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Anti-tumor activity and toxicity of HPMA copolymer conjugates bearing cytostatic drug
Tomalová, Barbora ; Kovář, Marek (advisor) ; Smetana, Karel (referee) ; Špíšek, Radek (referee)
7 ABSTRACT In this study, we addressed the biological activity and pharmacological features of selected HPMA copolymer-based drug conjugates. We determined their cytostatic activity in vitro as well as toxicity in vivo and therapeutic effcicacy in mouse tumor models. Assessment of maximum tolerated dose (MTD) of two structurally different HPMA copolymer-based conjugates bearing doxorubicin (DOX) attached via pH-sensitive hydrazon bond (HPMA- DOXHYD ) showed that high molecular weight non-degradable star HPMA-DOXHYD conjugate possesses relatively low MTD ~22.5 mg DOX/kg, while linear HPMA-DOXHYD has MTD ~85 mg DOX/kg. Thus, MTD of linear conjugate is 3.7 times higher than that of the star conjugate. Subsequently, we reported that linear conjugate proved to be more efficient in case of treatment of solid tumor EL4 lymphoma and star conjugate to be superior in case of BCL1 leukemia treatment. We also compared biological activity of star and linear HPMA copolymer-based conjugates bearing docetaxel (DTX) attached via pH-sensitive hydrazon bond (HPMA-DTXHYD ). MTD of star conjugate (~160 mg DTX/kg) was proved to be 4 times higher than MTD od free DTX (40 mg/kg). We were not able to determine MTD of linear conjugate as it exceeded 200 mg DTX/kg (the highest soluble dose we were able to administer as a bolus)....
Polymer drug carries based on HPMA copolymers facilitating solid tumour drug targeting and pH-triggered activation
Chytil, Petr ; Ulbrich, Karel (advisor) ; Sedláček, Jan (referee) ; Stiborová, Marie (referee) ; Smetana, Karel (referee)
2. Summary of the PhD. Thesis Introduction The use of synthetic polymer carriers of anticancer drugs represents a promising approach to cancer therapy. Conjugation of cýotoxic drugs with polymers may reduce their toxicity and immunogenicity, eliminate undesirable body interactions, improve their solubility, bioavailability and stability (enzymatic. thermal, etc.), and prolong blood clearance' Moreover, polStmer drug carriers may enable specific delivery to the diseased tissue and controlled drug release in therapeutically active form. Since the first papers were published in the late 1970's the concept of polymer drug carrier systems has been generally accepted. In principle basic water-soluble poll,tner drug delivery systems consist of three parts: of polymer carrier, biodegradable spacer and drug. Preferably, drugs are covalently bound to the pol}mers via spacers, which enable controlled release of active drug in the target tissue or cells. Probably, most of the studied polymer carriers of cancerostatic drugs have been designed as lysosomotropic systems, where the drug could be released by enzymes rn lysosomes of tumour cells. In recent years pH-triggered hydrolytic drug release has been intensively studied. Here, the presence of enzynes is not essential, as the drug might be released in endosomes in...
The effect of carbon nanostructures on human cell behavior and the role of fetal bovine serum in cell adhesion
Verdánová, Martina ; Hubálek Kalbáčová, Marie (advisor) ; Brábek, Jan (referee) ; Smetana, Karel (referee)
Graphene (G) and nanocrystalline diamond (NCD) are carbon allotropes and promising nanomaterials with an excellent combination of their properties, such as high mechanical strength, electrical and thermal conductivity, possibility of functionalization and very high surface area to volume ratio. For these reasons, G and NCD are employed next to electronics in biomedical applications, including implant coating, drug and gene delivery and biosensing. For a fundamental characterization of cell behavior on G and NCD, we studied osteoblast adhesion and proliferation on differently treated G and NCD. Generally, both G and NCD exhibited better properties for osteoblast cultivation than control tissue culture polystyrene. Better cell adhesion but lower cell proliferation were observed on NCD compared to G. The most surprising finding was that hydrophobic G with nanowrinkled topography enhanced cell proliferation extensively, in comparison to hydrophilic and flat G and both NCDs (hydrophobic and hydrophilic) with slightly higher roughness. Promoted cell proliferation enables faster cell colonization of G and NCD substrates, meaning faster new tissue formation which is beneficial in biomedical applications. Furthermore, it was shown that osteoblast adhesion was promoted in the initial absence of fetal bovine...
The Growth of vascular and skin cells on polymer materials for tissue engineering
Bačáková, Markéta ; Bačáková, Lucie (advisor) ; Smetana, Karel (referee) ; Daniel, Matej (referee)
The ideal vascular or skin substitute is able to simulate the functions of original vascular or skin tissue. To reach this goal, the tissue substitute should be based on a biomaterial scaffold of an appropriate structure and desirable physical and chemical properties. These properties strongly influence successful implantation of the substitute to the patient's organism, substitute durability in the organism, and the desired colonization of the scaffolds with cells. These properties have a great impact on the adhesion, proliferation, differentiation, and desired phenotypic maturation of cells. Most of the biomaterials used for constructing clinically used tissue substitutes do not have appropriate properties for sufficient cell colonization, and thus their surface modification is needed. This thesis focuses on the improvement of biomaterial surface properties for successful cell colonization by plasma treatment, or by grafting and coating biomaterials with bioactive substances and extracellular matrix proteins. The modification of polyethylene (PE) foils by Ar+ plasma discharge showed a positive effect on the spreading, proliferation, and phenotypic maturation of vascular smooth muscle cells (VSMC). Subsequent grafting of the plasma-activated surface with bioactive substances further influenced cell...
