Person: ÖZBAŞ, SUNA
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ÖZBAŞ
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SUNA
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Publication Metadata only Investigation of the Therapeutic Efficacy of Codelivery of psiRNA-Vascular Endothelial Growth Factor and pIL-4 into Chitosan Nanoparticles in the Breast Tumor Model(ELSEVIER SCIENCE INC, 2014) EREN, FATİH; Salva, Emine; Turan, Suna O.; Kabasakal, Levent; Alan, Saadet; Ozkan, Naziye; Eren, Fatih; Akbuga, JulideAngiogenesis has been known to increase tumor growth and for its metastatic potential in human tumors. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis and is a promising therapeutic target for breast cancer. VEGF is an essential target for RNAi-based gene therapy of breast cancer. Interleukin-4 (IL-4) may act as an anti-angiogenic molecule that inhibits tumor growth and migration in rats. The purpose of the present study was to improve therapeutic efficacy in breast cancer with the codelivery of siRNA-expressing plasmid targeting VEGF and IL-4-expressing plasmid encapsulating into chitosan nanoparticles (NPs). The codelivery of psiVEGF and pIL-4 plasmids greatly enhanced in vitro and in vivo gene-silencing efficiency. For the in vitro study, when psiVEGF and pIL-4 into chitosan NPs were combined (81%), the gene-silencing effect was higher than psiVEGF and pIL-4 NPs alone. The in vivo study breast tumor model demonstrated that the administration of coencapsulation of psiVEGF and pIL-4 into chitosan NPs caused an additive effect on breast tumor growth inhibition (97%), compared with containing NPs psiVEGF or pIL-4 alone. These results indicate that chitosan NPs can be effectively used for the codelivery of pIL-4 and siVEGF-expressing plasmid in a combination therapy against breast cancer. (c) 2013 Wiley Periodicals, Inc.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 The Development of Ternary Nanoplexes for Efficient Small Interfering RNA Delivery(2013) ÖZBAŞ, SUNA; Şalva, Emine; Özbaş Turan, Suna; Akbuğa, JülidePublication Open Access A new gene therapy approach by tenascin-c genome editing induces apoptosis and cell cycle arrest in triple- negative breast cancer cells(2023-02-01) ÖZBAŞ, SUNA; Bareke H., ŞALVA E., ÖZBAŞ S.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.Publication Open Access In vitro cytotoxic effect of PARP inhibitor alone and in combination with nab-paclitaxel on triple-negative and luminal A breast cancer cells(SPANDIDOS PUBL LTD, 2018-04-12) ÖZBAŞ, SUNA; Topcul, Mehmet; Cetin, Idil; Turan, Suna Ozbas; Ozar, Melek Ozlem KolusayinIn the present study, the in vitro cytotoxic effect of poly(ADP-ribose) polymerase (PARP) inhibitor alone and in combination with nab-paclitaxel was evaluated on human triple-negative breast cancer (TNBC) cell line MDA-MB-231 and human luminal A breast cancer cell line MCF-7. For this purpose, cell index (CI) values obtained from xCELLigence Real-Time Cell Analysis (RTCA) DP instrument, mitotic index (MI), labelling index (LI) and apoptotic index (AI) analysis among cell kinetic parameters were used. As a result of PARP inhibitor application, there was a significant decrease in CI, MI and LI and a significant increase in AI for all the experimental groups. After application of PARP inhibitor in combination with nab-paclitaxel, the CI values were decreased for both cell lines, and the differences between the control and all the experimental groups were statistically significant (P<0.01) for all applications. PARP inhibitor, alone or in combination with nab-paclitaxel offers a promising treatment modality in different breast cancer subtypes.Publication Open Access Generation of stable cell line by using chitosan as gene delivery system(SPRINGER, 2016-08) EKENTOK ATICI, CEYDA; Salva, Emine; Turan, Suna Ozbas; Ekentok, Ceyda; Akbuga, JulideEstablishing stable cell lines are useful tools to study the function of various genes and silence or induce the expression of a gene of interest. Nonviral gene transfer is generally preferred to generate stable cell lines in the manufacturing of recombinant proteins. In this study, we aimed to establish stable recombinant HEK-293 cell lines by transfection of chitosan complexes preparing with pDNA which contain LacZ and GFP genes. Chitosan which is a cationic polymer was used as gene delivery system. Stable HEK-293 cell lines were established by transfection of cells with complexes which were prepared with chitosan and pVitro-2 plasmid vector that contains neomycin drug resistance gene, beta gal and GFP genes. The transfection efficiency was shown with GFP expression in the cells using fluorescence microscopy. Beta gal protein expression in stable cells was examined by beta-galactosidase assay as enzymatically and X-gal staining method as histochemically. Full complexation was shown in the above of 1/1 ratio in the chitosan/pDNA complexes. The highest beta-galactosidase activity was obtained with transfection of chitosan complexes. Beta gal gene expression was 15.17 ng/ml in the stable cells generated by chitosan complexes. In addition, intensive blue color was observed depending on beta gal protein expression in the stable cell line with X-gal staining. We established a stable HEK-293 cell line that can be used for recombinant protein production or gene expression studies by transfecting the gene of interest.Publication Open Access Publication Open Access Plasmid