Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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Article Citation - Scopus: 13Her2-Targeted, Degradable Core Cross-Linked Micelles for Specific and Dual Ph-Sensitive Dox Release(John Wiley and Sons Inc, 2022) Bayram, N.N.; Ulu, G.T.; Topuzoğulları, M.; Baran, Y.; Dinçer, İşoğlu, S.Here, a targeted, dual-pH responsive, and stable micelle nanocarrier is designed, which specifically selects an HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles are prepared by core cross-linking via reversible addition−fragmentation chain-transfer (RAFT) polymerization with an acid-sensitive cross-linker followed by the conjugation of maleimide–doxorubicin to the pyridyl disulfide-modified micelles. Multifunctional nanocarriers are obtained by coupling HER2-specific peptide. Formation of micelles, addition of peptide and doxorubicin (DOX) are confirmed structurally by spectroscopical techniques. Size and morphological characterization are performed by Zetasizer and transmission electron microscope (TEM). For the physicochemical verification of the synergistic acid-triggered degradation induced by acetal and hydrazone bond degradation, Infrared spectroscopy and particle size measurements are used. Drug release studies show that DOX release is accelerated at acidic pH. DOX-conjugated HER2-specific peptide-carrying nanocarriers significantly enhance cytotoxicity toward SKBR-3 cells. More importantly, no selectivity toward MCF-10A cells is observed compared to HER2(+) SKBR-3 cells. Formulations cause apoptosis depending on Bax and Caspase-3 and cell cycle arrest in G2 phase. This study shows a novel system for HER2-targeted therapy of breast cancer with a multifunctional nanocarrier, which has higher stability, dual pH-sensitivity, selectivity, and it can be an efficient way of targeted anticancer drug delivery. © 2021 Wiley-VCH GmbHArticle Citation - WoS: 6Citation - Scopus: 6Investigation of Interactions of Doxorubicin With Purine Nucleobases by Molecular Modeling(Springer, 2022) Akdeniz, Esra Şahin; Selçuki, CenkDoxorubicin, an anthracycline antibiotic with anti-tumor activity, is produced by the bacterium Streptomyces peucetius. The interactions between doxorubicin and genetic material and the details of the intercalation with DNA have been controversial issues. Thus, the interactions of doxorubicin with purine nucleobases were studied by quantum mechanical methods. Initially, conformer analyses of doxorubicin were performed with Spartan 08 software and 319 different conformers from 422 initial structures for doxorubicin were obtained. Geometry optimizations and frequency analyses were performed for each structure using density functional theory (DFT) at B3LYP/6-31G** level using Gaussian 09 software. The most stable 20 conformers of doxorubicin and tautomers of purine nucleobases were optimized again with ɷB97XD/6-31G** level and their interactions were also analyzed at the same level. The Discovery Studio 3.5 Visualizer was used to draw the initial and optimized structures of investigated geometries. The noncovalent interactions (NCIs) were visualized by calculating reduced density gradient (RDG) with Multiwfn program. The color-filled isosurfaces and RDG scatter maps of most stable interaction geometries were plotted by Visual Molecular Dynamics (VMD) software and Gnuplot 5.3 software, respectively. This study showed that adenine, guanine, and hypoxanthine nucleobases interact with doxorubicin by forming strong hydrogen bonds and π-π interactions. Considering the normal cellular conditions, the effect of solvent (water) on the interaction geometries were also analyzed and when compared to gas phase it was determined that the movements of the molecules were restricted and there was a minimal change between initial and optimized structures in the aqueous phase.Article Citation - WoS: 1Citation - Scopus: 1Potansiyel Doksorubisin Taşıyıcı Sistemi Olarak Peg-endozom Parçalayıcı Peptit Konjugatının Değerlendirilmesi(Gazi Üniversitesi, 2020) Şen, Selin; Top, AybenIn this study, it was aimed to develop a doxorubicin (DOX) carrier system based on a PEGylated TAT-derived cell penetrating peptide (G(2)RQR(3)QR(3)G(2)S) and to investigate drug release, self-assembly and stability properties of