Glycogen-nucleic acid constructs for gene silencing in multicellular tumor spheroids

被引:42
作者
Wojnilowicz, Marcin [1 ,2 ]
Besford, Quinn A. [1 ,2 ]
Wu, Yun-Long [3 ,4 ]
Loh, Xian Jun [5 ,6 ]
Braunger, Julia A. [1 ,2 ]
Glab, Agata [1 ,2 ]
Cortez-Jugo, Christina [1 ,2 ]
Caruso, Frank [1 ,2 ]
Cavalieri, Francesca [1 ,2 ,7 ]
机构
[1] Univ Melbourne, ARC Ctr Excellence Convergent Bionano Sci & Techn, Parkville, Vic 3010, Australia
[2] Univ Melbourne, Dept Chem Engn, Parkville, Vic 3010, Australia
[3] Xiamen Univ, Sch Pharmaceut Sci, Fujian Prov Key Lab Innovat Drug Target Res, Xiamen, Peoples R China
[4] Xiamen Univ, Sch Pharmaceut Sci, State Key Lab Cellular Stress Biol, Xiamen, Peoples R China
[5] ASTAR, Inst Mat Res & Engn, 2 Fusionopolis Way,Innovis 08-03, Singapore 138634, Singapore
[6] Natl Univ Singapore, Dept Mat Sci & Engn, 9 Engn Dr 1, Singapore 117576, Singapore
[7] Univ Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Via Ric Sci 1, I-00133 Rome, Italy
基金
澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
Glycogen nanoparticles; RNA interference; Multicellular tumor spheroids; In vivo biodistribution; Prostate cancer; HUMAN-MELANOMA CELLS; SIRNA DELIVERY; IN-VITRO; CANCER-THERAPY; SURVIVIN EXPRESSION; DENDRITIC CELLS; SCATTERING DATA; NANOPARTICLES; THERAPEUTICS; ALPHA;
D O I
10.1016/j.biomaterials.2018.05.024
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
The poor penetration of nanocarrier-siRNA constructs into tumor tissue is a major hurdle for the in vivo efficacy of siRNA therapeutics, where the ability of the constructs to permeate the 3D multicellular matrix is determined by their physicochemical properties. Herein, we optimized the use of soft glycogen nanoparticles for the engineering of glycogen-siRNA constructs that can efficiently penetrate multicellular tumor spheroids and exert a significant gene silencing effect. Glycogen nanoparticles from different bio-sources and with different structural features were investigated. We show that larger glycogen nanoparticles ranging from 50 to 80 nm are suboptimal systems for complexation of nucleic acids if fine control of the size of constructs is required. Our studies suggest that 20 nm glycogen nanoparticles are optimal for complexation and efficient delivery of siRNA. The chemical composition, surface charge, and size of glycogen-siRNA constructs were finely controlled to minimize interactions with serum proteins and allow penetration into 3D multicellular spheroids of human kidney epithelial cells and human prostate cancer cells. We introduced pH sensitive moieties within the construct to enhance early endosome escape and efficiently improve the silencing effect in vitro. Glycogen-siRNA constructs were found to mediate gene silencing in 3D multicellular spheroids causing similar to 60% specific gene silencing. The optimized construct exhibited an in vivo circulation lifetime of 8 h in mice, with preferential accumulation in the liver. No accumulation in the kidney, lung, spleen, heart or brain, or signs of toxicity in mice were observed. Our results highlight the potential for screening siRNA nanocarriers in 3D cultured prostate tumor models, thereby improving the predictive therapeutic efficacy of glycogen-based platforms in human physiological conditions. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码:34 / 49
页数:16
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