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Biocompatible polymer systems for medical application
Hrochová, Michaela ; Etrych, Tomáš (advisor) ; Bárta, František (referee)
Polymer carriers for drug delivery are still an extensively studied topic in many research laboratories around the world. Polymer systems have an important role in the case of oncological diseases, where they allow to increase the therapeutic effect and significantly reduce the side effects of treatment. The present thesis is primarily focused on the synthesis of novel water-soluble biodegradable polymer systems based on N-(2- hydroxypropyl)methacrylamide enabling the treatment of solid tumors. As part of the work, four bifunctional transfer agents have been developed, which enable the direct synthesis of symmetric diblock polymers with a size of 20,000-100,000 g∙mol-1 with RAFT polymerization. The transfer agents introduce hydrolytically labile ester bonds into the structure of diblock polymers, which allow the diblock to break down into smaller fragments that can be excreted by the kidneys. The different structures of the chain transfer agents make it possible to control the breakdown of diblocks over a wide time range from 2,5 hours to 21 days. The advantages of the prepared diblock carriers are primarily the one-step synthesis, adjustable degradation time, and the possibility of modifying the end groups of the polymer chain. In the presence of bifunctional transfer agents, copolymers of HPMA...
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Polymeric nanomaterials for targeted inhibition of tumor growth
Šťastná, Katarína ; Etrych, Tomáš (advisor) ; Sedláček, Ondřej (referee)
Galectins are carbohydrate binding lectins which possess many biological activities related to the development and progression of cancer. The purpose of this bachelor's thesis is synthesis, physico- chemical and in vitro preliminary biological evaluation of novel glycopolymers with high affinity to galectin-3. Several biocompatible water-soluble linear and diblock N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers bearing multivalently presented glycomimetic ligands, were synthesized and characterized by number of analytical methods, i.e. GPC, UV-VIS spectrometry, DLS and NMR. The polymer carriers were synthesized by the controlled RAFT polymerization, their molecular weight ranged from 25,000-33,000 g/mol and showed quite low dispersity. Glycopolymers containing about 4 mol% of glycomimetic ligands showed high ability to inhibit apoptosis of T lymphocytes in vitro. Nevertheless, the hypothesis consisting in the improvement of biological activity due to the denser ligand presentation on diblock copolymers was not proved. The thesis concludes that the prepared glycopolymers, linear as well as diblocks, could hypothetically be convenient tools for synergic therapy with polymer drug delivery systems in cancer treatment. Keywords: polymers, HPMA copolymers, drug-free macromolecular therapeutics,...
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Polymer-based therapeutics for immunooncotherapy
Kashmel, Pavel ; Etrych, Tomáš (advisor) ; Bárta, František (referee)
This master thesis describes the synthesis, physico-chemical characterization and preliminary biological testing of water-soluble polymer conjugates of the model drug ZM241385. This drug was first derivatized and then connected to a polymer carrier in order to prepare a system suitable for targeted drug transport to tumor tissues. Improved pharmacokinetic parameters of the prepared polymeric systems carrying ZM241385 should be the basis for increased therapeutic activity of the polymeric nanosystem in tumor immunotherapy. Polymeric precursors were synthesized by controlled RAFT polymerization in order to prepare highly defined carrier systems. In the framework of this master thesis, two derivatives of the selected drug were prepared, differing in the carboxylic acid used and the mode of their binding to the polymeric carrier. For derivatization, 4-(2-oxopropyl)benzoic acid was used, in which case the prepared derivative was bound to the carrier via a hydrazone bond. This bond is pH sensitive and shows high stability at pH 7.4 (corresponds to the pH of the blood stream), and at a slightly acidic pH 5.5 (corresponds to the microenvironment of the tumor, or endosomes of tumor cells), its rapid hydrolysis occurs. For the second derivative, 5-azidopentanoic acid was used. An uncatalysed click reaction...
