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ÖgeDevelopment of selective iron-based fischer-tropsch catalysts to light olefins(Graduate School, 2023-08-29)Light olefins (alkenes) are among the key chemicals that are globally most produced from crude oil in amounts exceeding 200 million tons per year. They are hydrocarbons with at least one carbon - carbon double bond (C2-C4) namely, ethylene(C2H4), propylene(C3H6), and butylene(C4H8). Lower olefins (light olefins) are intermediates for the synthesis of a wide range of products such as solvents, polymers, drugs, detergents, and cosmetics. There are three types of olefins: alpha (also called ethylene molecules), beta, and gamma. Carbon-carbon double bond is located at the beginning, in the middle, and at the end of the olefin chain in alpha, beta, and gamma types, respectively. Currently, commercial light olefin production is mainly based on steam cracking of a broad range of hydrocarbon feedstock including naphtha, gas oil, condensates, ethane and propane. However, the production of lower olefins by steam cracking is one of the most energy-consuming processes of the chemical and petrochemical industry. The oil reserves are expected to be depleted at faster pace as the oil consumption surpasses the conventional oil production. As the conventional easy-reached oil reserves deplete, attempts are being made to use unconventional oil reserves for oil production. The extraction and upgrading of oil from unconventional oil reserves, however, may be expensive and involve release of higher amounts of CO2 release in comparison to conventional reserves. CO2, with its green-house effect, is widely claimed to be responsible for climate change and there is rapidly growing global awareness in this respect which leads to more and more stringent regulations about CO2 emissions. Therefore, many countries are searching for alternatives to reduce their reliance on imported crude oil and refined products and to comply with CO2 regulations. The new alternative fuels for olefin production are coal, natural gas and biomass. Light olefins may be produced from the synthesis gas (CO/ H2) obtained from gasification of these fuels by direct Fischer-Tropsch-to-Olefins (FTO) process. FTO is a catalytic process and the most crucial and critical issue of this process is using proper and effective catalyst(s). Although there are plenty of research available in literature focusing on FTO process, there still exists lack of a proper catalytic process to be used commercially in FTO. In this work, the aim was to make an effort to produce light olefins in direct unconventional way via FTS by synthesizing iron-based catalysts with different promoters and supports that can show high FTO performance, means high CO conversion and stability with time on stream, high selectivity to light olefins, and low selectivity to methane and CO2. In other words, the aim was to narrow the wide hydrocarbon range produced by FTS to C2-C4 olefins. To reach the goal of study, the catalysts have been synthesized in different routes and with promoters. Their performance has been evaluated via catalytic tests and catalytic activity-structure relation have been investigated. In this term, iron-based catalysts have been prepared both by precipitation and impregnation techniques. Precipitation route has been tuned as well by changing the alkalinity of the precipitation environment. To synthesize the first set of bulk catalysts, nitrate salt solutions of iron and zinc as prepared in a stoichiometry of Fe:Zn=2 have been co-precipitated with NH4OH (AH). Sodium has been incorporated to Fe.Zn precipitate by different routes; use of sodium nitrate during co-precipitation reaction (AH route) or its subsequent impregnation on co-precipitated Fe.Zn catalyst (AH-I route). Alternatively, Na2CO3 (SC) was employed instead of NH4OH (AH) for the initial precipitation to investigate the role of the precipitant and its effect on catalyst surface basicity in terms of Fischer-Tropsch activity. The basicity of the precipitate Fe.Zn (SC) has been altered by changing the number of washing cycles as well and impregnated with a sodium precursor for further basicity. The last route has been called as SC-I. In addition to Na, Cu and K promoters have been impregnated to Fe.Zn precipitate as well. For