the carrier system. In the preparation of the drug delivery system, denoted as mPEG-peptide-oxime-DOX, methoxypolyethylene glycol (mPEG) with M-n=1900 Da was used. DOX was attached to the mPEG-peptide carrier system via acid cleavable oxime bond. Control drug delivery system, lack of the peptide (mPEG-oxime-DOX) was also synthesized to assess the effect of the peptide on the physicochemical and DOX release properties of the carrier system. mPEG-oxime-DOX exhibited a pH programmed DOX release with respective % DOX release values of similar to 68% and similar to 28% at pH 5.0 and at pH 7.4 at the end of 54 h. For the mPEG-peptide-oxime-DOX, on the other hand, quite low DOX release (similar to 10-15 %) was observed for both pH values suggesting possible interactions between DOX and the peptide. Initial median size value (D50) of the mPEG-oxime-DOX was measured as similar to 24 nm, independent of pH. However, for the mPEG-peptide-oxime-DOX, quite lower D50 values (similar to 3 nm and similar to 6 nm at pH 5.0 and pH 7.4, respectively) were obtained due to the repulsions between the arginines in the peptide sequence. Sizes of both drug delivery systems, tended to increase upon incubation at physiological conditions for 1 day suggesting that longer PEG chains should be used to enhance the stability of the mPEG-peptide-oxime-DOX and mPEG-oximeDOX systems.Article Citation - WoS: 15Citation - Scopus: 13Cascade Therapy With Doxorubicin and Survivin-Targeted Tailored Nanoparticles: an Effective Alternative for Sensitization of Cancer Cells To Chemotherapy(Elsevier Ltd., 2019) Dağlıoğlu, Cenk; Kacı, Fatma NecmiyeChemotherapy frequently involves combination treatment protocols to maximize tumor cell killing. Unfortunately these intensive chemotherapeutic regimes, often show disappointing results due to the development of drug resistance and higher nonspecific toxicity on normal tissues. In cancer treatment, it is critically important to minimize toxicity while preserving efficacy. We have previously addressed this issue and proposed a nanoparticle-based combination therapy involving both a molecularly targeted therapy and chemotherapeutic agent for neutralizing antiapoptotic survivin (BIRC5) to potentiate the efficacy of doxorubicin (DOX). Although the particles exhibited strong anticancer effect on the lung carcinoma A549 and the cervical carcinoma HeLa cells, there were lower-level therapeutic outcomes on the colon carcinoma HCT-116, the leukemia Jurkat and the pancreatic carcinoma MIA PaCa-2 cells. Since targeted therapies are one of the key approaches for overcoming drug resistance, tailoring the treatment of cancer cells with distinct characteristics is necessary to improve the therapeutic outcome of cancer therapy and to minimize potential pharmacokinetic interactions of drugs. In the light of this issue, this study examined whether a cascade therapy with low-dose DOX and survivin-targeted tailored nanoparticles is more effective at sensitizing HCT-116, Jurkat and MIA PaCa-2 cancer cells to DOX-chemotherapy than simultaneous combination therapy. The results demonstrated that the sequential therapy with the protocol comprising addition of the nanoparticles after incubation of cells with DOX clearly advanced the therapeutic outcome of related cancer cells, whereas the reverse protocol resulted in a reduction or delay in apoptosis, emphasizing the critical importance of formulating synergistic drug combinations in cancer therapy.Article Citation - WoS: 12Citation - Scopus: 12Peg and Peg-Peptide Based Doxorubicin Delivery Systems Containing Hydrazone Bond(Springer Verlag, 2018) Balcı, Beste; Top, AybenmPEG and mPEG-peptide based drug delivery systems were prepared by conjugating doxorubicin (DOX) to these carrier molecules via hydrazone bond. The peptide, AT1, with a sequence of CG3H6G3E served as mPEG and doxorubicin attachment site. Histidines were incorporated to the sequence to improve pH responsiveness of the carrier molecule. Hydrodynamic diameters (mean sizes) of mPEG-based drug delivery system (mPEG-HYD-DOX) were measured as 9 ± 0.5 and 7 ± 0.5 nm at pH 7.4 and pH 5.0, respectively. Mean size of the aggregates of the peptide containing drug delivery system, mPEG-AT1-DOX, was determined as 12 ± 2 nm at neutral pH. At pH 5.0, on the