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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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