the impregnation route, activated carbon (AC) and nitrogen-doped AC have been used as support material. Fe:Zn of 2 with alkali promoters has been chosen since it resulted in high olefin selectivity for unsupported catalysts. Activated carbon (AC) and its nitrogen doped form have been used as support. Activated carbon has been treated with N-containing chemicals namely, HNO3, NH3 and urea in order to create nitrogenous surface functional groups over AC (Chemical modification of surface). The so-formed supports were denoted as AC-N1, AC-N2, and AC-N3, respectively upon treatment with HNO3, NH3, and urea. Co-impregnation has been applied as by first dissolving the metal salts in stoichiometric amounts in a minimum amount of water and then by wetting AC support with the metal salt solutions. All catalysts have been calcined, reduced and tested in a high pressure fixed-bed reactor to investigate their catalyst activity and performance in Fischer-Tropsch synthesis to light olefins (FTO). Test results were interpreted together with the characterizations such as BET surface areas via N2 adsorption, crystal phase identification by x-ray diffraction (XRD), elemental analysis by inductively coupled plasma (ICP-OES), thermal stability of supports using (TGA) analysis, morphological investigation by scanning electron microscopy (SEM), reducibility characteristics of active phases using H2-TPR , the basicity of Na promoted bulk catalysts by CO2-TPD, and SEM-EDS mapping to observe metal distribution in Na promoted catalysts and a carbon supported catalyst. As total alkalinity of precipitation affects hydrolysis and influences the composition of the intermediate hydrolytic complexes, the final features of metal hydroxide precipitates might be induced with the precipitation conditions. This was proved by the observed change on the textural properties of zinc ferrites such as total surface area, crystal size and morphology under different alkaline precipitation environment. Improved conversion due to the facilitated CO dissociation over basic sites and concomitant deactivation possibly through fouling might be interpreted as both the number of basic sites and strength were determinant on the final catalytic behavior. Na provides a surface with high electron density that leads to intensification of CO dissociation and adsorption. However, although this is a favorable effect, it has limitation in terms of alkali content of the catalyst and its dispersion. As mentioned before, there is an optimum basicity which ensures a balance between CO conversion to CHx and the rate of hydrocarbon chain growth and its termination. If this balance alters, long chain hydrocarbon may form and cover the catalyst surface which can block the active sites. Depleted surface vacancies might suppress the rate of CO dissociation with time on stream and result in high deactivation. In this case, the hydrocarbon distribution does not change significantly but deactivation dominates. When surface is covered with high C content, surface H deficiency may result in a decrease in hydrogenation activity that might end up with poor paraffin and methane selectivity. Alkali metals may also improve re-adsorption of olefinic intermediates which may further polymerize to C5+ species. Therefore, both C2-C4 olefin light olefin and C5+ selectivity increase in the presence of alkali promoter, sodium or potassium. However, potassium as with more alkalinity strength led to more coke formation over the catalytic surface, e.g. a total carbon content of 17% on the spent ⁓3%K-2Fe.Zn(SC) catalyst and thereby, a fast decrease in CO conversion from 88% to 55% has been observed. Copper (Cu) is a widely accepted promoter for facilitated reduction of iron oxides and it improves the catalyst stability when the reduction occurs at lower temperatures. Temperature programmed reduction (TPR) profile of the catalysts have shown the improved dispersion upon copper addition. AC and N-doped AC supported Fe.Zn catalysts have shown high and satisfactory FTO performance. High surface area of AC whether in N-doped form or not has provided improved catalytic stability. Supported catalysts in the same Fe:Zn ratio seemed to be less deactivated in comparison to the bulk catalysts. For all supported catalysts in Fe: Zn: P=2:1:0.2 molar ratios where P=Na and