Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Development of Ultrasound Triggered Drug Delivery Systems for Cancer Treatment(Izmir Institute of Technology, 2019) Önercan, Cansu; Kılıç Özdemir, Sevgi; Kılıç Özdemir, Sevgi; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyDoxorubicin (DOX) is one of the most commonly used hydrophilic anticancer drug in cancer treatment. However, when it is used in free form, it can attack not only cancer cells but also healthy cells. So as to prevent entering of DOX to the healthy cells, the encapsulation method is employed. Liposomes are suitable for encapsulation of DOX but the most important problems with the use of liposome are hand-foot syndrome and stomatitis. Encapsulation method is not enough because of these reasons, thus delivery of DOX to the desired site by targeted therapy has gained interest in recent years. In this study, DOX was encapsulated into liposomes and the DOX loaded liposomes (LipoDOX) was attached to microbubbles (MBs). MBs as ultrasound contrast agents are widely used in medical imaging. Use of MBs in combination of DOX loaded liposomes facilitates the uptake of the drug because ultrasound cavitation results in opening of transient pores in cell membrane via a process named sonoporation. Herein, MB-LipoDOX complex was engineered to optimize the size of the complex as well as the loaded DOX content. For this purpose, determination of incubation temperature and time for DOX loading into liposome and optimization of liposome formulation for maximum DOX loading were studied. Ratios of Lipid/Cholesterol/PEGylated lipid, PEG chain length and PEG molar ratio in liposome were determined. Also, determination of Strept Avidin (StAv) to Biotin ratio in LipoDOX and the amount of LipoDOX in LipoDOX-MB complex were studied. For characterization, Dynamic Light Scattering (DLS) method, Fluorescence Spectrometry method and Coulter Counter device were used. Lipoosme size was found to be associated with the pore size of polycarbonate membrane (200nm) resulting in liposomes at around 190±5 nm in size . When the PEGylated lipid with PEG chain of 2000 was used in liposome structure, particle size distribution is more monodispersed than the others. The maximum amount of DOX loaded liposomes was obtained at 32% Cholesterol, 5% DSPE-PEG2000, after 90 min. incubation at 65oC incubation. Optimum StAv to Biotin ratio in LipoDOX was determined as 1.0. The optimum molar ratio of Biotinylated lipids in LipoDOX was determined as 0.05% and the optimum molar ratio of Biotinylated lipids in MBs was determined as 8%.Master Thesis Determination of Therapeutic Effects of Multifunctional Micelle-Based Nanocarriers on Breast Cancer Cells(Izmir Institute of Technology, 2019) Ulu, Gizem Tuğçe; Baran, Yusuf; Ulu, Gizem Tuğçe; Baran, Yusuf; 01.01. Units Affiliated to the Rectorate; 04.03. Department of Molecular Biology and Genetics; 01. Izmir Institute of Technology; 04. Faculty of ScienceBreast cancer is the most common and frequent cause of death among women composed to all types of cancer. Current treatment protocols do not provide complete cure or selective drug delivery while targeted therapy can provide an important avenue for successful treatment of breast cancer. In this study, therapeutic effects of drug-conjugated nanocarrier system with enhanced stability and double moiety pH-sensitivity on breast cancer (SKBR-3- HER-2- positive), normal breast epithelial (MCF-10A, HER-2-negative) and chronic myeloid leukemia (K562, HER-2-negative) cells were determined. With this approach, SKBR-3 cells were targeted by single nanocarriers having selectivity with unused peptide ligand (HER-2), stability with cross-linking of core moiety, and cleavage by two sites of pHeffect and drug release properties. After physicochemical characterization of micellebased nanocarriers, cytotoxic, apoptotic and cytostatic effects of doxorubicin conjugated micelles were determined. Doxorubicin conjugated micelles with HER-2 peptide (DOX-HER-2-NCs) had more cytotoxic effects on HER-2 positive cells. Additionally, intracellular amounts of doxorubicin is higher in SKBR-3 cells with applied DOX-HER-2-NCs as determined by fluorescence imaging. The apoptosis rate was increased on SKBR-3 at 50% cell growth inhibition (IC50) as determined by Annexin-V/Propidium iodide double staining. However, there was not any significant change in loss of mitochondrial membrane potential. Additionally, DOX-HER-2-NCs resulted in cell cycle arrest at G2/M-phase in response to IC50 value. Besides, protein level of Bcl-2 did not change while protein level of Bax and Caspase-3 were increased as determined by Western Blotting. This project provides novel and more