Synthesis of pH-sensitive Nanogels and Their Application in siRNA Delivery

Ying Zhang; Liang Liu; Ting-hong Wang; Hua-yu Tian; Xue-si Chen

doi:10.11777/j.issn1000-3304.2017.17024

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Synthesis of pH-sensitive Nanogels and Their Application in siRNA Delivery

Research Article | 更新时间：2021-01-26

- Synthesis of pH-sensitive Nanogels and Their Application in siRNA Delivery
- Acta Polymerica Sinica Issue 7, Pages: 1150-1158(2017)
- 作者机构：
  
  1.中国科学院长春应用化学研究所生态环境高分子材料重点实验室长春 130022
  2.中国科学院大学北京 100049
  3.长春市朝阳区人民医院长春 130022
- 作者简介：
- 基金信息：
- DOI：10.11777/j.issn1000-3304.2017.17024
  CLC：
- Published：2017-7，
  
  Received：4 February 2017，
  
  Revised：13 April 2017，
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Ying Zhang, Liang Liu, Ting-hong Wang, Hua-yu Tian, Xue-si Chen. Synthesis of pH-sensitive Nanogels and Their Application in siRNA Delivery. [J]. Acta Polymerica Sinica (7):1150-1158(2017)
DOI：

Ying Zhang, Liang Liu, Ting-hong Wang, Hua-yu Tian, Xue-si Chen. Synthesis of pH-sensitive Nanogels and Their Application in siRNA Delivery. [J]. Acta Polymerica Sinica (7):1150-1158(2017) DOI： 10.11777/j.issn1000-3304.2017.17024.

摘要

通过分散聚合的方法，以改性了双键的葡聚糖（Dex-AA）作为交联剂，甲基丙烯酸二甲氨基乙酯（DMAEMA）作为单体，过硫酸铵（APS）和四甲基乙二胺（TEMED）分别作为引发剂和助引发剂，合成了不同交联度的、具有pH敏感内吞增强作用的葡聚糖纳米凝胶（DD-NGs），并测试了其复合siRNA进行转染的能力.实验结果表明，该纳米凝胶表面带有正电荷，具有较好的担载siRNA进入肿瘤细胞并沉默基因的能力，且具有pH响应粒径变化的性质.在pH=7.4的体液环境中，纳米凝胶与基因的复合物粒子较小；在肿瘤酸性（pH=6.8）条件下，纳米凝胶与基因的复合物粒子变大，显著地增强了肿瘤细胞对纳米凝胶与基因复合物的内吞.

Abstract

pH responsivenanogels (DD-NGs) with different degrees of crosslinking were synthesized through dispersion polymerization. In this polymerization

dextran modified with acrylic acid (Dex-AA) served as the crosslinker. 2-(Dimethylamino) ethyl methacrylate (DMAEMA) was the monomer

thus the nanogels changed the particle size at different pH values. Ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) were the initiator and the promoter

respectively. The structure and ability of mediating siRNA transfection of the DD-NGs were characterized. Also

for the DD-NGs/siRNA complexes

their particle size

zeta potential

TEM assay

pH sensitive cellular uptake (by confocal laser scan microscopy and flow cytometry) were investigated. The results indicated that the DD-NGs/siRNA complexes were positively charged and DD-NGs could mediate siRNA into tumor cells. Both in HeLa-Luc cells and Huh7-Luc cells

the complexes of the two kinds of DD-NGs and siRNA downregulated about 50% luciferase reporter gene

indicating an excellent efficiency of gene silencing. Moreover

the cellular cytotoxicity assay was performed

and both DD-NGs showed non-cytotoxicity compared with PEI25k toward HeLa-Luc cells and Huh7-Luc cells

achieving 70% cell viability at the concentration of 0.1 mg/mL. The DD-NGs/siRNA complexes showed positive charge (13-15 mV)

and suitable particle size (50-100 nm) for systemic circulation at physiological pH (pH=7.4)

but the complexes swelled to a much larger particle size (150-250 nm) at tumor matrix (pH=6.8)

revealing a particle size changeable property with pH. Particle size measurement and TEM assay accurately supported this conclusion. Finally

flow cytometry assay was conducted to measure quantitatively the cellular uptake ability of the DD-NGs/siRNA complexes by HeLa-Luc cells at pH=7.4 and 6.8. Because of the variation in particle size

an enhanced cellular uptake at tumor matrix (pH=6.8) was obtained compared with the physiological condition at pH=7.4. CLSM images redefined this result. A much brighter fluorescence intensity generated by Cy5-labeled-RNA was observed. The as-prepared nanogels exhibited pH-enhanced tumor targeting ability and cellular uptake without introducing any targeting molecules.

关键词

葡聚糖纳米凝胶基因传递pH敏感

Keywords

DextranNanogelsGene deliverypH sensitive

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State Key Laboratory of Bio-Fibers and Eco-Textiles, College of Materials Science and Engineering, Qingdao University

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Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University

Chinese Academy of Science Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China

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