K, high olefin selectivity of ⁓ 45-50% and high CO conversion of ⁓89-93%(stability) have been achieved. Using AC as the support of the catalyst, dispersion and hence the number of active sites have been increased and accessibility to each single active site has been improved as compared to the case in bulk catalysts. In conclusion, the hydrocarbon product distribution in the presence of alkali has been altered towards high C2-C4 olefin and C5+ selectivity values. The strength and homogeneity of surface basicity seemed effective in case of bulk catalysts. Highly active and selective bulk catalysts can be prepared by changing the precipitation conditions. Copper was seen to stabilize the catalytic activity by improving the dispersion and reducing the reduction temperatures of metal oxides. Activated carbon appeared as a suitable support for well dispersion of active sites. Its surface nature has been modified with nitrogen and slight changes in catalytic performance has been noticed. Improved thermal stability upon nitrogen doping was the only point to be remarked. All in all, Fe to Zn ratio of 2 as in zinc ferrite spinel crystals were active catalysts for Fischer-Tropsch reaction and reaction selectivity have been directed to light olefins when appropriately doped with alkali metals.
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ÖgeDevelopment of controlled release tablets and evaluation of release behavior for the treatment of Multiple Sclerosis (MS)(Graduate School, 2025-02-10)Polymers have played an integral role in advancing drug delivery technology by providing controlled release of therapeutic agents at fixed doses over long periods of time, cyclic dosing, and adjustable release of both hydrophilic and hydrophobic drugs. In the field of pharmaceuticals, achieving controlled and targeted drug release is of paramount importance. Over the years, researchers and scientists have explored various approches to optimize drug delivery systems. Among these innovative strategies, polymers effect has emerged as a game-changer. Polymers, with their unique propeties and versatile nature, have revolutionized on drug release within the body. The aim of this study is to develop a controlled drug release mechanism for the active ingredient fampridine, used in the treatment of multiple sclerosis (MS), by designing three different prototypes and presenting the release behavior results of fampridine. The first of the prototypes designed for this purpose encompasses modifications to the unit formulation of the reference product, Fampyra (10 mg extended-release tablets, Biogen Pharmaceuticals). This aims to observe the effect of the type and amount of polymer on the release of fampridine in the conventional dry blending process. Fampridine-containing tablets were prepared using the dry blending process and were compressed at 6-6.5 KN, 20 RPM. In vitro release tests were performed using USP Apparatus II (Paddle). The receptor media contained phosphate buffer pH 6.8, and tests were performed under the conditions of 37°C ± 0.5°C, 50 RPM for 24 hours. In vitro release tests were conducted using Waters HPLC with a UV or PDA detector. For the column, Waters Symmetry C18 100×4.6×3.5μ was used. All methods are validated according to ICH guidelines. Different types of Hydroxypropyl Methyl Cellulose (HPMC), known as K100LV, K100M, and K200M, were used as a polymer filler at various ratios in tablet formulations. All results were compared with the reference product, Fampyra. The purpose of this prototype is to determine how much the cellulose-based polymer present in the reference product affects the release of fampridine. It aims to investigate the impact of using different polymers on both the release of fampridine-containing tablets and the morphological characteristics of the tablets. The significance of this prototype lies in its ability to prevent patented excipients in the unit formula of original products from becoming an obstacle in the development of generic drugs, and to create a generic drug formulation that can achieve a similar effect without infringing on patents. Initially, the unit formula of the reference product was used directly; however, different excipients have been included in the unit formula to address the issues arising in the formulation of the generic drug. 1st