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    Chitosan-based delivery of CRISPR-Cas9 plasmid in breast cancer stem cells
    (Marmara Univ, 2023) Canak-Ipek, Tuba; Avci-Adali, Meltem; Ekentok Atici, Ceyda; Salva, Emine; Ozbas, Suna
    Clustered regularly interspaced short palindromic repeat (CRISPR)-associated Cas9 nuclease system (CRISPR/Cas9) has emerged as a powerful toolbox for cancer therapy, serving as a gene fixed-point knock-out method. However, suitable gene carrier systems are urgently needed to encapsulate the CRISPR/Cas9 system and to improve the uptake into the cancer cells for anti-cancer therapy. In cancer therapy, breast cancer stem cells should be also targeted besides tumor cells. In this study, we prepared chitosan/CRISPR-Cas9/protamine nanoplexes and performed in vitro characterization. The results showed that the chitosan/protamine complex increased the zeta potential of the VEGF CRISPR/Cas9 plasmid from negative to positive. In vitro cell culture studies showed that VEGF silencing efficiency was 46.19% and 30.2% in MCF-7 and MCF-7s, respectively, after 7 days. The invasion capacity of cancer cells decreased significantly for both cell types. The results indicate that chitosan/VEGF CRISPR/Cas9 plasmid/protamine complexes can be used to reduce VEGF expression, leading to a decrease in the invasion capacity of breast cancer as well as breast cancer stem cells and providing proof of concept for more advanced studies, including in vivo studies, of this system.
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    Combination therapy with chitosan/siRNA nanoplexes targeting PDGF-D and PDGFR-? reveals anticancer effect in breast cancer
    (Wiley, 2023) Salva, Emine; Ozbas, Suna; Alan, Saadet; Ozkan, Naziye; Ekentok-Atici, Ceyda; Kabasakal, Levent; Akbuga, Julide
    Background: Platelet derived growth factors (PDGF)-D and the expression of its receptor increase in neoplastic progression of cancer. Co-silencing of growth factor and receptor can be suggested as an important strategy for effective cancer therapy. In the present study, we hypothesized that suppression of PDGF-D signaling pathway with small interfering RNAs (siRNAs) targeting both PDGF-D and PDGF receptor (PDGFR)-beta is a promising strategy for anticancer therapy. Methods: Chitosan nanoplexes containing dual and single siRNA were prepared at different weight ratios and controlled by gel retardation assay. Characterization, cellular uptake, gene silencing and invasion studies were performed. The effect of nanoplexes on breast tumor growth, PDGF expression and apoptosis was investigated. Results: We have shown that downregulation of PDGF-D and PDGFR-beta with chitosan/siRNA nanoplex formulations reduced proliferation and invasion in breast cancer cells. In the in vivo breast tumor model, it was determined that the intratumoral administration of chitosan/siPDGF-D/siPDGFR-beta nanoplexes markedly decreased the tumor volume and PDGF-D and PDGFR-beta mRNA and protein expression levels and increased apoptosis. Conclusions: According to the results obtained, we evaluated the effect of PDGF-D and PDGFR-beta on breast tumor development and showed that RNAi-mediated inhibition of this pathway formulated with chitosan nanoplexes can be considered as a new breast cancer therapy strategy.
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    Investigation of therapeutic effects in the wound healing of chitosan/pGM-CSF complexes
    (Univ Sao Paulo, Conjunto Quimicas, 2022) Salva, Emine; Alan, Saadet; Karakoyun, Berna; Cakalagaoglu, Fulya; Ozbas, Suna; Akbuga, Julide
    Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to promote the growth, proliferation, and migration of endothelial and keratinocyte cells. Chitosan has been widely used as a biopolymer in wound-healing studies. The aim of this study was to investigate the in vitro proliferative effects of chitosan/pGM-CSF complexes as well as the therapeutic role of the complexes in an in vivo rat wound model. The effect of complexes on cell proliferation and migration was examined. Wounds were made in Wistar-albino rats, and examined histopathologically. The cell proliferation and migration were increased weight ratio- and time-dependently in HaCaT and NIH-3T3 cell lines. Wound healing was significantly accelerated in rats treated with the complexes. These results showed that the delivery of pGM-CSF using chitosan complexes could play an accelerating role in the cell proliferation, migration, and wound-healing process.
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    A New Gene Therapy Approach by Tenascin-C Genome Editing Induces Apoptosis and Cell Cycle Arrest in Triple- Negative Breast Cancer Cells
    (Galenos Publ House, 2023) Bareke, Halin; Salva, Emine; Ozbas, Suna
    BACKGROUND/AIMS: There is a pressing need for new therapies for the most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC). Tenascin-C (TN-C) codes for a tumor microenvironment-specific protein, which promotes apoptosis evasion and cell proliferation. The aim of this study was to knock down TN-C by using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to induce cancer cell apoptosis and stunt cell proliferation, laying the grounds for a new gene therapy approach in TNBC.MATERIALS and METHODS: The human TNBC cell line, MDA-MB-231 cells were transfected by TN-C-specific CRISPR/Cas9 plasmids. TN-C messenger RNA levels were assessed by real-time polymerase chain reaction to determine the knock-down efficiency. Two days after the transfection, the percentage of apoptotic cells and the proportion of cells in cell cycle phases were compared between the treatment and the control groups using flow cytometry. The resultant change in cell proliferation due to the knock-down was determined by MTT assay. RESULTS: Transfection with the TN-C CRISPR/Cas9 plasmid reduced TN-C levels in the cells by approximately 49% relative to the scrambled -control CRISPR/Cas9 transfected cells. This TN-C downregulation increased the percentage of cells in apoptosis and induced G1-phase arrest. The combined effect of apoptosis and cell cycle arrest led to a significant decrease in the number of cancer cells in the treatment group.CONCLUSION: Our successful preliminary study of a potential TNBC gene therapy based on TN-C genome editing by the CRISPR/Cas9 system led to significant decrease in TNBC cell numbers and it justifies the testing of this system in more advanced preclinical studies.