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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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