DNA-loaded chitosan/TPP nanoparticles for topical gene delivery(INFORMA HEALTHCARE, 2011-04) ÖZBAŞ, SUNA; Ozbas-Turan, Suna; Akbuga, JulideTopical application of plasmid DNA represents an attractive route of gene delivery. Although chitosan (CS) has been widely investigated as a gene-carrier, there is very limited information about the skin application of CS-based systems for DNA. This study evaluated pDNA-loaded chitosan nanoparticles (CS-NPs) for skin gene delivery. NPs were prepared by inducing the gelation of CS upon interaction with sodium tripolyphosphate. pSV-beta-Gal was used as a reporter gene. The size, surface charge, and the other in vitro characteristics of CS-NPs were examined. Primary human dermal fibroblast cells (HDF) and mouse fibroblast NIH 3T3 cell lines (ATCC CCL-92) were used for in vitro transfection studies. In in vivo study, CS-NPs were applied to the skin of baby and adult Sprague Dawley rats by spreading on the shaved area of the back of animals. During a week animals were sacrificed and skin biopsies were taken for beta-Gal expression. beta-galactosidase enzyme activity was determined spectrophotometrically at 420 nm. The distribution of beta-galactosidase expressing cells within the skin tissue was observed by X-gal histochemical method. beta-galactosidase was continuously expressed at the nanoparticle-treated skin during the 7 days. High and continuous beta-Gal expressions were obtained with CS-NPs, although it was low in the first day. When a comparison was made between the data of baby and adult rats, markedly high transfection were measured in the skin samples of the baby rats. NPs protected pDNA against the enzyme and serum attacks. In conclusion, CS-NPs showed in vivo transfection potential in rats for skin gene delivery.Publication Metadata only Inhibition of Glomerular Mesangial Cell Proliferation by siPDGF-B- and siPDGFR-beta-Containing Chitosan Nanoplexes(SPRINGER, 2017) ÖZBAŞ, SUNA; Salva, Emine; Turan, Suna Ozbas; Akbuga, JulideMesangioproliferative glomerulonephritis is a disease that has a high incidence in humans. In this disease, the proliferation of glomerular mesangial cells and the production of extracellular matrix are important. In recent years, the RNAi technology has been widely used in the treatment of various diseases due to its capability to inhibit the gene expression with high specificity and targeting. The objective of this study was to decrease mesangial cell proliferation by knocking down PDGF-B and its receptor, PDGFR-beta. To be able to use small interfering RNAs (siRNAs) in the treatment of this disease successfully, it is necessary to develop appropriate delivery systems. Chitosan, which is a biopolymer, is used as a siRNA delivery system in kidney drug targeting. In order to deliver siRNA molecules targeted at PDGF-B and PDGFR-beta, chitosan/siRNA nanoplexes were prepared. The in vitro characterization, transfection studies, and knockdown efficiencies were studied in immortalized and primary rat mesangial cells. In addition, the effects of chitosan nanoplexes on mesangial cell proliferation and migration were investigated. After in vitro transfection, the PDGF-B and PDGFR-beta gene silencing efficiencies of PDGF-B and PDGFR-beta targeting siRNA-containing chitosan nanoplexes were 74 and 71% in immortalized rat mesangial cells and 66 and 62% in primary rat mesangial cells, respectively. siPDGF-B- and siPDGFR-beta-containing nanoplexes indicated a significant decrease in mesangial cell migration and proliferation. These results suggested that mesangial cell proliferation may be inhibited by silencing of the PDGF-B signaling pathway. Gene silencing approaches with chitosan-based gene delivery systems have promise for the efficient treatment of renal disease.Publication Metadata only Synthesis of 1-aroyl-3,5-dimethyl-1H-pyrazoles as anti-HCV and anticancer agents(2014) ORUN, OYA; Aydin S., Kaushik-Basu N., Özbaş-Turan S., Akbuǧa J., Tiber P.M., Orun O., Gurukumar K.R., Basu A., Küçükgüzel Ş.G.1-Aroyl-3,5-dimethyl-1H-pyrazole derivatives (7-12) were synthesized from some hydrazides (1-6) with acetylacetone (2,4-pentanedione) by microwave irradiation. Their structures were elucidated by FT-IR and 1H-NMR spectral data and elemental analysis. Compound activities were evaluated against HCV NS5B and in cell based HCV reporters. Compound 8 was the most promising of this series in inhibiting intracellular NS5B activity and HCV RNA replication in reporter cells. The selected compounds 9, 10 and 12 by National Institue of Health were screened for their anticancer activity against 60 human tumor cell lines. Compound 9 (3-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-2′,4′- difluorobiphenyl-4-ol) possessed significant activity against human immortalized myelogenous leukemia (K-562) exhibiting cell growth promotion 30.05%, with inhibition of 69.95% at 10-5M concentration. Compounds 3 and 9 were evaluated for cell viability and growth inhibition by K-562 cells of MTT assay, at different doses (10-6- 10-2M). Further, compound 9 exhibited anticancer activity against K-562 cells with IC50 value of 4 μM . Apoptosis levels of compound 9 were determined for three different concentrations (10-6, 10-5 and 10-3M) at two time points (24 and 48 h). Compound 9 induced apoptosis of K-562 cells, thus suggesting that compound 9 might be a potential chemopreventive agent for chronic myelogenous leukemia. © 2014 Bentham Science Publishers.