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Polymer probes for photodynamic therapy of solid tumors
Kotalík, Kevin ; Etrych, Tomáš (advisor) ; Kovář, Marek (referee)
One of the currently studied promising strategies in advanced oncologic treatment is photodynamic therapy, a method based on the administration of so-called photosensitisers, i.e. photoactive compounds such as porphyrins, and subsequent irradiation of tumor tissue with light of appropriate wavelength. An excitation of the photosensitiser, present in the tumor area, is hence invoked and reactive oxygen species (ROS) are formed. These species afterward cause the apoptosis of the tumor cells, leading to destruction of tumor tissue. In photodynamic therapy, the strategy of administration of a prodrug which is metabolised to the active photosensitiser can be used with advantages. In photodynamic therapy, this prodrug may be 5-aminolevulinic acid (5-ALA) or its esters which are metabolised to protoporphyrin IX (PPIX), the photosensitiser proper. The targeted drug delivery to the tumor tissue can be achieved by using various delivery systems, e.g. water-soluble polymer conjugates carrying the drug. Due to their size, these polymer conjugates are accumulated in solid tumors on the basis of the enhanced permeability and retention (EPR) effect. Macromolecules can penetrate the tumor vasculature, which, unlike that of healthy tissue, is imperfectly developed and contains gaps between endothelial cells....
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The preparation and characterization of polymeric, enzymatically cleavable carriers for cancerostatic drugs
Zelený, Jan ; Etrych, Tomáš (advisor) ; Ječmen, Tomáš (referee)
As the development of cancerostatic drugs progresses it is becoming necessary to contemplate the question of how to deliver these drugs, which themselves tend to exhibit carcinogenic properties, effectively and accurately to the affected tissues and thus to circumvent their destructive effects upon the healthy parts of the organism. One approach to delivering drugs selectively to cancerous tissues is to make use of some of the specific properties which these tissues tend to possess, one of which being the so-called enhanced permeability and retention effect (EPR effect). This effect, which will be further discussed within this thesis, allows for macromolecules that are too massive to pass from the bloodstream into healthy tissue, to exit the blood vessels of cancerous tissue and to accumulate there. Therefore, a drug molecule can specifically enter cancerous tissue along with a suitable macromolecule, to which it is conveniently attached. If, moreover, the given drug is connected to the carrier molecule via an enzymatically cleavable spacer, it is possible to make use of lysosomal proteases (such as cathepsin B, which is overexpressed in some cancer cells) in order to attain its detachment from the carrier molecule and its subsequent activation. This bachelor thesis focuses on describing the...
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Watersoluble polymer nanomaterials tailored for anti-tumor therapy
Vinklerová, Laura ; Etrych, Tomáš (advisor) ; Škarková, Aneta (referee)
Anti-tumor treatment involves several therapeutic approaches. One of them is chemotherapy which uses low-molecular-weight cytostatic drugs, whose disadvantage is the systemic manifestation of cytostatic effects even in healthy tissue. As a result, at the end of the last century, a new concept of high molecular weight polymer nanomaterials was introduced that minimized the side effects of treatment. The binding of the drug to the polymeric nanomaterial makes it possible to improve the biodistribution of the drug in the body and thereby reduce its toxicity, while often leading to a significant increase in anti-tumor activity. The structure of the high-molecular-weight polymer nanomaterials and their drug conjugates utilizes the differences between healthy and tumor tissue. One of the important difference is the production of matrix metalloproteinase enzymes in the tumor microenvironment, which is mainly used to release polymer-bound drug in tumor tissue. Keywords: polymer nanomaterial, matrix metalloproteinase, release of the drug, penetration, EPR efect
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Polymeric delivery systems for immunooncotherapy
Šírová, Kateřina ; Etrych, Tomáš (advisor) ; Konvalinka, Jan (referee)
Oncological diseases are among the most common causes of death in developed countries and for some of them, current medicine still does not have satisfactory results. Designing of polymer therapeutics characterized by high molecular weight and controlled drug delivery is one of the perspective ways of development of new therapeutic protocols. Nowadays, scientists also focus on the research on anticancer immunological mechanisms and their potential use in cancer therapy. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been described in many types of malignancies. The function of STAT3 is very complex, the aberrant activation in cells of tumor microenvironment is related to many predominantly prooncogenic processes. This bachelor thesis is focused on synthesis of peptide inhibitor of STAT3 signaling, phosphopeptide pYLPQTV, and its conjugates with polymer carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA). The inhibitor and the polymeric conjugates have been characterized by several physico-chemical techniques; also, effect on proliferation of cancer cells have been tested in in vitro conditions, which proved slightly cytotoxic activity. A more detailed study and an optimization of methods for in vitro characterization will be necessary to further...