prototype's results showed that the type and proportion of polymer used in the unit formulation during the conventional dry blending process significantly affect the release of fampridine. As the viscosity of the polymer and its proportion in the formulation increased, adhesive problems occurred in the tablets, making the release of fampridine more challenging. Since delaying the release of fampridine was a desired outcome, aerosil, which has higher effectiveness than Avicel as a diluent in the formulation, was used to resolve the adhesion issues associated with the use of K200M, which has the highest viscosity. The time period during which the fampridine concentration is stabilized in the solvent medium was 12 hours for the reference product, while it has been extended to 18 hours in the revised unit formula of the generic drug formulation. The results are reproducible, and the methods used have been validated according to ICH guidelines. Second prototype delves into both the formulation of bio-based microspheres containing fampridine for the treatment of multiple sclerosis (MS) and provide an alternative way for the commercially available product (Fampyra 10 mg, Biogen). Encapsulation of fampridine was achieved using polyvinyl alcohol (PVA) and two different polymers know as sodium alginate (Na-Alg) and Chitosan (CS). According to the type of microsphere, Glutaraldehyde (GA) and hydrochloric acid (HCl) or glutaraldehyde and sodium hydroxide (NaOH) were used as cross-linking agents. Polymer ratio (PVA: Na-Alg and PVA:CS), drug: polymer (d: p) ratio, cross-linking agent ratio, and cross-linking time were evaluated on fampridine release. Release studies were analyzed using an ultraviole- visible (UV) spectrophotometer. The microspheres were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. (FT-IR). The particle size of fampridine-loaded microspheres were determined by the laser-light-scattering device. The purpose of preparing the second prototype is the lack of any studies in the literature regarding fampridine encapsulated by biological polymers, which have been gaining importance recently. By obtaining microspheres with increasingly effective biological polymers, a comparison of the release behaviors with tablets containing fampridine produced by classical methods has been achieved. This will enable the production of an alternative generic drug using a manufacturing method that does not exist in Turkey or even in the world for fampridine. As for results, the study was seperated into two sections. The first one is PVA:Na-Alg microspheres; it was determined that the highest release of fampridine obtained with microspheres prepared with PVA: Na-Alg (w: w) ratio as 1:1, drug: polymer ratio (w: w) as 1:2, cross-linking agent concentration as 2.5% GA + 3% (v:v) HCl, and cross-linking time as 5 minutes. It was observed that all microspheres have 300- 800 μm particle size and the particule size of the microspheres increases d: p ratio paralelly. The second one is PVA:CS microspheres, the highest release of fampridine obtained with microspheres prepared with a PVA:CS (w: w) ratio as 2:1, drug: polymer ratio as 1:2 (w: w), cross-linking agent concentration as 2.5% (v:v) GA + 1M NaOH, and cross-linking time as 5 minutes. It was observed that the release behavior of microspheres does not conform to Fick's Law, as typically seen in release systems created with hydrogels. The aim of the third prototype was to design oral controlled release osmotic pump tablets of fampridine and optimize the drug release profile using response surface methodology, Box Behnken Method. Ostmotic pump tablets were prepared by direct compression with using variying amount of polyoxhyethylene (PoE) which has different molecular weight (Mw) as 300,000 g/mole and 900,000 g/mole and punched as 1 mm and 2 mm with mini tablet punching machine. Constant amount of Celluloce based Opadry EC (10%) (w: w) was used as coating solution. Formulation of tablets and release optimization evaluated with Box Behnken design. 