Co-Delivery of p53 Restored and E7 Targeted Nucleic Acids by Poly (Beta-Amino Ester) Complex Nanoparticles for the Treatment of HPV Related Cervical Lesions.

Jinfeng Xiong,Hui Wang,Hui Shen,Da Zhu,Xinyu Mei,Guannan Li,Jiahui Ding

doi:10.3389/fphar.2022.826771

Jinfeng Xiong, Hui Wang + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2022.826771

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Abstract

The p53 gene has the highest mutation frequency in tumors, and its inactivation can lead to malignant transformation, such as cell cycle arrest and apoptotic inhibition. Persistent high-risk human papillomavirus (HR-HPV) infection is the leading cause of cervical cancer. P53 was inactivated by HPV oncoprotein E6, promoting abnormal cell proliferation and carcinogenesis. To study the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer by restoring p53 expression and inactivating HPV oncoprotein, and to verify the effectiveness of nano drugs based on nucleic acid delivery in cancer treatment, we developed poly (beta-amino ester)537, to form biocompatible and degradable nanoparticles with plasmids (expressing p53 and targeting E7). In vitro and in vivo experiments show that nanoparticles have low toxicity and high transfection efficiency. Nanoparticles inhibited the growth of xenograft tumors and successfully reversed HPV transgenic mice’s cervical intraepithelial neoplasia. Our work suggests that the restoration of p53 expression and the inactivation of HPV16 E7 are essential for blocking the development of cervical cancer. This study provides new insights into the precise treatment of HPV-related cervical lesions.

Highlights

P53, the most commonly mutated gene in human cancer, is essential for maintaining the stability of the human genome (Blandino and Di Agostino, 2018; Mendiratta et al, 2021)
To study the treatment of CIN and cervical cancer by restoring p53 expression and inactivating HPV oncoprotein, and to verify the effectiveness of nano drugs based on nucleic acid delivery in cancer treatment, we attempted to reverse cervical intraepithelial neoplasia by vaginal injection of nanoparticles composed of PBAE537 and plasmids, providing a new idea strategy for precise treatment of cervical cancer
Nanoparticles were prepared at different mass ratios of PBAE537 to green fluorescent protein (GFP) (5:1, 10:1, 20:1, 40:1, 80:1, and 100:1), and the plasmid encapsulation ability of PBAE537 was determined by agar gel electrophoresis

Summary

Introduction

P53, the most commonly mutated gene in human cancer, is essential for maintaining the stability of the human genome (Blandino and Di Agostino, 2018; Mendiratta et al, 2021). Its loss is a key event in the development of various tumors (Klco and Mullighan, 2021; Rudin et al, 2021). P53 plays an important role in protecting cells from malignant transformation by inducing cell cycle arrest or apoptosis (Zhou et al, 2019). In spontaneous p53 mutant lymphoma and sarcoma models, the restored expression of wild-type p53 resulted in tumor growth arrest (Wang et al, 2011). Activating p53-dependent apoptosis in zebrafish inhibited angiogenesis (Zhou et al, 2016). Restoring p53 expression induced cycle arrest and apoptosis in non-small cell lung cancer (NSCLC) (Lu et al, 2017). Restoring p53 expression is a promising method in a variety of tumors

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