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Functionalized microporous polymer networks prepared from ethynylarenes
Stahlová, Sabina ; Sedláček, Jan (advisor) ; Etrych, Tomáš (referee) ; Červený, Libor (referee)
The preparation of a new group of functionalized conjugated polymer networks has been described based on spontaneous quaternization polymerization of ethynylpyridines with bis(bromomethyl)arenes. The networks consisted of polyacetylene chains with pyridyl and pyridiniumyl pendants cross-linked with -CH2(arylene)CH2- links. The variation of the ratio of monomer and quaternization agent in the feed modified the ratio of pyridyl and pyridiniumyl groups in the networks (pyridyl/pyridiniumyl ratios from 0 to 1.32). The networks did not exhibit a permanent microporosity that could be confirmed by nitrogen adsorption at 77 K. Nevertheless, all networks were active in capture of CO2 at 293 K (up to 0.73 mmol CO2/g, 750 Torr). It has been hypothesized that CO2 capture reflected formation of a temporary porous texture of the networks through conformational changes of the network segments enabled by the segments mobility at room temperature. The preparation of functionalized conjugated polymer networks with permanent micro/mesoporosity (SBET up to 667 m2 /g) has been described that was based on chain coordination copolymerization of acetylenic monomers. The copolymerization of 1,4-diethynylbenzene or 4,4'-diethynylbiphenyl with mono or diethynylbenzenes bearing NO2 or CH2OH groups has been demonstrated as...
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Enzyme-triggered polymer probes for fluorescence-guided surgery of solid tumors
Horáková, Lenka ; Etrych, Tomáš (advisor) ; Kaňa, Martin (referee)
This work is focused on the synthesis of macromolecular hydrophilic polymer conjugates with fluorophores for visualization of solid tumors. These polymer probes were designed for their utilization within the image-guided endoscopic surgery, where the boundaries of the tumor tissue would be fluorescently marked after i.v. administration. Polymer carriers should provide prolonged circulation of the probe in the body and the transport of the fluorescent dye into the desired place. Polymer probes based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers prepared by radical copolymerization containing fluorescent dye cyanine7-NH2 (Cy7- NH2) were synthetized and evaluated. The dye was conjugated to the carrier via an enzymatically cleavable peptide linker, specifically Gly-Phe-Leu-Gly and Val-Cit-4-aminobenzylalcohol. The enzymatic hydrolysis of these polymer conjugates was studied using a model lysosomal enzyme cathepsin B. In vitro study was carried out using hypopharyngeal cancer cell line FaDu, in which the internalization of the probes into cells and accumulation in cell compartments was evaluated by the fluorescent confocal microscopy. Key words: nanomaterials, polymer probes, fluorescence, EPR effect [IN CZECH]
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Polymer probes for guided endoscopic surgery of solid tumors
Horák, Dominik ; Etrych, Tomáš (advisor) ; Bouček, Jan (referee)
1 Abstract: This work focuses on development of both low- and high-molecular substances usable in fluorescent navigated endoscopic surgery with an emphasis on the characteristics of both tumor tissue and the substance itself. The usage of low-molecular substances, such as indocyanine green, has been abandoned over the past years, mostly due to poor localization and short circulation time. New polymer probes such as those based on pHPMA, were introduced to resolve these flaws. They benefit from the enhanced permeability and retention effect of the tumor tissue which is specific for macromolecules. The attachment of fluorophores to polymer carriers induces quenching, therefore novel systems are being designed to be able to release the fluorophore for example due to acidic environment of a tumor tissue or the overexpression of some peptidases. The experimental part of this work is dedicated to such polymer system with a pH-sensitive spacer-bound fluorophore. Keywords: polymer probes, fluorescence, pH-sensitive, nanomaterials, controlled release, quenching, Cyanine7 [IN CZECH]
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