3 factors and 15 levels were used to optimize drug release profile. PoE amount and hole diameter were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected. The Box-Behnken analysis results showed that the optimum release of fampridine occurred when PoE amount was approximately 300 mg. (Mw=300,000 g/mole), with a 2 mm hole diameter. These results are consistent with existing literature and experimental studies and regarding the kinetic results, all tablets exhibited zero-order kinetic. As for evaluating the release of fampridine in the three designed prototypes, it was found that in the first prototype, the release of fampridine was extended by 6 hours compared to the reference product due to minor changes in the polymer and diluent within the formulation. Although promising results were observed in the other prototypes as well, the differentiation of the generic drug's form from the original drug will necessitate clinical studies. Therefore, it is expected that the efficacy of the microspheres will need to be demonstrated through long-term stability studies and that the clinical trials will yield positive results in order to establish them as an alternative to the reference product. This thesis is significant both in the treatment of MS and in research related to the active ingredient fampridine, as such a comprehensive study has not been conducted before. The methodologies employed aim to enhance the comfort of patients suffering from MS and improve the side effect profile of the medication. If the clinical trials of the designed prototypes against the reference product are successful, this research will provide an alternative therapeutic option accessible to patients.
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ÖgeOlefin/paraffin separation in polymer/mof mixed-matrix membranes(Graduate School, 2023-12-22)Membranes, due to their low cost, high energy efficiency and ease of processing, have aroused great interest in the field of gas separation. Polymer membranes currently occupy a dominant position in the commercial market, despite the existing tradeoff between permeability and selectivity associated with their use. Over the past decade a novel class of inorganic-organic porous materials, Metal-Organic Frameworks (MOFs), has emerged as a new research domain in solid state materials. These hybrid nanoporous materials formed by the self-assembly of metal ions or clusters, linked together via a variety of bridging ligands, creating stable open structures with sufficiently large pores for industrially-important applications, such as in gas adsorption, storage and separation. Indeed, a number of recent studies have demonstrated that MOFs could be optimal candidates for membrane-based gas separation processes. In addition, owing to the remarkable properties of MOFs, an alternative strategy to overcome the selectivity/permeability trade-off limits of polymer membranes is to make mixed-matrix membranes (MMMs), in which MOF particles are incorporated into polymer matrices. Typically, the alkane/alkene separation is highly topical since it was identified recently as one of the "7 chemical separation to change the world". Propylene (C3H6) is with ethylene (C2H4), the largest feedstock in petrochemical industries with a global production that exceeds 200 million tons per year, with these chemicals mostly used to produce polymer-grade and plastic products, particularly the widely utilized polypropylene. The objective of the PhD will be to predict the separation performances of a series of MMMs for diverse olefin/paraffin separation based on atomistic models constructed for the corresponding MMMs using a combination of force field and quantum calculations. More specifically, we implement an MC/MD simulation scheme to perform simulations of membrane permeation processes. This prediction will pave the way towards the development of the corresponding MMM and their separation testing by collaborators.
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ÖgeMitoksantron taşıma amaçlı BSA-kaplı, folik asit ile hedeflendirilmiş manyetik karbon nanotüplerin geliştirilmesi(Lisansüstü Eğitim Enstitüsü, 2025-01-10)Günümüzde yılda 15 milyondan fazla insana kanser teşhisi konulmaktadır. Vücutta bölgesel olarak başlayan kanser zamanla uzak bölgelere yayılır ve tedavi edilemez hale gelir. Mevcut tedavi yöntemlerinde her geçen gün gelişmeler yaşansa da hastalığın tedavisi halen istenen optimum yöntemlerden uzaktır. Kanser tedavisinde en kritik nokta, ilacın sağlıklı dokulara zarar vermesini engelleyip, tümörlü dokularda birikmesini sağlamaktır. Kanser tedavisine yönelik