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Öğe Antisense oligonucleotide delivery to cancer cell lines for the treatment of different cancer types(Taylor & Francis Ltd, 2016) Kilicay, Ebru; Erdal, Ebru; Hazer, Baki; Turk, Mustafa; Denkbas, Emir BakiAmphiphilic poly(3-hydroxylalkanoate) (PHA) copolymers find interesting applications in drug delivery. The aim of this study was to prepare nucleic acid adsorbed on (PHB-b-PEG-NH2) nanoparticle platform for gene delivery. For this purpose, PHB-b-PEG-NH2 block copolymers were synthesized via transesterification reactions. The copolymers obtained were characterized by Proton Nuclear Magnetic Resonance (H-1-NMR), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) techniques. The cytotoxic, apoptotic and necrotic effects of these nanoparticles in the MDA 231 human breast cancer cell, the A549 human lung cancer cell and the L929 fibroblast cell lines were also investigated.Öğe Calcified and mechanically debilitated three-dimensional hydrogel environment induces hypertrophic trend in chondrocytes(Sage Publications Ltd, 2016) Celik, Ekin; Bayram, Cem; Akcapinar, Rumeysa; Turk, Mustafa; Denkbas, Emir BakiCurrently, the main focus on tissue engineering strategies is to mimic the extracellular matrix of the related tissues. Many studies accomplished to build tissue scaffolds to act as the natural surroundings of the specific interest, which can be established to behave like either healthy or unhealthy tissues. The latter one of these conditions is a quite new approach and crucial for the design of three-dimensional in vitro disease models. This study investigates the potential of a composite scaffold consisting hydroxyapatite-integrated fluorenyl-9-methoxycarbonyl diphenylalanine hydrogels by focusing on the optimization of this hybrid scaffold for the development of an in vitro model of degenerative cartilage. Cell growth, chondrocyte proliferation, extracellular matrix production, hypertrophy marker monitoring, scaffold mechanical properties, and morphological analysis were evaluated. Fluorenyl-9-methoxycarbonyl diphenylalanine dipeptides were dissolved in null cell culture media and pH decreased sequentially to compel peptides to self-organize into fibrous hydrogel scaffolds. Nano-hydroxyapatite crystals were incorporated into fluorenyl-9-methoxycarbonyl diphenylalanine hydrogels during the gelation to investigate the effect on chondrocytes. It is observed that hydroxyapatite incorporation into peptide hydrogels significantly increased the alkaline phosphatase activity and assymetrical cell divisions, which is appraised as an outcome of chondrocyte hypertrophy. It is concluded that chondrocytes develop a hypertrophic potential when they are cultured in a media with nano-hydroxyapatites in a three-dimensional cell culture matrix mimicking the extracellular matrix conditions of degenerative cartilage.Öğe Downregulation of ABCE1 via siRNA affects the sensitivity of A549 cells against chemotherapeutic agents(Humana Press Inc, 2015) Kara, Goknur; Tuncer, Sema; Turk, Mustafa; Denkbas, Emir BakiATP-binding cassette E1 (ABCE1) is involved in several biological functions in cancer cells such as tumor proliferation, antiapoptotic pathway and chemoresistance mechanism. This work aimed to investigate the alterations in chemosensitivity of A549 lung cancer cells for 5-Fluorouracil (5-FU) and irinotecan by silencing ABCE1 using specific small interfering RNAs (siRNA). The cells were treated with low doses of drugs, alone and also their combinations with ABCE1 siRNA. Cytotoxicity, cell proliferation and apoptosis/necrosis evaluations were performed in order to examine the effects of the combined treatment. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the downregulation of ABCE1. We also investigated the levels of B cell lymphoma 2 (Bcl-2) and mammalian target of rapamycin (mTOR) after the treatments by RT-PCR. Downregulation of ABCE1 improved the anticancer effects of 5-FU in inducing cell viability/proliferation inhibition and apoptosis/necrosis, whereas interestingly, almost did not change or slightly reduced the anticancer effects of irinotecan. ABCE1 expression significantly decreased by transfecting the cells with ABCE1 siRNA. Moreover, Bcl-2 and mTOR levels changed after the single or combined therapy in parallel with the apoptotic and antiproliferation effect. In conclusion, the simultaneous treatment of lung cancer cells with ABCE1 siRNA and 5-FU exhibited synergistic or additive effects; however, ABCE1 siRNA and irinotecan had unexpected antagonistic effects. Our findings demonstrate that the strategy of downregulation of ABCE1 may be included in conventional 5-FU chemotherapy for lung cancer, minimizing the usage of 5-FU at high dosages.