Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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Article Enhanced Doxorubicin Cytotoxicity on Breast Cancer Spheroids by Aptamer Targeted Co-Delivery With Hyaluronidase(Wiley, 2025) Kavruk, Murat; Demirel, Dide Su; Bonyadi, Farzaneh; Guner, Buket Cakmak; Dursun, Ali Dogan; Vakifahmetoglu, Cekdar; Ozalp, Veli CengizBreast cancer is one of the most prevalent solid tumors in women and can be classified into subtypes based on molecular characteristics, such as hormone receptor status and HER2 expression. Aptamers, highly specific affinity molecules, are extensively studied for targeted drug delivery using nanocarriers to enhance anti-cancer efficacy. This study focused on HER2-responsive co-delivery of doxorubicin and hyaluronidase via aptamer-gated mesoporous silica nanoparticles to improve therapeutic outcomes in solid tumors. SK-BR-3 spheroids are employed as a model for resistant tumor environments in solid tumors. Previous research is shown that conjugating cytotoxic drugs with nanoparticles or cells enhances drug penetration into tumor spheroids. In this work, doxorubicin is loaded into mesoporous silica nanoparticles and capped with HER2-specific aptamers, while the particle surface is functionalized with hyaluronidase. This dual-functionalized nanocarrier system achieves an approximate to 8.5-fold increase in cytotoxicity compared to aptamer-targeted delivery lacking hyaluronidase. The enhanced effect is attributed to hyaluronidase-mediated loosening of the spheroid structure, facilitating nanoparticle penetration and localized release of doxorubicin at high concentrations on HER2-positive cells.Article 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: 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: 33Citation - Scopus: 35Upregulation of Multi Drug Resistance Genes in Doxorubicin Resistant Human Acute Myelogeneous Leukemia Cells and Reversal of the Resistance(Taylor and Francis Ltd., 2007) Baran, Yusuf; Gür, Bala; Kaya, Pelin; Ural, Ali Uğur; Avcu, Ferit; Gündüz, UfukThe major problem in the treatment of acute myeloid leukemia (AML) patients results from multidrug resistance to administered anticancer agents. Drug resistance proteins, MDR1 and MRP1, which work as drug efflux pumps, can mediate the multidrug resistance of human leukemia cells. In this study, the mechanisms of resistance to doxorubicin-induced cell death in human HL60 AML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of doxorubicin resulted in the selection of HL60/DOX cells, which expressed about 10.7-fold resistance as compared to parental sensitive cells. The expression analyses of MRP1 and MDR1 drug efflux proteins in doxorubicin-sensitive and -resistant HL60 cells revealed that there was an upregulation of MRP1 gene in HL60/DOX cells as compared to parental sensitive cells. On the other hand, while there was no expression of MDR1 gene in parental cells, the expression of MDR1 gene was upregulated in HL60/DOX cells. HL60/DOX cells also showed cross-resistance to cytosine arabinoside (Ara-c). This resistance was reversed by a combination therapy of Ara-c and cyclosporine A. However, the expression levels of CD15 and CD16 surface markers were significantly decreased in HL60/DOX cells.