yapılan çalışmalar; malzeme, moleküler biyoloji, genetik, mühendislik, biyokimya ve cerrahi gibi birçok farklı alanda çalışan araştırmacıların katkısını kapsar ve optimum çözüme ulaşmada bunlardan hiçbiri tek başına başarılı olamaz. Mitoksantron (MTO), kanser tedavisinde yaygın olarak kullanılan antrasendion bazlı bir antikanser ilacıdır. Fakat sağlıklı hücreler/dokular üzerindeki spesifik olmayan etkileri ve çözünürlüğünün düşük olması nedeniyle klinik kullanımı sınırlıdır. Son yıllarda kanser tedavisine yönelik en önemli yaklaşımlardan biri, MTO benzeri ilaçların toksisitesini azaltmaya yönelik hedefli ilaç taşıyıcı nanosistemlerdir. Bu çalışma, dünyada kalp ve damar hastalıklarından sonra ölüme en çok neden olan kanser hastalığının tedavisine katkı sağlayacak MTO taşıyıcı sistemlerin tasarlanması amacıyla kurgulanmıştır. Literatürdeki benzer çalışmalara kıyasla tez çalışması kapsamında geliştirilen nanotaşıyıcı sistemin hem manyetik özellik hem de ligand içerecek şekilde tasarlanması ile ilacın sağlıklı hücrelere kıyasla kanserli hücrelerde salımının gerçekleşmesinin sağlanması hedeflenmiştir. Böylelikle mevcut tedavi yöntemlerinin neden olduğu en büyük sınırlamalardan biri olan sağlıklı hücrelere olan toksik etkinin de minimum seviyede tutulması amaçlanmıştır. Pasif hedefleme ile kanserli ve sağlıklı hücreler arasındaki yapısal farklılıklardan (pH, sıcaklık, geçirgenlik vb.) yararlanılırken, aktif hedefleme için kanserli bölgede reseptörünün fazla olması nedeniyle folik asit bağlı ve manyetik özelliğe sahip nanotaşıyıcılar hazırlanmıştır. Biyolojik uygulamalardaki potansiyellerini artırmak amacıyla son yıllarda manyetik özelliğe sahip karbon nanotüpler (mKNT) geliştirilmiş ve böylece uygulama alanları daha spesifik hale getirilmiştir. mKNT'ler, ilacın harici bir manyetik alan altında tümör bölgesine hedeflenmesini kolaylaştırabilirken, tümör bölgesinin sıcaklığını 46 °C'ye kadar artırarak hipertermi etkisi sağlayabilir. Böylelikle mKNT'ler kanser tedavisinde kemoterapi ilacının yan etkilerinin azaltılması, ilacın hedefe iletilmesi ve dış uyarıcılar ile hipertermi etkisiyle hedef hücrenin/dokunun ortadan kaldırılmasını sağlayarak çok yönlü taşıyıcılar olarak kullanılabilir ve tedavi aşamasında ilaçtan maksimum verim alınması sağlanabilir. Karbon yapıların ilaç taşıyıcı sistemlerde iskelet olarak kullanılabilmesi için istenen özelliklere sahip olması gerekmektedir. Saf KNT hidrofobik ve toksik özellik gösterir. Bu durumu gidermek için; kovalent veya kovalent olmayan yöntemlerle çeşitli moleküller KNT'ye bağlanarak KNT'nin toksik özelliği iyileştirilebilir. Plazmada en bol bulunan protein olan sığır serum albümin (BSA) biyouyumlu olması nedeniyle kaplama malzemesi olarak dikkat çekmektedir. BSA'nın yapısal konfigürasyonu çeşitli ligand bağlanma bölgeleri sağlar ve BSA, KNT'lerin sitotoksisitesini önemli ölçüde azaltabilir. Yayınlanan çalışmalarda antikanser ilaçların kanser hücrelerine karşı seçiciliğini artırmak için hazırlanan nanotaşıyıcılara manyetik özelliğin yanı sıra birçok aktif hedefleme ligandı da konjuge edilmiştir. Bu ligandlar arasında folik asit (FA), düşük maliyeti, toksik olmaması ve yüksek stabilitesi nedeniyle en duyarlı hedefleme moleküllerinden biridir. Ayrıca FA'nın folat reseptörüne (FR) bağlanma afinitesi yüksektir ve FR'ler birçok farklı kanser hücresinde aşırı eksprese edilir. Çalışmanın ilk aşamasında sentezlenen mKNT'ler, BSA ile kovalent yöntemle fonksiyonelleştirilmiştir. BSA-kaplı mKNT (mKNT-BSA), Fourier dönüşümlü kızılötesi (FT-IR) spektroskopisi, Raman spektroskopisi, X-ışını fotoelektron spektroskopisi (XPS), termogravimetrik analiz (TGA), titreşimli örnek manyetometresi (VSM) ve geçirimli elektron mikroskobu (TEM) gibi ileri analiz teknikleriyle karakterize edilmiştir. Analiz sonuçları mKNT'nin BSA ile kovalent modifikasyonunun başarılı olduğunu göstermiştir. Bir sonraki aşamada, BSA-kaplı mKNT'ler, hedeflenen dağıtıma yönelik spesifik olmamaları nedeniyle FA ile fonksiyonelleştirilmiştir (mKNT-BSA-FA). FA-bağlı nanotaşıyıcılar FT-IR, taramalı elektron mikroskobu (SEM), XPS, VSM ve TGA teknikleri kullanılarak karakterize edilmiştir. mKNT-BSA-FA'nın karakterizasyon sonuçları, nanotaşıyıcının doyum manyetizasyon değerinin manyetik hedefli ilaç dağıtım sistemlerinde kullanımı için uygun olduğunu ortaya koymuştur. Sonraki aşamada, mKNT'lerin