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Published on: December 15, 2010
Therapeutic pCRISPRi Delivery to Lung Squamous Cell Carcinoma by Combining Nanobubbles and Ultrasound
Taiki Yamaguchi1, Yoko Endo-Takahashi1, Takumi Amano1
1Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan.
Abstract:
Background/Objectives: Lung squamous cell carcinoma (SCC), a major subtype of non-small cell lung cancer, remains a significant clinical challenge due to a scarcity of actionable molecular targets and the limited effectiveness of current targeted therapies. Emerging treatment strategies inhibit the gene expression of lineage survival oncogenes such as ΔNp63 and SOX2. CRISPR interference (CRISPRi) is a promising method to downregulate these genes; however, the efficacy depends on effective delivery. Here, we focused on the delivery system using nanobubbles (NBs) and ultrasound (US) for site-specific CRISPRi delivery to SCC. We evaluated the therapeutic efficacy of plasmid-based CRISPRi (pCRISPRi) targeting SOX2 or ΔNp63 using intratumoral pCRISPRi/NBs injections followed by US. Methods: A mixture of NBs and pCRISPRi was injected directly into the tumors and exposed to US-induced cavitation to facilitate pCRISPRi uptake. Tumor volume was measured every other day, and apoptosis was assessed by TUNEL assay. Results: In a lung SCC xenograft model, NBs/US-mediated pCRISPRi delivery induced apoptosis and significantly suppressed tumor growth. Conclusions: These findings suggest that US-guided, NB-facilitated delivery of pCRISPRi can locally suppress lineage survival oncogenes and trigger tumor cell death, representing a promising targeted therapy for lung SCC. Additionally, this platform could be adapted to other cancers by targeting alternative factors.
Insights
Ultrasound and nanobubble technology effectively delivered CRISPR interference (CRISPRi) gene therapy to lung squamous cell carcinoma (SCC) tumors. This approach suppressed key oncogenes, reduced tumor growth, and induced cancer cell death.
Area of Science:
- Oncology
- Gene Therapy
- Nanotechnology
Background:
- Lung squamous cell carcinoma (SCC) presents challenges due to limited molecular targets and therapy effectiveness.
- Targeting lineage survival oncogenes like SOX2 and ΔNp63 is a promising therapeutic strategy.
- Efficient delivery of gene-modulating tools like CRISPR interference (CRISPRi) is crucial for therapeutic success.
Purpose of the Study:
- To evaluate the efficacy of nanobubbles (NBs) and ultrasound (US) for site-specific delivery of plasmid-based CRISPR interference (pCRISPRi) targeting SOX2 or ΔNp63 in lung SCC.
- To assess the therapeutic potential of this delivery system in suppressing oncogene expression and inducing tumor cell death.
Main Methods:
- Intratumoral injection of a mixture of NBs and pCRISPRi targeting SOX2 or ΔNp63.
- Application of ultrasound (US) to induce cavitation and enhance pCRISPRi uptake within tumors.
- Monitoring tumor volume changes and assessing apoptosis via TUNEL assay in a lung SCC xenograft model.
Main Results:
- NBs/US-mediated pCRISPRi delivery significantly suppressed lung SCC tumor growth in a xenograft model.
- The treatment induced apoptosis in tumor cells, indicating therapeutic efficacy.
- Successful local delivery and downregulation of target oncogenes were achieved.
Conclusions:
- Ultrasound-guided, nanobubble-facilitated delivery of pCRISPRi offers a promising targeted therapy for lung SCC by suppressing oncogenes and promoting tumor cell death.
- This delivery platform has potential for adaptation to other cancer types by targeting different oncogenic factors.
