Hyperbranched poly(β-amino ester) based polyplex nanopaticles for delivery of CRISPR/Cas9 system and treatment of HPV infection associated cervical cancer

Xueqin Gao, Zhuang Jin, Xiangyu Tan, Chong Zhang, Chenming Zou, Wei Zhang, Jiahui Ding, Bhudev C. Das, Konstantin Severinov, Inga Isabel Hitzeroth, Priya Ranjan Debata, Dan He, Xin Ma, Xun Tian, Qinglei Gao, Jun Wu, Rui Tian, Zifeng Cui, Weiwen Fan, Zhaoyue HuangChen Cao, Yuxian Bao, Songwei Tan, Zheng Hu

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)654-668
    Number of pages15
    JournalJournal of Controlled Release
    Volume321
    DOIs
    Publication statusPublished - 10 May 2020

    Keywords

    • Cervical cancer
    • CRISPR/Cas9
    • HPV
    • Hyperbranched copolymer
    • Poly(β-amino ester)

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