Nanoparticles Based on Poly (β-Amino Ester) and HPV16-Targeting CRISPR/shRNA as Potential Drugs for HPV16-Related Cervical Malignancy

Mol Ther. 2018 Oct 3;26(10):2443-2455. doi: 10.1016/j.ymthe.2018.07.019. Epub 2018 Jul 25.

Abstract

Persistent high-risk HPV infection is the main cause of cervical cancer. The HPV oncogene E7 plays an important role in HPV carcinogenesis. Currently, HPV vaccines do not offer an effective treatment for women who already present with cervical disease, and recommended periodical cervical screenings are difficult to perform in countries and areas lacking medical resources. Our aim was to develop nanoparticles (NPs) based on poly (β-amino ester) (PBAE) and HPV16 E7-targeting CRISPR/short hairpin RNA (shRNA) to reduce the levels of HPV16 E7 as a preliminary form of a drug to treat HPV infection and its related cervical malignancy. Our NPs showed low toxicity in cells and mouse organs. By reducing the expression of HPV16 E7, our NPs could inhibit the growth of cervical cancer cells and xenograft tumors in nude mice, and they could reverse the malignant cervical epithelium phenotype in HPV16 transgenic mice. The performance of NPs containing shRNA is better than that of NPs containing CRISPR. HPV-targeting NPs consisting of PBAE and CRISPR/shRNA could potentially be developed as drugs to treat HPV infection and HPV-related cervical malignancy.

Keywords: HPV; PBAE; cervical cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics
  • Disease Models, Animal
  • Female
  • Human papillomavirus 16 / genetics*
  • Human papillomavirus 16 / pathogenicity
  • Humans
  • Mice, Nude
  • Nanoparticles / administration & dosage*
  • Papillomavirus E7 Proteins / antagonists & inhibitors
  • Papillomavirus E7 Proteins / genetics*
  • Polymers / administration & dosage
  • Polymers / chemistry
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy*
  • Uterine Cervical Neoplasms / virology

Substances

  • Papillomavirus E7 Proteins
  • Polymers
  • RNA, Small Interfering
  • oncogene protein E7, Human papillomavirus type 16
  • poly(beta-amino ester)