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硫代烷基化甘露糖修饰的树枝状大分子（G3）/α-环糊精共轭物作为抗原呈递细胞选择性小干扰RNA载体的设计与评估

Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/α-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

作者信息

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

机构信息

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

出版信息

AAPS J. 2014 Nov;16(6):1298-308. doi: 10.1208/s12248-014-9665-9. Epub 2014 Sep 19.

DOI:10.1208/s12248-014-9665-9
PMID:25236864
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4389755/
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.

摘要

为了设计并评估硫代烷基化甘露糖修饰的树枝状聚合物（第3代；G3）与α-环糊精的缀合物（Man-S-α-CDE (G3)）作为新型抗原呈递细胞（APC）选择性siRNA载体的潜在用途，我们研究了siRNA与Man-S-α-CDEs (G3)形成的复合物的RNA干扰效应。Man-S-α-CDE (G3，甘露糖平均取代度（DSM）为4)/siRNA复合物在大鼠肺泡巨噬细胞系NR8383细胞和小鼠树突状细胞系JAWSII细胞中均具有强大的RNA干扰效应，这得益于其适当的物理化学性质、甘露糖受体（MR）介导的细胞摄取以及siRNA复合物从吞噬体的有效逃逸。此外，在电荷比高达100（载体/siRNA）时，α-CDE (G3, DS2)和Man-S-α-CDE (G3, DSM4)与siRNA形成的复合物的细胞毒性活性几乎可以忽略不计。综上所述，这些结果表明Man-S-α-CDE (G3, DSM4)有潜力成为一种新型的APC选择性siRNA载体。

相似文献

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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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[2]
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[3]
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本文引用的文献

[1]
A dual-functionally modified chitosan derivative for efficient liver-targeted gene delivery.

J Biomed Mater Res A. 2012-12-3

[2]
Potential use of lactosylated dendrimer (G3)/α-cyclodextrin conjugates as hepatocyte-specific siRNA carriers for the treatment of familial amyloidotic polyneuropathy.

Mol Pharm. 2012-4-30

[3]
Inhibitory effect of siRNA complexes with polyamidoamine dendrimer/α-cyclodextrin conjugate (generation 3, G3) on endogenous gene expression.

Eur J Pharm Sci. 2011-8-28

[4]
Synthesis and characterization of mannosylated pegylated polyethylenimine as a carrier for siRNA.

Int J Pharm. 2011-8-12

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Biomaterials. 2011-7-7

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J Control Release. 2010-9-17

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Biomaterials. 2010-6-11

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Bioorg Med Chem Lett. 2010-4-2

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J Control Release. 2010-3-10

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Silence. 2010-2-1

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