Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Development of Peg-Peptide Conjugate Based Curcumin Delivery Systems(01. Izmir Institute of Technology, 2022) Top, Ayben; Top, Ayben; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyIn this study, a drug delivery system based on Pluronic F127 and a peptide conjugate was proposed. The F127-peptide conjugate was prepared by the reaction between succinimidyl functionalized F127 (SC-F127) and peptide. SC-F127 was synthesized using disuccinimidyl carbonate and DMAP. Folic acid-functionalized F127 (FA-F127) was also prepared to obtain active targeting copolymers. Four peptides containing pH-responsive multiple histidines and endosome disruptive GFWFG domain were synthesized using the Fmoc procedure. H-Gly-2-ClTrt resin and Rink amide MBHA resin were used to synthesize side-chain-protected and deprotected peptides, respectively. 2-chlorotrityl resin failed in synthesizing the high-purity peptides with adjacent histidines in their sequences. Peptide-4 having a sequence of GGH6GFWFG, was prepared with acceptable purity using rink amide MBHA resin and was conjugated to SC-F127. Curcumin was loaded to F127 and F127-peptide using the thin film method with DCM solvent. Almost all curcumin was encapsulated into F127 micelles. However, the entrapment efficiency % of the F127-peptide micelles was ~86% due to the lower solubility of F127-peptide conjugate in DCM. Dynamic light scattering experiments were used to determine the stability and size distribution of the micelles. Number-based size distributions of both micelles indicated that a single peak between 10 and 30 nm was independent of pH. The peak position did not change upon incubating the micelles at 37oC up to a few days. Initially, intensity-based results of both samples indicate bidisperse populations at pH 5.0 and 7.4. Curcumin-loaded F127 micelles aggregated in the three days, as revealed by the formation of the third peak above 1000 nm independent of pH. Curcumin-loaded F127-peptide micelles, on the other hand, retain their stability for up to five days at neutral pH. For this sample, the third peak was observed only at pH 5.0 on days 2 and 5.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 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 Preparation and Characterization of Polymer Based Composite Nanospheres for Bone Infection Prevention(Izmir Institute of Technology, 2018) Kımna, Ceren; Tıhmınlıoğlu, Funda; Tıhmınlıoğlu, Funda; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyCurrently, bone tissue engineering applications comprise the development of smart materials that can induce tissue regeneration meanwhile supporting the defect site of the body. Despite of the advancements, inflammation is still a serious problem that threatens human health at the post-implantation period. To overcome potential inflammations, antibiotic therapy is commonly employed in clinical trials. However, antibiotic therapy causes some side effects such as ototoxicity and nephrotoxicity, especially when applied in high doses. Therefore, local drug delivery systems play a vital role in bone disorders due to the elimination of disadvantages introduced by conventional methods. In the presented study, it was aimed to develop chitosan-based composite nanospheres as a controlled drug delivery system against bone infections. Accordingly, chitosan and montmorillonite nanoclay was homogenized with microfluidizer and electrosprayed to obtain spherical nanoparticles. The optimum electrospraying conditions were investigated using response surface methodology. Vancomycin and Gentamicin antibiotics were incorporated in the polymeric matrix to provide controlled release at the defect region to overcome inflammations after implantation. The prepared nanospheres were characterized in terms of morphology, hydrodynamic size distribution, surface charge, drug encapsulation efficiency and release profiles. The dominant drug release mechanism was determined by empirical mathematic models. Drug loaded nanospheres have been successfully produced with a size range of 180-350 nm. High encapsulation efficiency was achieved (80-95%) with a controlled drug release up to 30 days. Fickian diffusion was found as the main mechanism in drug delivery from spherical CS/MMT nanocomposites. The in vitro release medium of nanospheres showed strong antimicrobial activity against gram-positive S. aureus and gram-negative E. coli bacteria. Furthermore, it was found that the nanospheres did not show any cytotoxic effect to 3T3 and SaOS-2 cell lines. These results demonstrated that the prepared nanospheres can be a promising option for bone infection prevention.Master Thesis Peg-Peptide Drug Carrier Systems With Enzymatic Degradation Units(Izmir Institute of Technology, 2016) Yüksel, Nesligül; 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 drug delivery systems with high drug release rate, capable of overcoming multidrug resistance of cancer cells. The first generation drug delivery system (DDS) denoted as mPEG-AT3-DOX was prepared by methoxy polyethylene glycol (mPEG) and peptide conjugation, and the model anticancer drug, DOX, was attached to the mPEG-peptide carrier system using stable amide linkage. mPEG was used to increase blood circulation time of the DDS. Designed peptide (AT3 = CG3H6R2ALALG3E) controls release of the drug via RRALAL sequence, which is a substrate for a lysosomal enzyme, cathepsin B, overexpressed in most of the tumor cells. pH responsive histidines and reactive amino acids (glutamic acid and cysteine) for drug and mPEG conjugations were also added to the peptide sequence. The peptide synthesized by using Fmoc chemistry was conjugated to mPEG-maleimide via Michael addition reaction. DOX was attached to the carboxylic acid group present in the carrier system (mPEG-AT3) via amide linkage. Mass spectroscopy and HPLC were used to assess the purity of the AT3 and mPEG-AT3. At pH 7.4, mPEG-AT3-DOX exhibited bimodal size (hydrodynamic diameter) distribution at about 15 and 30 nm independent of pH. % DOX release from mPEG-AT3-DOX was observed to be below 10 % at neutral pH and pH 5.0 in the absence of cathepsin B, and increased to 17 ± 2 % in the presence of cathepsin B. Complete degradation of AT3 peptide within three hours in the presence of cathepsin B suggests lower than expected DOX release is due to aggregation tendency of the DDS. Cytotoxicity of the conjugates was evaluated using the lung cancer (A549) and prostate cancer (PC3) cell lines. At the end of 24 hours the absolute IC50 values of free DOX and mPEG-AT3-DOX were obtained as 1.37 ± 0.05 and 1.33 ± 0.11 for the A549 cell line, 1.51 + 0.07 and 1.63 + 0.80 μg equivalent DOX / ml for the PC3 cell line, respectively. Considering, these results, the second generation DDS will be designed to have more pronounced pH sensitive property by increasing the number of histidines in the peptide domain.Master Thesis Development of Peg and Peg-Peptide Based Drug Delivery Systems(Izmir Institute of Technology, 2016) Balcı, Beste; Top, Ayben; Top, Ayben; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyIn this study, two types of drug delivery systems (DDS) were prepared; mPEG (methoxy polyethylene glycol)-HYD (hydrazide)-DOX and mPEG-peptide-(HYD)-DOX. In the design of the conjugates, mPEG was used to increase the blood circulation time. HYD provided an acid cleavable bond between the carrier molecule and DOX, whereas peptide containing histidines imparted pH responsiveness of the molecule. Doxorubicin (DOX) was selected as a model anti-cancer drug. DDS were synthesized using two steps; hydrazide functionalization of carboxylic acid of the carrier molecule followed by DOX conjugation. Hydrazide form of the carrier molecules denoted as HYD1 and HYD2 were obtained using adipic acid dihydrazide (AADH) and carbohydrazide (CH), respectively. To increase DOX conjugation, trifluoroacetic acid (TFA) and DOX amounts were changed and the reactions were carried out at the conditions giving the highest DOX conjugation (mPEG-HYD:DOX:TFA= 2.5mg:2mg:20μL per 1 mL of DMSO). The peptide (AT1=CGGGHHHHHHGGGE) was synthesized using solid phase peptide synthesis (SPPS) and PEGylated using mPEG-maleimide to obtain mPEG-AT1 conjugate. The purity of AT1 and mPEG-AT1 were confirmed using mass spectroscopy and high performance liquid chromatography (HPLC). DOX conjugation percentages were obtained as 62 7, 60 3 and 35 + 3 for mPEG-HYD1-DOX, mPEG-HYD2-DOX and mPEG-AT1-HYD1-DOX, respectively. Drug release studies indicated modest pH responsiveness of the carrier molecules obtained using AADH. On the other hand, mPEG-HYD2-DOX released 13% of drug at the end of the 72h independent of pH. For mPEG-AT1-DOX, drug release percentage values were obtained as 15% and 30% at pH 7.4 and 5.0 respectively. Cytotoxicity of the conjugates of DDS was determined using lung cancer (A-549) cell lines. DOX equivalent IC50 values were determined as 20, 40 and 5 for mPEG-HYD1-DOX, mPEG-HYD2-DOX and mPEG-AT1-DOX respectively.Master Thesis Synthesis of Silica Nano Particles With Custom-Made Morphology for Controlled Drug Delivery(Izmir Institute of Technology, 2012) Siretli, Çağrı; Polat, Mehmet; Polat, Mehmet; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyThe purpose was to have nanosized particles with low energy perimeters which function as non-reacting transporters for targeted delivery along with high energy sites inside the pores to achieve controlled release of specialized chemicals. Surfactants were used in combination with both base and acid catalyzed methods to achive desired structural properties and the characterization studies such as SEM, TEM, FTIR, BET surface area, pore size, size and zeta potential measurements were conducted. The effect of surfactants on mesoporous silica production changed depending on the type of methods. In the case of base catalysed method in alcohol, formation of stabilized emulsions with different sizes and their effect on the size and shape of silica particles was proposed. The