Formulation of lipid nanoparticles (LNP) encapsulating micro-RNA for topical treatment of high-grade squamous intraepithelial lesions (HSIL) lesion

People involved

Ziyun Cheng (Postdoctoral Fellow sponsored by the PRC) - Precision Medicine in Oncology (PrMiO), Erasmus University Medical Center Rotterdam

Abstract

In August 2020, the World Health Organization endorsed the global strategy for cervical cancer elimination, setting targets for vaccinating 90% of girls against HPV, screening 70% of women by the age of 35, and treating 90% of women with pre-cancer conditions by 2030. High-risk HPV infection is pivotal in cervical cancer development through high-grade squamous intraepithelial lesions (HSIL), with a 10-30% likelihood of progressing to cancer.1) Given the discomfort and limitations of standard treatments, there's an urgent need for innovative targeted modalities for HSIL. The development of an anchorage-independent phenotype is a crucial event in the progression from HSIL to cancer. Our findings indicate that downregulation of two micro RNA, miR-129-5p and miR-193b-3p correlates with anchorage-independent growth in HPV-transfected cells and transfection with these miRNAs selectively diminishes the growth capability of HPV-transfected cells in anchorage-independent conditions,2)3) suggesting their potential as selective and safe therapeutics to enhance current treatments for HPV-induced precancers.

This project aimed at formulating matured miR-129-5p and miR-193b-3p in lipid nanoparticle comprising ionizable lipids (LNP), for topical treatment of HSIL. The formulation includes excipients as mucosal penetration enhancers and buffer with limited buffering capacity. Furthermore, the study investigates the impact of lipid composition on the extracellular and intracellular behavior of LNPs by comparing two approved ionizable lipids, evaluating the effect of anchor unit length (2C18 versus 2C14) of PEGylated lipid, and delineating the influence of PEG density on LNP efficacy concerning cellular interaction, transfection, and penetration through mucus. These comprehensive analysis seeks to find an optimal balance between these formulation parameters.

Recognizing the significance of eliminating cervical cancer in women's health, as outlined in global health policies, we anticipate that the findings of this study will draw substantial attention. And through the utilization of LNP composed of ionizable lipids for use in the acidic cervicovaginal tract, the project not only extends the applicability of LNP for gene delivery beyond systemic administration but also to streamline their topical application across various mucosal barriers.

Benefit for the community

While existing literature lacks investigations into the utilization of LNP comprising ionizable lipids for gene delivery to the cervicovaginal tract, the present study fills a gap in the current research landscape by investigating the application of LNPs containing ionizable lipids for gene delivery through mucosal barriers.

By exploring a non-systemic route of administration, it has the potential to broaden the scope of LNP applications in gene therapy. The research contributes unique insights into the use of mucus-penetrating enhancers for topical application of lipid-based drug delivery systems.

Additionally, the study provides valuable information on the impact of lipid composition on both cellular transfection efficiency and mucosal drug delivery. The developed platform offers a versatile means for delivering various nucleic acid-based therapeutics to different mucosal areas, thereby broadening the practical applications of this approach.

Visit the supervisors lab

Contact to Dr. Mohamadreza Amin.