effective treatment of breast cancer by using multifunctional properties of nanocarriers.Master Thesis Development of Endosome Disruptive Peptide and Peg Conjugate Based Doxorubicin Delivery System(Izmir Institute of Technology, 2019) Özkıyıcı, Selin; Top, Ayben; Top, Ayben; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyIn this study, it was aimed to develop a drug carrier system including a TAT-derived cell penetrating peptide in order to provide fast transport of anticancer drugs from endosomal compartments to nucleus. The drug delivery system, denoted as mPEGpeptide- oxime-DOX, was based on polyethylene glycol, endosome disruptive peptide (G2RQR3QR3G2S), and doxorubicin (DOX) conjugate. Control drug delivery system, lack of the peptide (mPEG-oxime-DOX) was also synthesized to assess the effect of the peptide on the physiochemical and drug release properties of the drug carrier. As the first synthesis step, mPEG-OH was converted to mPEG-aldehyde form using DMSO-acetic anhydride oxidation reaction and aldehyde functionalization was determined by using FTIR and NMR spectroscopy. The peptide and mPEG-peptide were synthesized using solid phase synthesis protocol, and their purities were confirmed using HPLC and MALDI-TOF mass spectroscopy analyses. Prior to DOX conjugation, hydroxyl group of serine residue in the mPEG-peptide system was oxidized to aldehyde. The anticancer drug was attached to the carrier molecules via amine-aldehyde reaction forming an acid cleavable oxime bond. Drug release, size distribution, and stability of the PEG-peptideoxime- DOX system were evaluated and compared with those results of the control drug delivery system. For mPEG-oxime-DOX, a pH programmed DOX release with the respective % DOX release values of ~68 % and ~28 % at pH 5.0 and pH 7.4 was observed. For mPEG-peptide-oxime-DOX, on the other hand, quite low DOX release (~10-15 %) was obtained for both pH values suggesting possible interaction between DOX and the peptide. Mean size value of the mPEG-oxime-DOX was measured as ~24 nm. However, mPEG-peptide-oxime-DOX, had quite lower hydrodynamic diameter values (~3nm and ~6 nm at pH 5.0 and pH 7.4, respectively) possibly due to repulsions between the arginines in the peptide domain. Observation of the morphology and evaluation of the cytotoxicity of these drug delivery systems are underway.Master Thesis Lab-on-a-chip devices for drug screening(Izmir Institute of Technology, 2019) Gökçe, Begüm; Pesen Okvur, Devrim; Çağır, Ali; Pesen Okvur, Devrim; Çağır, Ali; 04.03. Department of Molecular Biology and Genetics; 04.01. Department of Chemistry; 04. Faculty of Science; 01. Izmir Institute of TechnologyBreast cancer is one of the cancers with the highest incidence and mortality rates in women in Turkey as well as in the world. Tumor micro environment comprises of cancer and normal cells, extracellular matrix, soluble biological and chemical factors. Research has shown that cell shape, adhesion, migration, response to growth factors and drugs are different in 2D and 3D culture. Today, only 8 out of 100 anti-cancer clinical trial gives effective results. 3D cell culture systems have shown to be a necessary step between in vitro, in vivo and clinical studies. Therefore, it is necessary to better understand the interactions of cancer cells with their micro environment, for which new cell culture setups are required. The most apparent disadvantage of widely used 3D cell culture setups is the lack of stromal cells. The systems to be developed should both provide a 3D environment and comprise multiple cell types. The drug screen in 3D tri-culture method with a lab-on-a-chip device, that will be developed in this study will be able to answer these needs. Cell lines that represent different breast cancer types alone or together with stromal cells were cultured in 3D in the to be developed lab-on-a-chip; by determining the effects of drugs with different targets on the viability and distribution of cells, a drug screening method is developed.Master Thesis Development of Drug-Loaded Microbubbles for In-Vitro Applications in Cell Biology(Izmir Institute of Technology, 2017) Coşkun, Sema; Özdemir, Ekrem; Özdemir, Ekrem; Sultan Altun, Zekiye; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyDoxorubicin (DOX) is one of the drugs for cancer therapy. When DOX is used in solution, it affects not only the cancer cells but also the healthy cells. In order to eliminate possible side effects, DOX was encapsulated within liposomes and applied for the cancer therapy. Because the circulation time for liposomes is longer in the body, they accumulate in capillaries, especially at the finger tips and at the toe of the foot called the