Person: EKENTOK ATICI, CEYDA
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EKENTOK ATICI
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CEYDA
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Publication Metadata only The cellular uptake and endosomal escape mechanisms of chitosan-protamine-siRNA nanoplexes for efficient gene transfection and silencing(2021-09-11) EKENTOK ATICI, CEYDA; ÖZBAŞ, SUNA; CÖMEZ, BİRNUR; ŞALVA E., EKENTOK C., CÖMEZ B., ÖZBAŞ S., AKBUĞA F. J.Aim: The use of antisense-based molecules in gene expression inhibition has allowed the design of a new pathway for therapeutics. In order to ensure that oligonucleotides with gene silencing potential can be used effectively in therapy, a suitable carrier system is required that can be transported to the target site. In this study, gene silencing activities of siRNA targeted to the LacZ gene were compared and the gene delivery capabilities, transfection efficiency, cellular uptake and endosomal escape mechanisms of nanoplexes prepared with siRNA and chitosan/protamine polymers were investigated. Material and methods: Nanoplex formulations were prepared by simple complexation method of chitosan/protamine polymers and oligonucleotides. The particle size and zeta potential of the prepared nanoplexes were measured, and their serum and enzyme stability were investigated. In order to determine the transfection and gene silencing activities of the selected formulations, HEK293 cells stably expressing beta-gal were prepared, inhibition of beta-gal protein was measured by enzymatic assay and suppression by X-gal method was evaluated microscopically. Cellular uptake and endosomal escape mechanisms of nanoplexes were studied. Results: Chitosan/Protamine/siLacZ nanoplexes have been observed to protect siRNA against enzymatic and serum degradation for up to 48 hours. It was observed that the transfection efficiency was the highest in the formulations prepared together with chitosan/protamine at a rate of 10/10/1. It was observed that the transfection increased significantly with the increase in the ratio of chitosan and protamine. Transfection efficiency was found to be 88.60% at a rate of 10/10/1. In the cellular uptake study, it was observed that the inhibitor that reduced cellular uptake the most was phenylarsine oxide, and the uptake of siRNA carried by nanoplexes was 56%. There was no decrease in cellular uptake when chlorpromazine hydrochloride inhibitor was administered. This indicated that the nanoplexes were not uptake by clathrin-mediated endocytosis. It was observed that cellular uptake was 75% with colchicine, this inhibitor decreases cellular uptake by inhibiting microtubules in cells. Conclusion: It has been shown that cellular uptake and transfection studies with chitosan/protamine nanoplexes can be used as an effective carrier system for siRNA transport.Publication Metadata only Hedeflendirilmiş Nanopartiküllerin transdermal taşınması ve in vitro değerlendirilmesi(Jenny Stanford Publishing, 2021-11-01) EKENTOK ATICI, CEYDA; SEZER, ALİ DEMİR; ÇELİK, AYSUN; Ekentok Atıcı C., Çelik A., Sezer A. D.Publication Metadata only Administration of Ad5 chitosan PEG-aptamer vector delivering PDGF-D shRNA decreases tumor growth in rat breast cancer model(2021-10-01) EKENTOK ATICI, CEYDA; Ekentok-Atici C., Akbuga J.Publication Open Access Viral vector platforms within the gene therapy landscape(2023-01-01) EKENTOK ATICI, CEYDA; EKENTOK ATICI C.Gene therapy is the treatment of a disease through transferring genetic material (DNA/RNA) into the cells of patients. The transferred gene can act following ways: (i) enabling expression of the transferred gene, (ii) inhibiting the expression of a target gene and (iii) modifying a target gene. Gene therapy clinical trials started nearly fifty years ago with treatment of inherited monogenic disorder. Soon after that, gene therapy based clinical approaches was extended to acquired diseases such as cancer [1]. Since the first successful gene therapy clinical trial on a four-year girl who had ADA deficiency was initiated in 1990, more than 30 gene therapy products have been approved worldwide by different authorities [2]. Several approaches like physical methods (electroporation, microinjection, biolistic etc.), chemical methods (polymers, lipids, peptides etc.) and biological methods (adenoviruses, adeno-associated viruses, retroviruses etc.) can be employed to deliver the DNA inside cells. No single method works best for all applications. Factors that determine the choice of the method include cost, reproducibility, toxicity, mechanism of delivery, ease of use, and efficiency [3]. Adenoviral vectors (Ads), adeno-associated viral vector (AAVs), retroviral vectors (RVs) and lentiviral vectors (LVs) are the most common viral delivery systems for gene therapy applications. These systems have the benefits of high transfection potency and constant expression of therapeutic genes. However, limitations in large scale virus production, immunogenicity, toxicity