Öğe The effect of calcium chloride concentration on alginate/Fmoc-diphenylalanine hydrogel networks(Elsevier Science Bv, 2016) Celik, Ekin; Bayram, Cem; Akcapinar, Rumeysaa; Turk, Mustafa; Denkbas, Emir BakiPeptide based hydrogels gained a vast interest in the tissue engineering studies thanks to great superiorities such as biocompatibility, supramolecular organization without any need of additional crosslinker, injectability and tunable nature. Fmoc-diphenylalanine (FmocFF) is one of the earliest and widely used example of these small molecule gelators that have been utilized in biomedical studies. However, Fmoc-peptides are not feasible for long term use due to low stability and weak mechanical properties at neutral pH. In this study, Fmoc-FF dipeptides were mechanically enhanced by incorporation of alginate, a biocompatible and absorbable polysaccharide. The binary hydrogel is obtained via molecular self-assembly of FmocFF dipeptide in alginate solution followed by ionic crosslinldng of alginate moieties with varying concentrations of calcium chloride. Hydrogel characterization was evaluated in terms of morphology, viscoelastic moduli and diffusional phenomena and the structures were tested as 3D scaffolds for bovine chondrocytes. In vitro evaluation of scaffolds lasted up to 14 days and cell viability, sulphated glycosaminoglycan (sGAG) levels, collagen type II synthesis were determined. Our results showed that alginate incorporation into FmocFF hydrogels leads to better mechanical properties and higher stability with good biocompatibility. (C) 2016 Elsevier B.V. All rights reserved.Öğe Effects of ABCE1 Down-Regulation by RNAi on Chemosensitivity of Lung Cancer Cells(Int Inst Anticancer Research, 2014) Kara, Goknur; Tuncer, Sema; Turk, Mustafa; Denkbas, Emir Baki…Öğe Novel layer-by-layer self-assembled peptide nanocarriers for siRNA delivery(Royal Soc Chemistry, 2017) Bozdogan, Betul; Akbal, Oznur; Celik, Ekin; Turk, Mustafa; Denkbas, Emir BakiAll complex and functional structures of nature consist of simple building blocks that are thermodynamically balanced and self-assembled at the molecular level. Production of functional bio-nanomaterials with molecular self-assembly mechanisms, based on a bottom-up approach, has become increasingly important in recent years. In this study, a biodegradable and biocompatible siRNA nanocarrier system, consisting of diphenylalaninamide (FFA) based nanoparticles, was developed for silencing of HER2, a gene known to be overexpressed in breast cancer. FFA contains an amide functional group that has a dipolar nature with zero net charge. Here we report an original approach to functionalizing peptide nanoparticles based on layer-by-layer polyelectrolyte deposition (LbL PD) technique. The resulting well-defined FFA nanoparticles (FFANPs) were coated with polycationic poly-Llysine (PLL) by cation-dipole interaction, giving rise to a net positive surface charge. The PLL coating improved the physical stability of FFANPs at physiological pH and temperature. The cationized FFANP was then interacted with the polyanionic siRNA, forming an FFANP-PLL/siRNA complex. Nanoparticles were then interacted with PLL one more time, to create a third layer that can prevent degradation of the siRNA by nucleases and achieve effective delivery of the siRNA into the cytoplasm. These original FFANP-PLL/siRNA/PLL were optimized to achieve efficient in vitro gene silencing. Overall, this study shows that FFANP-PLL/siRNA/PLL are promising gene carriers for gene silencing therapies.