MTO yükleme ve salım profilleri değerlendirilmiştir. Saf ve kaplanmış mKNT'ler için pH 9'da ilaç yükleme ve fizyolojik (pH 7,4) ve lizozomal pH'ta (pH 5,5) salım deneyleri gerçekleştirilmiştir. mKNT-BSA-FA'nın en düşük ilaç yükleme kapasitesine ve en yüksek ilaç salım (%) miktarına sahip olduğu görülmüştür. Bu duruma mKNT'nin protein ve folik asit ile fonksiyonelleştirilmesinden sonra hidrofilik özellik kazanması neden olmuştur. Nanotaşıyıcıların sitotoksik etkileri sağlıklı HEK293T ve kanserli MDA-MB-231 hücre hatlarında incelenmiş ve her iki hücre hattı üzerinde de doza bağlı sitotoksik etkileri olduğu görülmüştür. Biyouyumlu BSA ve FA ile yapılan fonksiyonelleştirme mKNT'lerin toksisitesini azaltmıştır. Ayrıca, MTO yüklü mKNT, mKNT-BSA ve mKNT-BSA-FA'nın MDA-MB-231 hücrelerinin canlılığını önemli ölçüde azaltmasına rağmen aynı konsantrasyondaki serbest MTO'ya göre daha az sitotoksik etki gösterdiği belirlenmiştir. Sonuçlar, mKNT-BSA-FA'nın çift hedefleme özelliği nedeniyle geleneksel tedavi yöntemlerine kıyasla daha verimli bir ilaç dağıtım sistemi olabileceğini göstermektedir. İlaç taşıma amaçlı tasarlanan malzemenin süperparamanyetik özelliği, harici manyetik alan uygulanarak ilacın hedeflenen bölgeye iletilmesini ve geleneksel kanser tedavisinin neden olduğu kısıtlamaların giderilmesini sağlar. pH'a duyarlı salım, gelişmiş dispersiyon ve süperparamanyetik özelliğe sahip mKNT-BSA-FA, MTO taşıma amaçlı bir nanosistem olarak düşünüldüğünde iyi bir seçim ve umut verici bir adaydır.
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ÖgeInvestigation of the mechanisms of hERG1 blocker toxins as anti-cancer agent with molecular modeling techniques(Graduate School, 2024-02-20)Ion channels are membrane-inserted proteins which regulate the movement of ions through cell membrane. Potassium (K+) ion channels ubiquitously exist in almost all species and locate in cell membranes. Members of this channel family play important roles in cellular signaling, including various processes. It is well-known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis. Because of their location on cell surface and their well-known pharmacology, they can be used as potential targets in anticancer therapies. The human ether-a-go-go related gene 1 (hERG1) K+ channels play crucial role in the heart, different regions of brain, endocrine cells, smooth muscle cells, and numerous tumor cells. It is known that the inherited mutations of hERG1 gene may lead to the disorder of cardiac repolarization (i.e., long QT syndrome (LQTS)), which may result in sudden cardiac death. It is known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis and some specific toxins were investigated for diverse therapeutic applications on targeting the hERG1 K+ channel. Thus, investigation of channel/toxin interactions mechanisms in atomic level is an important topic for the development of toxin-based therapeutics. Thus, in the first part of this thesis, the interaction mechanisms of two toxins named as BeKm-1 and BmTx3b with the closed-state hERG1 channel have been studied by using different molecular modeling techniques including protein-protein docking and molecular dynamics (MD) simulations. The crucial residues of toxins in channel interactions have been elucidated. It is found that R1, K6, K18, R20, K23 and R27 residues in BeKm-1 and F1, K7, K19, K20 and K28 in BmTx3b are the important residues involved in the strong interactions with the closed-state hERG1 K+ channel. The results of this study can be used by medicinal chemists in the designing of diverse therapeutic applications of natural or synthetic peptides targeting the closed state hERG1 K+ channels. In the second part of the thesis, the information that obtained from hERG-BeKm-1 and hERG-BmTx3b interactions, was used to design de novo peptides. The designed de novo peptides were investigated on open-state hERG. In addition to de novo peptides, peptidomimetics and FDA-approved molecules were included in the study to increase the number of molecules studied. It is believed that the data obtained in the thesis study will provide guidance for hERG inhibition for therapeutic purposes. In this way, it is expected to be able to eliminate various types of disease without causing sudden cardiac death.
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