E7-Targeted Nanotherapeutics for Key HPV Afflicted Cervical Lesions by Employing CRISPR/Cas9 and Poly (Beta-Amino Ester)

Abstract

Jinfeng Xiong,1,* Songwei Tan,2,* Long Yu,3 Hui Shen,1 Shen Qu,4 Chong Zhang,2 Ci Ren,1 Da Zhu,1 Hui Wang1 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 4School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Da Zhu; Hui Wang Tel + 86-27-83663351Fax [phone]Email [email protected]; [email protected]: Persistent HR-HPV (high-risk human papillomavirus) infection is the main cause of cervical cancer. The HPV oncogene E7 plays a key role in HPV tumorigenesis. At present, HPV preventive vaccines are not effective for patients who already have a cervical disease, and implementation of the recommended regular cervical screening is difficult in countries and regions lacking medical resources. Therefore, patients need medications to treat existing HPV infections and thus block the progression of cervical disease.Methods: In this study, we developed nanoparticles (NPs) composed of the non-viral vector PBAE546 and a CRISPR/Cas9 recombinant plasmid targeting HPV16 E7 as a vaginal treatment for HPV infection and related cervical malignancies.Results: Our NPs showed low toxicity and high biological safety both in vitro (cell line viability) and in vivo (various important organs of mice). Our NPs significantly inhibited the growth of xenograft tumors derived from cervical cancer cell lines in nude mice and significantly reversed the cervical epithelial malignant phenotype of HPV16 transgenic mice.Conclusion: Our NPs have great potential to be developed as a drug for the treatment of HPV-related cervical cancer and precancerous lesions.Keywords: HR-HPV infection, cervical cancer, nanoparticles, PBAE, gene therapy, HPV16 transgenic mice

Keywords

• hr-hpv infection
• cervical cancer
• nanoparticles
• pbae
• gene therapy
• k14-hpv16 mouse models