DNA nanotherapy for pre-neoplastic cervical lesions

Area of Science:

• Biomedical Engineering
• Molecular Oncology
• Nanomedicine

Background:

• Human Papillomavirus type 16 (HPV16) is a major cause of cervical cancer.
• Targeted therapies aim to selectively eliminate cancer cells while sparing healthy ones.
• Nanoparticle delivery systems offer potential for precise drug and gene delivery.

Purpose of the Study:

• To evaluate targeted nanoparticle delivery of DNA encoding diphtheria toxin (DT-A) for HPV16-infected cell death.
• To assess the specificity of the HPV16 Long Control Region (LCR) for activating gene expression in HPV16-infected cells.
• To investigate the use of a thermal-sensitive gel for targeted delivery of nanoparticles to cervical cells.

Main Methods:

• Formulation of poly(β-amino ester) nanoparticles with DNA constructs (HPV16 LCR-DT-A or HPV16 LCR-Luciferase).
• In vivo studies using HPV16(+) CaSki cervical cancer xenografts in mice to assess tumor growth inhibition.
• Bioluminescent imaging to evaluate HPV16 LCR regulatory sequence activity in vivo and ex vivo.
• Evaluation of Lutrol F127 thermal gel for targeted nanoparticle delivery in ex vivo cervical tissue and following intravaginal administration.

Main Results:

• The HPV16 LCR demonstrated gene expression activity in cervical epithelial cells, but not exclusively in HPV16-infected cells.
• HPV/DT-A-nanoparticle treatment, when delivered via Lutrol F127 gel, led to DT-A expression and cell death in exposed cervical cells.
• Nanoparticle delivery using the thermal gel effectively restricted exposure to cervical cells.

Conclusions:

• A specific HPV16 DNA sequence for targeting gene expression solely to HPV16-infected cells requires further discovery.
• Topical application of nanoparticle/Lutrol F127 gel mixtures represents a viable strategy for targeted DNA delivery to cervical pre-cancerous lesions.
• This approach holds potential for localized treatment of cervical abnormalities.