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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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Biocompatible polymer nanomaterials with non-steroid drugs tailored for anti-inflammation therapy
Běhalová, Kateřina ; Etrych, Tomáš (advisor) ; Kovář, Marek (referee)
The main aim of this bachelor thesis was synthesis and physico-chemical and preliminary biological characterization of water-soluble biocompatible polymeric system for targeted delivery of acetylsalicylic acid to inflamed tissue. Such polymer conjugates should be employed in the future for the therapeutic use within the treatment of chronic inflammatory diseases. The project included the preparation of a series of suitable acetylsalicylic acid derivatives and the synthesis of a polymeric carrier based on N-(2-hydroxypropyl) methacrylamide copolymer. Finally, the acetylsalicylic acid derivative was attached to the polymer forming a polymeric conjugate with pH-sensitive bond between the drug derivative and polymer chain, thus allowing controlled release of the drug in the target site. The work includes SEC, NMR and HPLC characterization of all synthesized compounds, verification of their stability in solutions with different pH and results of the release of drug derivatives from the polymeric carrier at physiological pH, or mildly acidic pH modeling inflamed environment. Moreover, the cytotoxicity bioassay of acetylsalicylic acid derivatives using LDH assay did not prove any cytoxicity at the level of necrotic activity. Also, their cyclooxygenase 1 inhibitory activity was observed and discussed. The polymeric...
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