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Design and Evaluation of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugates as Antigen-Presenting Cell-Selective siRNA Carriers

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Abstract

To design and evaluate the potential use of thioalkylated mannose-modified dendrimer (generation 3; G3) conjugates with α-cyclodextrin (Man-S-α-CDE (G3)) as novel antigen-presenting cell (APC)-selective siRNA carriers, we investigated the RNAi effects of siRNA complexes with Man-S-α-CDEs (G3). Man-S-α-CDE (G3, average degree of substitution of mannose (DSM) 4)/siRNA complex had the potent RNAi effects in both NR8383 cells, a rat alveolar macrophage cell line, and JAWSII cells, a mouse dendritic cell line, through adequate physicochemical properties, mannose receptor (MR)-mediated cellular uptake, and efficient phagosomal escape of the siRNA complex. In addition, cytotoxic activities of the siRNA complexes with α-CDE (G3, DS2) and Man-S-α-CDE (G3, DSM4) were almost negligible up to a charge ratio of 100 (carrier/siRNA). Taken together, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential for a novel APC-selective siRNA carrier.

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Acknowledgments

This work was partially supported by Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (23590045).

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Authors and Affiliations

  1. Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan

    Keiichi Motoyama, Ryosuke Mitsuyasu, Chiho Akao, Takahiro Tanaka, Ayumu Ohyama, Nana Sato, Taishi Higashi & Hidetoshi Arima

  2. Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto, Japan

    Ayumu Ohyama & Hidetoshi Arima

Authors
  1. Keiichi Motoyama
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  2. Ryosuke Mitsuyasu
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  3. Chiho Akao
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  4. Takahiro Tanaka
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  5. Ayumu Ohyama
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  6. Nana Sato
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  7. Taishi Higashi
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  8. Hidetoshi Arima
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Corresponding author

Correspondence to Hidetoshi Arima.

Electronic supplementary material

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Supplementary Figure 1

FAB-MS (a) and 1H-NMR (b) spectra of 1-α-d-mannosyl-oxypropyl-thio-ethyl-carboxylic acid (PPTX 138 kb)

Supplementary Figure 2

1H-NMR spectra of Man-S-α-CDEs (G3) in D2O (PPTX 73.3 kb)

Supplementary Figure 3

Intracellular distribution of TRITC-Man-S-α-CDE (G3, DSM4) after transfection with siRNA complex in NR8383 cells. TRITC-Man-S-α-CDE (G3, DSM4)/siRNA complex was incubated for 1 h. The amount of siRNA was 10 μg. The charge ratio of carrier/siRNA was 50/1 (PPTX 1.65 MB )

Supplementary Figure 4

Effects of Man-S-α-CDE (G3, DSM4)/siRNA complex on expression of INF-β mRNA in NR8383 cells (PPTX 49.1 kb)

Supplementary Figure 5

Proposed scheme for APC-selective RNAi efficiency of Man-S-α-CDE (G3, DSM4)/siRNA complex (PPTX 107 kb)

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Motoyama, K., Mitsuyasu, R., Akao, C. et al. Design and Evaluation of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugates as Antigen-Presenting Cell-Selective siRNA Carriers. AAPS J 16, 1298–1308 (2014). https://doi.org/10.1208/s12248-014-9665-9

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  • DOI: https://doi.org/10.1208/s12248-014-9665-9

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