Structure-function organization of the cell nucleus.Microscopical analysis of nuclear subcompartments.
Jůda, Pavel ; Cmarko, Dušan (advisor) ; Mokrý, Jaroslav (referee) ; Kučera, Tomáš (referee) ; Smetana, Karel (referee)
Pavel Jůda - Abstract The cell nucleus is a complex cellular organelle. The nucleus and nuclear processes are organized into functionally and morphologically separated nuclear subcompartments. This thesis is particularly concerned with the three following nuclear subcompartments: sites of DNA replication, Polycomb bodies and nuclear inclusions constituted of inosine monophosphate dehydrogenase 2 (IMPDH2). First, we examined the relationship between MCM proteins and DNA replication. Using immunofluorescent labeling of cells extracted prior fixation and applying cross-correlation function analysis, we showed that MCM proteins are present at the sites of active DNA synthesis. Our results contributed to the solving of the first part of so-called MCM paradox. Second, we studied the structural basis of the Polycomb bodies. Based on fluorescence microscopy studies, Polycomb bodies have been considered to be the nuclear subcompartments formed by the accumulation of Polycomb proteins in the interchromatin compartment. In our work, using correlative light electron microscopy and experimental changes in macromolecular crowding, we clearly showed that a Polycomb body is a chromosomal domain formed by an accumulation of heterochromatin structures, rather than a typical nucleoplasmic body. Third, we were interested in...
Healing wound as a model for the study of cell interactions
Gál, Peter ; Smetana, Karel (advisor) ; Motlík, Jan (referee) ; Brábek, Jan (referee)
Healing wound as a model for the study of cell interactions Abstract Galectins play an important role in the processes of cell proliferation, differentiation, migration and extracellular matrix formation. Furthermore, galectins are able to transfer cellular signals and to participate in cell interaction. It has been proven that galectins play an important role in the microenvironment formation of a tumor and/or healing wound. This study demonstrated significant role of galectins, in particular Galectin-1, in wound healing and cell interactions (endothelial cells, fibroblasts and keratinocytes) forming a part of the granulation tissue and tumor stroma. We have demonstrated that the extracellular matrix rich on Galectin-1 creates a suitable environment for the cultivation of keratinocytes. Galectin-1 also induces differentiation of fibroblasts into myofibroblasts. The knowledge of above mentioned processes is important to better understand the complexity of cancer biology and its parallel to wound healing. Key words: tissue repair, regeneration, galectin, tumor
Immunocompetent cells and their importance in immunopathological conditions
Podrazil, Michal ; Bartůňková, Jiřina (advisor) ; Reiniš, Milan (referee) ; Smetana, Karel (referee)
Pokroky v současné imunologii vedou k lepšímu porozumění interakcí mezi imunitním systémem a nádory, což vzbuzuje zájem o využití imunitního systému v léčbě nádorových onemocnění. V úvodní části práce jsou shrnuty teoretické poznatky o mechanismech protinádorové imunitní odpovědi a jednotlivých složkách imunitního systému podílejících se na tomto procesu. Ústřední úlohu v této interakci reprezentují dendritické buňky. Právě jejich využitím v klinické medicíně se dlouhodobě zabývá naše pracoviště. V této práci se věnuji několika dílčím cílům. První z nich je analýza zastoupení jednotlivých subpopulací imunokompetentních buněk v imunoterapeutickém léčivém přípravku na bázi dendritických buněk proti karcinomu prostaty- DCVAC/PCa vyvinutého na Ústavu imunologie, dále praktickým aspektům přípravy této formy aktivní buněčné imunoterapie a její optimalizaci za podmínek správné výrobní praxe. Výsledky této části byly součástí farmaceutické dokumentace, která vedla ke schválení výrobního postupu i zahájení klinických studií u pacientů s karcinomem prostaty regulačními autoritami. Dalším krokem bylo následné praktické testování imunoterapie DCVAC/PCa nejprve v pilotní "first-in-men" aplikaci u pacienta s pokročilým metastatickým karcinomem prostaty a následně klinické hodnocení tohoto preparátu v rámci 2...
Novel avenues for the preparation of antifouling scaffolds for tissue engineering
Kostina, Nina ; Michálek, Jiří (advisor) ; Smetana, Karel (referee) ; Vlček, Petr (referee)
Non-specific protein adsorption -protein fouling- is an adverse effect occurring at the surface of most artificial materials which come into contact with biological fluids, affecting various biomedical devices and tissue engineering scaffolds. In order to address this ubiquitous problem the preparation of scaffolds resistant to protein fouling (antifouling) was proposed. The main goal of this Thesis was the development of strategies for the preparation of antifouling scaffolds for tissue engineering. The work consisted of three steps: (i) the selection of monomers leading to antifouling properties by utilizing model system based on polymer brushes; (ii) preparation of antifouling hydrogels of different properties and architecture by copolymerization with zwitterionic carboxybetaine monomers, selected from model experiment; and (iii) modification of the surface of poly( -caprolactone) (PCL) nanofibers by growing four types of polymer brushes resistant to protein fouling. The scaffolds presented in this work showed variety of unique properties, such as hydration (up to 30000%), elongation (up to 1800%), self-healing, biodegradation, availability of functional groups and complex pore structure. Importantly, all scaffolds showed significant reduction of protein fouling and non-specific cell adhesion and can be...

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