hand-and-foot syndrome. Here, we proposed to couple the liposomes containing DOX with the microbubbles as the ultrasound contrast agent and deliver the drug to the area of interest. Therefore, DOX was loaded within the liposomes and characterized for their DOX contents. The DOX containing liposomes were conjugated with microbubbles through the avidin-biotin chemistry. It was found that the loaded- DOX content within the liposomes was Langmuir-type. The loaded DOX content increased at lower DOX concentrations and leveled off at higher DOX concentrations. The Langmuir constants can be used in designing DOX loading experiments. The DOX containing liposomes were coupled with the microbubbles and found an optimum of 7.0 for the avidin/biotin mole ratio on the microbubbles. At the optimum avidin/biotin ratio, the conjugated lipo-DOX amount was 3×10-8 μg-DOX/MB. It was concluded that the DOX molecules can be loaded within the liposomes and easily conjugated with the microbubbles and employed in cancer treatments.Master Thesis Comparison Od Side Effects of Anti-Cancer Drugs in 2d and 3d And, Classical and Cell-On Cultures(Izmir Institute of Technology, 2016) Kankale, Deniz; Çağır, Ali; Pesen Okvur, Devrim; Pesen Okvur, Devrim; Çağır, Ali; 04.03. Department of Molecular Biology and Genetics; 04.01. Department of Chemistry; 04. Faculty of Science; 01. Izmir Institute of TechnologyThe studies that aim to assess the effects of drugs developed against cancer at the cellular level use multiwell plates. However, these classical systems fail to reproduce the in-vivo like microenvironment necessary for realistic assessment. In addition, classical cell culture systems use high amount of materials increasing cost. On the other hand, lab-on-a-chip systems use minimal volumes of reagents and more importantly can mimic the in-vivo microenvironment via spatial and temporal control. Furthermore, it is known that cell response to drugs can be very different in 2D and 3D cell culture setups. Doxorubicin is a widely used anticancer drug. Here, doxorubicin uptake by highly metastatic human breast cancer cell line MDA-MB-231 and normal mammary epithelial cell line MCF10A were investigated using 2D and 3D, classical and cell-on-a-chip cultures. Drug uptake at 24, 48 and 72 hours various concentrations of the drug determined by measuring signal intensities from fluorescence microscopy images of cells. For cell viability assay, cells were stained with dapi and two cell lines were compared in systems. According to results, it was observed that 3D cell culture environment in chip provides more in-vivo like environment with less reagent consumption and cell viability is not correlated only with drug uptake.Master Thesis The Effect of Doxorubicin-Albumin Magnetic Nanoparticles on Prostate and Lung Cancer Cells(Izmir Institute of Technology, 2012) Zeybek, Ayça; Şanlı Mohamed, Gülşah; Şanlı Mohamed, Gülşah; 04.01. Department of Chemistry; 04. Faculty of Science; 01. Izmir Institute of TechnologyChemotherapy is a major therapeutic approach for treatment of a wide range of cancers. But unfortunately, this therapeutic approach has got a lot of side effects on healthy tissues as well as cancerous cells. Although doxorubicin is one of the most potent and widely used anticancer drugs, it has some side effects on healthy tissues, as well. Therefore, most researchers have studied various doxorubicin carrier systems for targeted delivery. For this purpose, doxorubicin loaded magnetic albumin nanospheres (M-DOX-BSA-NPs) were synthesized. The main objective of this project was basically to determine the cytotoxic, apoptotic and cell cycle effects of BSA-NPs, M-BSA-NPs, DOX, BSA-DOX-NPs and M-DOX-BSA-NPs against prostate and lung cancer cells and compare them. Beside this, it is aimed to understand how cells look like before and after giving doxorubicin and M-DOX-BSA-NPs by using optical microscopy and compare them. Another objective of this project was to determine where M-DOX-BSA-NPs reach out into the cell by using concofal microscopy; and to explore proteins’ differentiations between control groups and lung and prostate cancer cells in which DOX and M-DOX-BSA-NPs were applied, by proteomic studies. In this study, the experimental results which were also supported by literature findings, demonstrated that M-DOX-BSA-NPs were more toxic than free doxorubicin, and this complex was more effective for prostate cancer cells than lung cancer cells. As a result of this study, it was determined that this complex was synthesized as a target chemotherapy drug delivery system. Accordingly, this complex may affect to other cancer types, and it can be carried out by new drug designers and treatments.