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Hyperbranched poly(β-amino ester) based polyplex nanopaticles for delivery of CRISPR/Cas9 system and treatment of HPV infection associated cervical cancer.
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2020-02-28 , DOI: 10.1016/j.jconrel.2020.02.045
Xueqin Gao 1 , Zhuang Jin 2 , Xiangyu Tan 3 , Chong Zhang 4 , Chenming Zou 1 , Wei Zhang 4 , Jiahui Ding 4 , Bhudev C Das 5 , Konstantin Severinov 6 , Inga Isabel Hitzeroth 7 , Priya Ranjan Debata 8 , Dan He 9 , Xin Ma 10 , Xun Tian 11 , Qinglei Gao 3 , Jun Wu 12 , Rui Tian 2 , Zifeng Cui 2 , Weiwen Fan 2 , Zhaoyue Huang 2 , Chen Cao 11 , Yuxian Bao 13 , Songwei Tan 4 , Zheng Hu 14
Affiliation  

Persistent high-risk HPV infection is the main factor for cervical cancer. HPV E7 oncogene plays an important role in HPV carcinogenesis. Down-regulation of E7 oncogene expression could induce growth inhibition in HPV-positive cells and thus treats HPV related cervical cancer. Here we developed a non-virus gene vector based on poly(amide-amine)-poly(β-amino ester) hyperbranched copolymer (hPPC) for the delivery of CRISPR/Cas9 system to specifically cleave HPV E7 oncogene in HPV-positive cervical cancer cells. The diameter of polyplex nanoparticles (NPs) formed by hPPCs/linear poly(β-amino ester) (PBAE) and plasmids were approximately 300 nm. These hPPCs/PBAE-green fluorescence protein plasmids polyplex NPs showed high transfection efficiency and low toxicity in cells and mouse organs. By cleaving HPV16 E7 oncogene, reducing the expression of HPV16 E7 protein and increasing intracellular retinoblastoma 1 (RB1) amount, hPPCs/PBAE-CRISPR/Cas9 therapeutic plasmids polyplex NPs, especially highly branched hPPC1-plasmids polyplex NPs, exhibited strong growth inhibition of cervical cancer cells in vitro and xenograft tumors in nude mice. Together, the hPPCs/PBAE polyplex NPs to deliver HPV16 E7 targeted CRISPR/Cas9 system in this study could potentially be applied to treat HPV-related cervical cancer.

中文翻译:

基于超支化聚(β-氨基酯)的复合纳米颗粒,用于递送CRISPR / Cas9系统并治疗与HPV感染相关的宫颈癌。

持续的高危HPV感染是宫颈癌的主要因素。HPV E7癌基因在HPV癌变中起重要作用。E7癌基因表达的下调可以诱导HPV阳性细胞的生长抑制,从而治疗HPV相关的宫颈癌。在这里,我们开发了一种基于聚(酰胺-胺)-聚(β-氨基酯)超支化共聚物(hPPC)的非病毒基因载体,用于递送CRISPR / Cas9系统以特异性切割HPV阳性宫颈癌中的HPV E7癌基因。细胞。由hPPC /线性聚(β-氨基酯)(PBAE)和质粒形成的复合纳米颗粒(NPs)的直径约为300 nm。这些hPPCs / PBAE-绿色荧光蛋白质粒polyplex NPs在细胞和小鼠器官中显示出高转染效率和低毒性。通过切割HPV16 E7癌基因,降低HPV16 E7蛋白的表达并增加细胞内视网膜母细胞瘤1(RB1)的量,hPPCs / PBAE-CRISPR / Cas9治疗质粒多聚体NP,尤其是高度分支的hPPC1-质粒多聚体NP,在体外和异种移植物中表现出对宫颈癌细胞的强抑制作用裸鼠体内的肿瘤。一起,在本研究中提供hPPCs / PBAE polyplex NPs以HPV16 E7为靶点的CRISPR / Cas9系统可潜在地用于治疗HPV相关的宫颈癌。
更新日期:2020-02-28
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