other hand, mPEG-AT1-DOX exhibited a size distribution between 20 and 100 nm centered at about 40 nm. Comparison of % DOX release values of the drug delivery systems obtained at pH 7.4 and pH 5.0 indicated that mPEG-AT1-DOX has enhanced pH sensitivity. DOX equivalent absolute IC50 values were obtained as 0.96 ± 0.51, 21.9 ± 5.9, and 5.55 ± 0.75 μg/mL for free DOX, mPEG-HYD-DOX, and mPEG-AT1-DOX, respectively. Considering more pronounced pH sensitivity and cytotoxicity of mPEG-AT1-DOX, the use of both pH responsive functional groups and acid cleavable chemical bond between the carrier molecule and drug can be a promising approach in the design of drug delivery systems for cancer therapy.Article Citation - WoS: 42Citation - Scopus: 47Ph Responsive Glycopolymer Nanoparticles for Targeted Delivery of Anti-Cancer Drugs(Royal Society of Chemistry, 2018) Yılmaz, Gökhan; Güler, Emine; Geyik, Caner; Demir, Bilal; Özkan, Melek; Odacı Demirkol, Dilek; Özçelik, Serdar; Timur, Suna; Becer, C. RemziOver the past decade, there has been a great deal of interest in the integration of nanotechnology and carbohydrates. The advances in glyconanotechnology have allowed the creation of different bioactive glyconanostructures for different types of medical applications, especially for drug delivery and release systems. Therefore, the use of more efficient biocompatible nanocarriers with high loading capacity, low overall toxicity and receptor-mediated endocytosis specificity is still in focus for the enhancement of the therapeutic effect. Conjugation of sugar derivatives onto gold nanoparticles presents unique properties that include a wide array of assembling models and size-related electronic, magnetic and optical properties. Here, pH-responsive drug-conjugated glycopolymer-coated gold nanoparticles were prepared by functionalization of gold nanoparticles with thiol-terminated glycopolymers and then subsequent conjugation of doxorubicin (DOX). Among the four different glycopolymers, their drug release, physicochemical characterization (spectroscopy, particle size and surface charge) and in vitro bioapplications with four different cell lines were compared. As a result, pH-sensitive drug delivery via sugar-coated AuNPs was performed thanks to hydrazone linkages between glycopolymers and DOX. Comparative viability tests also demonstrated the efficiency of glycopolymer-DOX conjugates by fluorescence cell imaging. The obtained results reveal that AuNP homoglycopolymer DOX conjugates (P4D) have significant potential, especially in human neuroblastoma cells in comparison to cervical cancer cells and lung cancer cells.Article Citation - WoS: 4Citation - Scopus: 4PEG-peptide conjugate containing cathepsin B degradation unit as a doxorubicin carrier system(TUBITAK, 2018) Şentürk, Nesligül; Top, AybenA drug delivery system (DDS) containing a cathepsin B degradable sequence and pH-responsive histidines was prepared by methoxypolyethylene glycol and peptide conjugation. Doxorubicin was attached to the carrier system using amide linkage to give the final form of the DDS, denoted as mPEG-AT3-DOX. mPEG-AT3-DOX exhibited a bimodal size distribution at about 15 and 30 nm independent of pH, whereas the size of the control DDS containing no peptide sequence, mPEG-DOX, was measured as ∼ 15–20 nm. At the end of 72 h, % doxorubicin release from both of the DDSs was observed to be below 8.5 ± 3% in the absence of cathepsin B, and it increased to 17 ± 2% in the presence of cathepsin B for mPEG-AT3-DOX. Complete degradation of AT3 peptide within 3 h upon incubation with cathepsin B suggests that lower than expected doxorubicin release is likely due to the aggregation tendency of mPEG-AT3-DOX. Absolute IC50 values indicated that the cytotoxicity trend of the samples is in the order of free DOX ≥ mPEG-AT3-DOX >mPEG-DOX. Considering these results, PEG-peptide-doxorubicin conjugates can be promising candidates in cancer therapy if they are designed to have more pronounced pH-responsive behavior to increase the drug release rate.Article Citation - WoS: 25Citation - Scopus: 23Synthesis and Characterization of Aicar and Dox Conjugated Multifunctional Nanoparticles as a Platform for Synergistic Inhibition of Cancer Cell Growth(American Chemical Society, 2016) Dağlıoğlu, Cenk; Okutucu, BurcuThe