A nucleus-targeting peptide antagonist towards EZH2 displays therapeutic efficacy for lung cancer

Mei Jiang; Xiaocui Fang; Lilusi Ma; Mingpeng Liu; Mengting Chen; Jingyi Liu; Yanlian Yang; Chen Wang

doi:10.1016/j.ijpharm.2022.121894

A nucleus-targeting peptide antagonist towards EZH2 displays therapeutic efficacy for lung cancer

Int J Pharm. 2022 Jun 25:622:121894. doi: 10.1016/j.ijpharm.2022.121894. Epub 2022 Jun 6.

Authors

Mei Jiang¹, Xiaocui Fang², Lilusi Ma², Mingpeng Liu², Mengting Chen², Jingyi Liu², Yanlian Yang³, Chen Wang⁴

Affiliations

¹ CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China; Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, PR China.
² CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
³ CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: yangyl@nanoctr.cn.
⁴ CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: wangch@nanoctr.cn.

PMID: 35680109
DOI: 10.1016/j.ijpharm.2022.121894

Abstract

EZH2 is an overexpressed nuclear protein associated with relatively poor survival and chemoresistance in lung cancer. In this study, a nucleus-targeting peptide antagonist EIP103 capable of penetrating cell membrane and nuclear envelope was identified, and has high binding affinity towards EZH2 localized in the nucleus of lung cancer cells. To improve the stability and therapeutic efficacy of EIP103, PEG-PE micelle encapsulated EIP103 (M-EIP103) was successfully conducted. In vitro results indicated that M-EIP103 exhibited better stability, higher intracellular uptake and stronger cytotoxicity than free EIP103 in H446 and A549 cells. Mechanistic studies suggested that M-EIP103 inhibited proliferation by down-regulating the H3K27me3 expression level in cancer cells. In vivo assays further confirmed that both EIP103 and M-EIP103 significantly inhibited lung cancer progression. Notably, enhanced therapeutic efficacy of EIP103 by PEG-PE micelle encapsulation could be identified. The observed anti-tumor activity of EIP103 and M-EIP103 demonstrated a promising therapy to improve clinical treatment of lung cancers as well as other EZH2-overexpressing malignant cancers. This study also illustrates the feasibility of developing targeted delivery of therapeutic peptides to nucleus for cancer therapy.

Keywords: Antagonistic peptide; Cancer therapy; Nanomicelle; Nucleus-targeting.

MeSH terms

A549 Cells
Cell Line, Tumor
Cell Proliferation
Enhancer of Zeste Homolog 2 Protein / metabolism
Humans
Lung Neoplasms* / pathology
Micelles*
Peptides

Substances

Micelles
Peptides
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein