Taishi; Tsuchiya, Akira; Niidome, Takuro; Katayama, Yoshiki; Hattori, Kenjiro; Takeuchi, Tomoko.

:: Molecular pharmaceutics, 巻 9, 番号 9, 04.09.2012, p. 2591-2604.

研究成果: ジャーナルへの寄稿記事

Arima, H, Yoshimatsu, A, Ikeda, H, Ohyama, A, Motoyama, K, Higashi, T, Tsuchiya, A, Niidome, T, Katayama, Y, Hattori, K & Takeuchi, T 2012, 'Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier', Molecular pharmaceutics, 巻. 9, 番号 9, pp. 2591-2604. https://doi.org/10.1021/mp300188f
Arima, Hidetoshi ; Yoshimatsu, Ayumi ; Ikeda, Haruna ; Ohyama, Ayumu ; Motoyama, Keiichi ; Higashi, Taishi ; Tsuchiya, Akira ; Niidome, Takuro ; Katayama, Yoshiki ; Hattori, Kenjiro ; Takeuchi, Tomoko. / Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier. :: Molecular pharmaceutics. 2012 ; 巻 9, 番号 9. pp. 2591-2604.
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T1 - Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier

AU - Arima, Hidetoshi

AU - Yoshimatsu, Ayumi

AU - Ikeda, Haruna

AU - Ohyama, Ayumu

AU - Motoyama, Keiichi

AU - Higashi, Taishi

AU - Tsuchiya, Akira

AU - Niidome, Takuro

AU - Katayama, Yoshiki

AU - Hattori, Kenjiro

AU - Takeuchi, Tomoko

PY - 2012/9/4

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N2 - 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.

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