effect of surfactants was attributed to their effect on a) the emulsification process and b) silica-silica and silica-surfactant interactions involved. In the case of base catalysed silica production in water, however, surfactant micelles were used as templates to produce pores. The effect of surfactant type and concentration was attributed to their effect on the CMC, micelle shape and size. Rod-like (~400 nm) at high and spherical (~200 nm) particles at low concentrations were synthesized. Here the surface area of ~1000 m2/g and average pore size of ~3 nm were obtained. Carbonization of these materials were performed to obtain nanosized silica particles with low energy perimeters successfully. Acid catalysed silica production in water was similar. Rod-like (600-800 nm) and cubic (800-1000 nm) nanoparticles were produced. These particles exhibited lower surface area of ~700 m2/g and larger pore size of ~5 nm.Master Thesis Use of Fibroin/Hyaluronic Acid Matrices as a Drug Reservoir in Iontophoretic Transdermal Delivery(Izmir Institute of Technology, 2004) Kuduğ, Emre; Batıgün, Ayşegül; Batıgün, Ayşegül; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyTransdermal drug delivery is gaining importance due to the extensive research in genetics and resulting increase of protein and peptide based drugs in the market. In order to develop materials to be used in iontophoretic transdermal drug delivery systems, various forms of silk fibroin (SF) and blending agents as hyaluronic acid (HA) have been tested for their feasibility as a potential drug reservoir. For this purpose different forms of silk such as raw silk, degummed silk fibroin, insolubilized freezedried fibroin, membranes of fibroin in pure and blended with HA were investigated for their adsorption capacities of timolol maleate, which is used as the model drug. It was found that silk fibroin and derivatives have considerable adsorption capacities for timolol maleate with 0.35 mmol per gram, comparable with commercial membranes. The insolubilization of the membranes was required for drug loading and delivery in aqueous media. Membrane insolubility was achieved by post treatment, manipulation of drying conditions, and blending with different agents. Configurational changes of fibroin protein and interactions between silk fibroin and hyaluronic acid were investigated by Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analyses. Insoluble fibroin glutaraldehyde membranes were produced. The obtained insoluble membranes were investigated for drug delivery performance in a custom-made diffusion cell under passive diffusion and iontophoretic conditions. It was demonstrated that the silk fibroin glutaraldehyde films could be successfully used for controlled drug delivery. It was found that current densities of 1.5 and 3 mA/cm2 were suitable to accomplish controlled delivery of the drug in a pulsatile manner. The results of this study are expected to be useful in controlled transdermal delivery of positively charged drug molecules.Master Thesis Application of Silk Fibroin in Controlled-Release of Theophylline(Izmir Institute of Technology, 2004) Özgarip, Yarkın; Bayraktar, Oğuz; Bayraktar, Oğuz; 03.02. Department of Chemical Engineering; 03. Faculty of Engineering; 01. Izmir Institute of TechnologyPolimerik malzemeler kullanılarak ilaç salınım proseslerini modellemek amacı ile çalımalar yapılmaktadır. Organik bazlı polimerik çözeltiler ile ilaçların kaplanması hala çok yaygın olmasına ramen ,organik bazlı polimerik çözeltilerin toksik ve çevreye zaralı olması nedeni ile ilaç endüstrisi farklı kaplama malzemeleri üzerine çalımaya balamıtır. Su bazlı kaplama teknikleri, organik polimerik çözeltilerin neden olduğu toksik özellikleri ortadan kaldırmak amacı ile kullanılmaktadır. Bu çalımada kontrollü ilaç salınım mekanizmasını elde etmek için kaplama malzemesi olarak su bazlı fibroin çözeltisi ve model ilaç olarak da teophylline kullanılmıtır. laç tabletleri ısıl işlem görmü silk fibroin, polietilenglikol (PEG) ve fibroin çözeltisi karıımı ile kaplanmıtır. Ek olarak EDC ile kroslink edilmi fibroin çözeltisiden elde edilen kaplamanın ilaç salınımına etkisi aratırılmıtır. Bütün örneklerin ilaç salınım profilleri UVspectrofotometre kullanılarak dissolusyon testi ile yapılmıtır. Ayrıca PEG konsantrasyonunun ve film kaplama kalınlıının etkileri aratırılmıtır. Taramalı elektron mikroskobu kullanılarak filmlerin morfolojisi ve film kaplama kalınlıkları bulunmutur. PEG in plastikletirici etkisinin ve fibroinin EDC ile kroslink edilmesinin, ilacın kontrollü bir ekilde salınmasını saladıı gözlemlenmitir. Hedef profile göre %17 PEG içeren fibroin çözeltisi ile kaplanan tabletlerin %70 salınım profilinde çözünme süresi 345 dakika olarak bulunmutur. laç salınım hızı ve tablet kaplama kalınlıı arasında bir baıntı elde edilmitir. EDC ile kroslink edilen fibroin çözeltisiyle kaplanan tabletlerde , kaplama kalınlıı arttıkça ilaç salınımı azalmıtır. Film kaplama kalınlıını 7.68 mm.ye getirilerek istenen ilaç salınımı elde edilmitir.