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Peptide-Based Nanoparticles for αvβ3 Integrin-Targeted DNA Delivery to Cancer and Uterine Leiomyoma Cells
Anna Egorova1, Alexander Selutin2, Marianna Maretina1
1Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia.
Abstract:
Uterine leiomyoma is the most common benign tumor of the reproductive system. Current therapeutic options do not simultaneously meet the requirements of long-term efficiency and fertility preservation. Suicide gene delivery can be proposed as a novel approach to uterine leiomyoma therapy. Non-viral vehicles are an attractive approach to DNA delivery for gene therapy of both malignant and benign tumors. Peptide-based vectors are among the most promising candidates for the development of artificial viruses, being able to efficiently cross barriers of DNA transport to cells. Here we described nanoparticles composed of cysteine-crosslinked polymer and histidine-arginine-rich peptide modified with iRGD moiety and characterized them as vehicles for plasmid DNA delivery to pancreatic cancer PANC-1 cells and the uterine leiomyoma cell model. Several variants of nanoparticles were formulated with different targeting ligand content. The physicochemical properties that were studied included DNA binding and protection, interaction with polyanions and reducing agents, size, structure and zeta-potential of the peptide-based nanoparticles. Cytotoxicity, cell uptake and gene transfection efficiency were assessed in PANC-1 cells with GFP and LacZ-encoding plasmids. The specificity of gene transfection via αvβ3 integrin binding was proved in competitive transfection. The therapeutic potential was evaluated in a uterine leiomyoma cell model using the suicide gene therapy approach. The optimal formulation was found to be at the polyplex with the highest iRGD moiety content being able to transfect cells more efficiently than control PEI. Suicide gene therapy using the best formulation resulted in a significant decrease of uterine leiomyoma cells after ganciclovir treatment. It can be concluded that the application of iRGD-modified peptide-based nanoparticles has a high potential for cellular delivery of DNA therapeutics in favor of uterine leiomyoma gene therapy.
Insights
New peptide-based nanoparticles effectively deliver suicide genes to uterine leiomyoma cells, offering a promising fertility-sparing gene therapy approach. This novel non-viral vector shows potential for treating this common reproductive system tumor.
Area of Science:
- Biomedical Engineering
- Gene Therapy
- Nanotechnology
Background:
- Uterine leiomyoma is the most common benign tumor in the female reproductive system.
- Existing treatments often compromise long-term efficacy and fertility preservation.
- Suicide gene therapy presents a novel therapeutic strategy for uterine leiomyoma.
Purpose of the Study:
- To develop and characterize novel peptide-based nanoparticles for targeted DNA delivery.
- To evaluate the efficacy of these nanoparticles in delivering suicide genes to uterine leiomyoma cells.
- To assess the potential of iRGD-modified nanoparticles for fertility-sparing uterine leiomyoma gene therapy.
Main Methods:
- Formulation of cysteine-crosslinked polymer and histidine-arginine-rich peptide nanoparticles, modified with iRGD.
- Physicochemical characterization including DNA binding, size, and zeta-potential.
- Assessment of cytotoxicity, cell uptake, and gene transfection efficiency in pancreatic cancer and uterine leiomyoma cell models.
- Evaluation of suicide gene therapy efficacy using the optimal nanoparticle formulation.
Main Results:
- The optimal iRGD-modified peptide-based nanoparticle formulation demonstrated efficient DNA delivery and transfection.
- Targeting specificity was confirmed via αvβ3 integrin binding.
- The best formulation showed higher transfection efficiency compared to control PEI (polyethylenimine).
- Suicide gene therapy with the optimal nanoparticles significantly reduced uterine leiomyoma cell viability post-ganciclovir treatment.
Conclusions:
- iRGD-modified peptide-based nanoparticles are effective non-viral vectors for DNA delivery in uterine leiomyoma cells.
- This approach holds significant potential for developing fertility-sparing gene therapies for uterine leiomyoma.
- Further research into these nanoparticles could advance uterine leiomyoma treatment strategies.
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