Öğe Preparation and characterization of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHX) based nanoparticles for targeted cancer therapy(Elsevier Science Bv, 2011) Kilicay, Ebru; Demirbilek, Murat; Turk, Mustafa; Guven, Eylem; Hazer, Baki; Denkbas, Emir BakiTargeted drug delivery systems are one of the most promising alternatives for the cancer therapy. Rapid developments on nanomedicine facilitated the creation of novel nanotherapeutics by using different nanomaterials. Especially polymer based nanoparticles are convenient for this purpose. In this study; a natural polymer (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), PHBHHX) was used as a base matrix for the production of a novel nanotherapeutic including antineoplastic agent, Etoposide and attached folic acid as a ligand on the nanoparticles. Modified solvent evaporation technique was used for the production of PHBHHX nanoparticles and the average size of the obtained PHBHHX nanoparticles were observed in the range of 180 nm and 1.5 mu m by the change in experimental conditions (i.e., homogenization rate, surfactant concentration and polymer/solvent ratio). By the increase in homogenization rate and surfactant concentration, size of the nanoparticles was decreased, while the size was increased by the increase in polymer/solvent ratio. Drug loading ratio was also found to be highly affected by polymer/drug ratio. Surface charge of the prepared nanoparticles was also investigated by zeta potential measurements. In the cytotoxicity tests; Etoposide loaded and folic acid attached PHBHHX nanoparticles were observed as more effective on HeLa cells than Etoposide loaded PHBHHX nanoparticles without attached folic acid. The cytotoxicity of folic acid conjugated PHBHHX nanoparticles to cancer cells was found to be much higher than that of normal fibroblast cells, demonstrating that the folate conjugated nanoparticles has the ability to selectively target to cancer cells. In addition, apoptotic/necrotic activities were evaluated for all formulations of the PHBHHX nanoparticles and parallel results with cytotoxicity tests were obtained. These studies demonstrate that the folic acid attached and Etoposide loaded PHBHHX nanoparticles seem as promising for the targeted cancer therapy. (C) 2011 Elsevier B.V. All rights reserved.Öğe Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells(Springer, 2015) Cengiz, Bagdat Burcu; Asik, Mehmet Dogan; Kara, Goknur; Turk, Mustafa; Denkbas, Emir BakiIn recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3: 1. Loading efficiencies of 98.69 % +/- 0.051 and 98.83 % +/- 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.Öğe Transscleral Delivery of Bevacizumab-Loaded Chitosan Nanoparticles(Amer Scientific Publishers, 2019) Ugurlu, Nagihan; Asik, Mehmet Dogan; Cakmak, Hasan Basri; Tuncer, Sema; Turk, Mustafa; Cagil, Nurullah; Denkbas, Emir BakiPurpose: The aim of this study was to synthesize bevacizumab-loaded nanoparticles and evaluate their effects on the treatment of posterior segment diseases via subtenon injections. Methods: Bevacizumab-loaded chitosan nanoparticles (BLCNs) were synthesized by the ionic gelation method, and their physicochemical characteristics and in vitro release profile were studied. The BLCNs were characterized using atomic force microscopy (AFM), FTIR spectroscopy, dynamic light scattering, and scanning electron microscopy. The BLCNs were delivered into rabbits' eyes via posterior subtenon injections. An immunohistochemical evaluation of the ocular tissues was performed, and the vitreous humor and serum bevacizumab levels were measured by ELISA. Results: Bevacizumab-loaded chitosan nanoparticles with a diameter of 80 to 380 nm were prepared and characterized. In vitro studies showed that after the first 5 days of the experiment, a significant increase in the drug release maintained the desired drug dosage for 3 weeks. Immunohistochemical in vivo studies revealed that there were BLCNs penetrating through the sclera. Furthermore, the intravitreal bevacizumab concentration reached a maximum concentration of 18 mu g/ml, and it decreased to 6 mu g/ml after only a week. Conclusion: The results revealed that subtenon injection of BLCNs is a promising alternative to intravitreal injections. In addition to the ELISA studies, immunohistochemical experiments confirmed that BLCNs enable transscleral bevacizumab penetration, and BLCN usage may provide the required bevacizumab levels for the treatment of posterior segment diseases.