and insertional mutagenesis are their common disadvantages. Current strategies to overcome these disadvantages are; (i) localized delivery and transcriptional targeting for toxicity and off-target effects (ii) immunosuppressive drugs and anti-inflammatory agents for immune response and (iii) biomaterial-mediated viral gene delivery [4]. The polymers can be used for viral vector modification and evolving hybrid vectors is a promising strategy for gene therapy applications. Surface modification of Ads with cationic polymers can be done by (i) non-covalent coating (physical modification) (ii) covalent coating (chemical modification). Non-covalent coating strategies gain attention because of ease of manipulation [5]. In our recent study we aimed to prepare Ad/chitosan hybrid vector to deliver shPDGF-D in breast cancer cell line MDA-MB-231. We covalently coat Ad surface with different amount and molecular weight chitosan and investigate gene silencing efficiency of vectors. In vitro cell culture studies showed that both low and high molecular weight chitosan increased PDGF-D silencing efficiency of Ad5 vector at 48 hours significantly. Also, the invasion ability of MDA-MB-231 cells decreased after treatment with coated Ad vector correlated with PDGF-D silencing results [6]. In conclusion, the results showed that non-covalent modification of Ad surface with polymers increased in vitro silencing efficiency, which may allow decrease viral dose for safer and efficient therapy.Publication Open Access A Comparison Study of Fiber Diameter's Effect on Characteristic Features of Donepezil/Curcumin-Loaded Polycaprolactone/Polylactic Acid Nanofibers(2022-05-01) EKENTOK ATICI, CEYDA; GÜNDÜZ, OĞUZHAN; ÇAM, MUHAMMET EMİN; TATAR, ESRA; YAVUZ, AYŞE NUR; Aydin S., Kabaoglu I., Guler E., Topal F., YAVUZ A. N., EKENTOK ATICI C., TATAR E., Gurbuz F., GÜNDÜZ O., ÇAM M. E.Nanofibers (NFs) offer an alternative option for the treatment of Alzheimer\"s disease (AD) by addressing unmet clinical problems. In this study, anti-AD drugs, donepezil (DO) and curcumin (CUR), are loaded in polylactic acid/polycaprolactone NFs. The effect of fiber diameter on drug release behavior is mainly observed, and the successful loading of DO and CUR to NFs is demonstrated. The tensile strength of DO/CUR-loaded NFs (DNFs) with lower fiber diameter is found to be higher. The working temperature is increased by the decrease of glass transition temperature and increase of the melting temperature after loading drugs. Furthermore, the increase in the percentage of swelling and decrease in the degradation rate for NFs are observed due to the increase of fiber diameter. Encapsulation efficiency and burst release percentages for DNFs are augmented by the increase of fiber diameter. Nevertheless, DNFs exhibit a sustained drug release manner over 2 weeks. NFs do not demonstrate a toxic effect on L929 (mouse fibroblast) cells, and additionally, they promote cell proliferation. Considering all these results, it is proven that the fiber diameter affects all characteristic features of NFs, and DNFs lead to a new and promising drug delivery system for the treatment of AD.Publication Open Access Combination therapy with chitosan/siRNA nanoplexes targeting PDGF-D and PDGFR-β reveals anticancer effect in breast cancer(2022-11-22) EKENTOK ATICI, CEYDA; Şalva E., Özbaş S., Alan S., Özkan N., Ekentok-Atıcı C., Kabasakal L., Akbuğa J.Publication Metadata only Chitosan-based delivery of CRISPR-Cas9 plasmid in breast cancer stem cells(2023-01-01) EKENTOK ATICI, CEYDA; ÖZBAŞ, SUNA; Canak-Ipek T., Avci-Adali M., EKENTOK ATICI C., ŞALVA E., ÖZBAŞ S.© 2023 Marmara University Press.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.Publication Metadata only Chitosan modification-enhanced silencing effect of Ad5-shPDGF-D vector in breast cancer cell Line MDA-MB-231.(2022-04-29) EKENTOK ATICI, CEYDA; Ekentok-Atıcı C., Akbuğa J.Publication Open Access Preparation and in vitro characterization of laminarin based hydrogels(MARMARA UNIV, 2021) SEZER, ALİ DEMİR; Erden, Sila Tumen; Atici, Ceyda Ekentok; Comez, Birnur; Sezer, Ali DemirHydrogels are one of the most effective pharmaceutical forms because of several advantages in the treatment of burn and wound headings. Laminarin is a storage polysaccharide derived from brown algae and member of the 1-3-beta-D-glucan family. It is a heparin-like molecule and plays role in hemoslasis, regulation of cell growth and regeneration. Also, indirectly functional in neovascularizalion. In addition, accelerates the formation of fibroblast activity and re-epithelization. Aim of this study is prepare laminarin hydrogels and evaluate the ill vitro characteristics of hydrogels for use in various wounds. For this purpose, different hydrogel formulations prepared and examined, and evaluated by water absorption Ca racily, viscosity, rheological and mechanical properties and bioadhesion. II was observed that hydrogels prepared with laminarin are an ideal wound dressing as expected.