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Inhibition of P-glycoprotein-mediated multidrug resistance and STAT3 signaling pathway through polymeric conjugates bearing protease inhibitor derivatives
Starenko, Daniil ; Kovář, Marek (advisor) ; Truksa, Jaroslav (referee)
Tumor cells expressing high levels of some ABC transporters (mainly P-glycoprotein) can become resistant to many structurally and functionally different drugs. Such multidrug resistance can be a significant barrier for a successful chemotherapy of malignant diseases. There is a considerable amount of small-molecular-weight compounds capable of potent inhibition of P-glycoprotein, but none of them are approved for the clinical use. STAT3 is a transcription factor important for many physiological processes, but its constitutive activation may lead to the malignant transformation and chemotherapy resistance in tumor cells. This molecule is thus potential target for anticancer drugs. The inhibition of STAT3 signaling should lead to lower cancer cell proliferation and their increased susceptibility to induction of apoptosis. Considerable attention is given to increase the effectiveness and to lower the adverse effects of conventional cytostatic agents via using nanomaterials and drug delivery systems in the research of new cancer therapy approaches. Polymeric carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers are promising candidates in this field. The main aim of this diploma thesis was to evaluate the effectiveness of several HIV protease inhibitor (ritonavir, lopinavir, indinavir,...
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Antitumor activity of the polymeric conjugates bearing derivatives of protease inhibitors and conventional cytostatics for the treatment of head and neck tumors
Běhalová, Kateřina ; Kovář, Marek (advisor) ; Vodička, Pavel (referee)
Head and neck cancers account for about 4,6 % of all malignancies worldwide and their incidence is increasing. However, the development of chemotherapeutics in this field is rather stagnating. One promising approach seems to be the repurposing of drugs originally developed and clinically used as HIV protease inhibitors, which have also been described to have anticancer activity. Esterification of the OH group of these drugs with 5-methyl-4-oxohexanoic acid allows their attachment via pH-sensitive hydrazone linkage to a hydrophilic and biocompatible HPMA copolymer carrier. This binding provides an improvement in the pharmacokinetics of the drug, prolongs its circulation time in the bloodstream, lowers its side effects and it also allows passive accumulation of the drug in the tumor tissue due to the EPR effect. Six protease inhibitors in total (ritonavir, lopinavir, saquinavir, indinavir, nelfinavir and atazanavir) were derivatized as described above. Ritonavir and its derivative had been tested in a previous project and were used as reference substances. After initial determination of in vitro cytostatic and cytotoxic activity in FaDu (human head and neck carcinoma), SCC7 (murine squamous cell carcinoma), 4T1 (murine breast carcinoma) and CT26 (murine colon carcinoma) cell lines, lopinavir derivative was...
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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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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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Multivalent carbohydrate ligands of galectins
Hovorková, Michaela ; Křen, Vladimír (advisor) ; Kavan, Daniel (referee)
Galectins are proteins, wich belong to a group of lectins that are able to bind to saccharide units and they specifically recognize glycans exposed to the surface of the cells. Galectins participate in vivo, for example, in carcinogenesis, angiogenesis or fibrosis. Their occurrence increases significantly in connection with a number of pathogenic processes, therefore they can be used as markers for some types of cancer or cardiopathology and also for the targeted binding of therapeutics and/ or imaging agents in diagnosis and therapy. Galectin-3 has a specific structure known as chimeric and it is capable of forming multivalent oligomers. The natural ligands of galectins are glycans containing terminal β-galactosides, especially N-acetyllactosamine, but the binding of monovalent glycans is very weak. Glycoconjugates with high affinity to galectin receptors are optimally multivalent, biocompatible and stable in vivo. These criteria accomplish carbohydrate ligands conjugated to soluble and structurally flexible N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In this work two types of functionalized disaccharides based on N-acetyllactosamine (Galβ4GlcNAc) and its structural analogue of N,N'-diacetyllactosamine (GalNAcβ4GlcNAc) was prepared by enzymatic synthesis. For the synthesis were used...
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Use of polymer prodrugs containing cucurbitacin D for the treatment of experimental tumors
Hrabánková, Klára ; Šírová, Milada (advisor) ; Grobárová, Valéria (referee)
Chemotherapy is still the most widely used anti-cancer treatment. The majority of chemotherapeutics inhibit proliferating cells generally, not selectively cancer cells. The side effects associated with chemotherapy can be partly limited by conjugating a cytotoxic drug with a polymer nanocarrier. Such binding facilitates solubility in aqueous solutions, reduces systemic toxicity; and passively targets the drug directly into the tumour through the enhanced permeability and retention (EPR) effect. This thesis focuses on testing polymer conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) carrying cucurbitacin D (CuD), a naturally occurring compound with potential anti-cancer activity. The mechanism of action is not elucidated yet, but several studies have depicted the inhibitory effect on signal transducer and activator of transcription 3 (STAT3) transcription factor. A STAT3 signalling pathway is overexpressed in several cancer cell lines and is also involved in the differentiation of myeloid- derived suppressor cells (MDSCs). We examined the therapeutic effect of the HPMA copolymers based on CuD in combined therapy with other polymer chemotherapeutics. CuD conjugates have shown in vitro cytotoxic effect on several model cancer cell lines. The combination with conjugates carrying doxorubicin...
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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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Multivalent carbohydrate ligands of galectins
Hovorková, Michaela ; Křen, Vladimír (advisor) ; Kavan, Daniel (referee)
Galectins are proteins, wich belong to a group of lectins that are able to bind to saccharide units and they specifically recognize glycans exposed to the surface of the cells. Galectins participate in vivo, for example, in carcinogenesis, angiogenesis or fibrosis. Their occurrence increases significantly in connection with a number of pathogenic processes, therefore they can be used as markers for some types of cancer or cardiopathology and also for the targeted binding of therapeutics and/ or imaging agents in diagnosis and therapy. Galectin-3 has a specific structure known as chimeric and it is capable of forming multivalent oligomers. The natural ligands of galectins are glycans containing terminal β-galactosides, especially N-acetyllactosamine, but the binding of monovalent glycans is very weak. Glycoconjugates with high affinity to galectin receptors are optimally multivalent, biocompatible and stable in vivo. These criteria accomplish carbohydrate ligands conjugated to soluble and structurally flexible N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In this work two types of functionalized disaccharides based on N-acetyllactosamine (Galβ4GlcNAc) and its structural analogue of N,N'-diacetyllactosamine (GalNAcβ4GlcNAc) was prepared by enzymatic synthesis. For the synthesis were used...
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