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Antitumor activity of HPMA copolymer-bound gemcitabine conjugate potentiation by IAP inhibitors
Ivančík, Martin ; Kovář, Marek (advisor) ; Anděra, Ladislav (referee)
Cancer represents a significant global health challenge, with a substantially increasing incidence. There is a critical need for enhanced prevention, early detection, and improved therapeutic approaches to treat malignant diseases. While chemotherapy remains a standard treatment for many cancers, its efficacy is often limited by cytotoxic effects on healthy cells and numerous side toxicities. In response to these challenges, novel strategies such as combination therapies and drug delivery systems have emerged. In this project, we investigated the cytostatic and cytotoxic effects of two inhibitors of IAP (inhibitor of apoptosis) proteins, LCL-161 and AZD5582, and their potential to boost the anticancer activity of gemcitabine. These compounds were evaluated in five human cancer cell lines: pancreatic (PANC1, BxPC- 3, MiaPaca-2), prostatic (PC-3), and breast (MDA-MB-231) carcinomas. Both IAP inhibitors demonstrated anticancer activity as single agents, with the MiaPaca-2 and BxPC-3 cell lines showing the highest sensitivity. No correlation was observed between the expression levels of IAP genes (cIAP1, cIAP2, XIAP) and the sensitivity of cell lines to IAP inhibitors. However, four of five tested cell lines possessed a consistent pattern in the expression of these three genes. IAP inhibitors were able...
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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 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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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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