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Targeted delivery of CXCR4-siRNA by scFv for HER2(+) breast cancer therapy
Kuo Jiang1, Jia Li2, Jipeng Yin3
1Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
Abstract:
Therapeutics based on short interfering RNAs (siRNAs) have great potential to treat human diseases. However, the clinical application of siRNAs has been limited by their poor intracellular uptake, low serum stability, and inability to target specific cells. In this study, we addressed this lack of specificity by synthesizing a molecularly targeted CXCR4-siRNA (CXCR4si) for the treatment of HER2(+) breast cancers using a HER2-scFv-arginine nonamer peptide fusion protein (e23sFv-9R) as an siRNA carrier. The e23sFv-9R binding siRNA is able to specifically deliver the siRNA to HER2(+) breast cancer cells and concentrate and persist in orthotopic HER2(+) breast cancer xenografts for at least 36 h. CXCR4si delivered by e23sFv-9R inhibited CXCR4 gene expression, reduced proliferation and metastasis and induced apoptosis in the HER2(+) breast cancer BT-474 cell line in vitro. Moreover, the systemic delivery of CXCR4si by e23sFv-9R is able to suppress tumor growth, reduce metastasis and prolong survival in mice bearing HER2(+) xenografts. This approach causes no systemic toxicity and does not activate the innate immune response, suggesting that a fusion protein carrying CXCR4si shows promise in the treatment of HER2-overexpressing breast cancer.
Insights
This study developed a targeted siRNA delivery system for HER2-positive breast cancer. The novel fusion protein carrier successfully delivered CXCR4-siRNA to cancer cells, inhibiting tumor growth and metastasis with no observed toxicity.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Therapeutics
Background:
- Short interfering RNAs (siRNAs) show therapeutic promise but face challenges in delivery and specificity.
- HER2-positive breast cancer requires targeted treatment strategies to improve efficacy and reduce side effects.
Purpose of the Study:
- To develop a targeted siRNA delivery system for HER2-positive breast cancers.
- To evaluate the efficacy of a fusion protein carrier (e23sFv-9R) for delivering CXCR4-siRNA (CXCR4si) to HER2-positive cancer cells.
Main Methods:
- Synthesized a fusion protein (e23sFv-9R) linking HER2-targeting peptide with an arginine nonamer.
- Utilized the fusion protein to specifically deliver CXCR4si to HER2-positive breast cancer cells (BT-474) in vitro and in vivo xenograft models.
- Assessed gene expression, cell proliferation, apoptosis, tumor growth, metastasis, and survival.
Main Results:
- The e23sFv-9R carrier specifically delivered CXCR4si to HER2-positive cells, concentrating in tumors for over 36 hours.
- CXCR4si treatment inhibited CXCR4 gene expression, reduced proliferation and metastasis, and induced apoptosis in vitro.
- Systemic delivery suppressed tumor growth, reduced metastasis, and prolonged survival in mice with HER2-positive xenografts.
- The treatment showed no systemic toxicity or innate immune response activation.
Conclusions:
- The fusion protein-mediated delivery of CXCR4si is a promising strategy for treating HER2-overexpressing breast cancer.
- This targeted approach overcomes key limitations of siRNA therapeutics, offering potential for improved clinical outcomes.