success of cancer treatment depends on the response to chemotherapeutic agents. However, malignancies often acquire resistance to drugs if they are used frequently. Combination therapy involving both a chemotherapeutic agent and molecularly targeted therapy may have the ability to retain and enhance therapeutic efficacy. Here, we addressed this issue by examining the efficacy of a novel therapeutic strategy that combines AICAR and DOX within a multifunctional platform. In this context, we reported the bottom-up synthesis of Fe3O4@SiO2(FITC)-FA/AICAR/DOX multifunctional nanoparticles aiming to neutralize survivin (BIRC5) to potentiate the efficacy of DOX against chemoresistance. The structure of nanoparticles was characterized by dynamic light scattering (DLS), zeta-potential measurement, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and electron microscopy (SEM and STEM with EDX) techniques. Cellular uptake and cytotoxicity experiments demonstrated preferentially targeted delivery of nanoparticles and an efficient reduction of cancer cell viability in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat, and MIA PaCa-2). These results indicate that the multifunctional nanoparticle system possesses high inhibitory drug association and sustained cytotoxic effect with good biocompatibility. This novel approach which combines AICAR and DOX within a single platform might be promising as an antitumor treatment for cancer.Article Citation - WoS: 10Citation - Scopus: 10High-Copy Overexpression Screening Reveals Pdr5 as the Main Doxorubicin Resistance Gene in Yeast(Public Library of Science, 2015) Demir, Ayşe Banu; Koç, AhmetDoxorubicin is one of the most potent anticancer drugs used in the treatment of various cancer types. The efficacy of doxorubicin is influenced by the drug resistance mechanisms and its cytotoxicity. In this study, we performed a high-copy screening analysis to find genes that play a role in doxorubicin resistance and found several genes (CUE5, AKL1, CAN1, YHR177W and PDR5) that provide resistance. Among these genes, overexpression of PDR5 provided a remarkable resistance, and deletion of it significantly rendered the tolerance level for the drug. Q-PCR analyses suggested that transcriptional regulation of these genes was not dependent on doxorubicin treatment. Additionally, we profiled the global expression pattern of cells in response to doxorubicin treatment and highlighted the genes and pathways that are important in doxorubicin tolerance/toxicity. Our results suggest that many efflux pumps and DNA metabolism genes are upregulated by the drug and required for doxorubicin tolerance.Article Citation - WoS: 13Citation - Scopus: 15In Vitro Evaluation of Doxorubicin-Incorporated Magnetic Albumin Nanospheres(John Wiley and Sons Inc., 2014) Zeybek, Ayça; Şanlı Mohamed, Gülşah; Ak, Güliz; Yılmaz, Habibe; Şanlıer, Şenay H.Magnetic albumin nanospheres that incorporate doxorubicin (M-DOX-BSA-NPs) were prepared previously by our research group to develop magnetically responsive drug carrier system. This nanocarrier was synthesized as a drug delivery system for targeted chemotherapy. In this work, cytotoxic effects of doxorubicin (DOX)-loaded/unloaded or magnetic/non-magnetic nanoparticles and free DOX against PC-3 cells and A549 cells were determined with the MTT test and the results were compared with each other. DOX-loaded magnetic albumin nanospheres (M-DOX-BSA-NPs) were found more cytotoxic than other formulations. The quantitative data obtained from flow cytometry analysis further verified the higher targeting and killing ability of M-DOX-BSA-NPs than free DOX on both of the cancer cell lines. Additionally, the results of cell cycle analysis have showed that M-DOX-BSA-NPs affected G1 and G2 phases. Finally, cell images were obtained using spin-disk confocal microscopy, and cellular uptake of M-DOX-BSA-NPs was visualized. The findings of this study suggest that M-DOX-BSA-NPs represent a potential doxorubicin delivery system for targeted drug transport into prostate and lung cancer cells. In this study, we found that M-DOX-BSA-NPs provide many advantages as targeted drug delivery, enhanced drug killing ability and bioavailability based on cytotoxicity, flow cytometry, and confocal microscopy image results.