Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy

被引:0
作者
Qingfei Zhang
Gaizhen Kuang
Shasha He
Sha Liu
Hongtong Lu
Xiaoyuan Li
Dongfang Zhou
Yubin Huang
机构
[1] Chinese Academy of Sciences,State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry
[2] University of Science and Technology of China,Department of Medical Oncology
[3] Affiliated Cancer Hospital of Zhengzhou University,School of Pharmaceutical Sciences
[4] Southern Medical University,undefined
来源
Nano Research | 2021年 / 14卷
关键词
CRISPR/Cas9; gene editing; EZH2; Pt(IV)-backboned polymeric nanoplatform; combination therapy;
D O I
暂无
中图分类号
学科分类号
摘要
CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment. However, development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges. Herein, a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system (NPCSPt/pEZH2) and synergistic treatment of prostate cancer. The pEZH2/Pt(II) could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells. The EZH2 gene disruption efficiency could be achieved up to 32.2% of PC-3 cells in vitro and 21.3% of tumor tissues in vivo, leading to effective suppression of EZH2 protein expression. Moreover, significant H3K27me3 downregulation could occur after EZH2 suppression, resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II) to nuclear DNA for enhanced apoptosis. Taken together, substantial proliferation inhibition of prostate cancer cells and further 85.4% growth repression against subcutaneous xenograft tumor could be achieved. This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery, but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.
引用
收藏
页码:601 / 610
页数:9
相关论文
共 315 条
  • [11] Ran F A(2015)Near-infrared upconversion–activated CRISPR-Cas9 system: A remote-controlled gene editing platform Nat. Genet 47 1187-111
  • [12] Cox D(2019)Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas Adv. Mater. 31 e1905751-4908
  • [13] Lin S L(2019)Dual-locking nanoparticles disrupt the PD-1/PD-L1 pathway for efficient cancer immunotherapy Nat. Nanotechnol 14 974-874
  • [14] Barretto R(2017)A biodegradable nanocapsule delivers a Cas9 ribonucleoprotein complex for Adv. Sci 4 1700175-1068
  • [15] Habib N(2017) genome editing ACS Nano 11 95-1078
  • [16] Hsu P D(2019)Genome editing for cancer therapy: Delivery of Cas9 protein/sgRNA plasmid via a gold nanocluster/lipid core-shell nanocarrier Adv. Sci 6 1801423-810
  • [17] Wu X B(2018)Artificial virus delivers CRISPR-Cas9 system for genome editing of cells in mice Proc. Natl. Acad. Sci. USA 115 4903-477
  • [18] Jiang W Y(2006)Multistage delivery nanoparticle facilitates efficient CRISPR/dCas9 activation and tumor growth suppression Nature 439 871-222
  • [19] Marraffini L A(2010)Nonviral gene editing via CRISPR/Cas9 delivery by membrane-disruptive and endosomolytic helical polypeptide Nat. Biotechnol 28 1057-629
  • [20] Ran F A(2010)The polycomb group protein EZH2 directly controls DNA methylation Nat. Biotechnol 28 1069-299