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Substituated Poly(ethylene Glycols) as Drugs Carriers
Pravda, Martin ; Hrabálek, Alexandr (advisor) ; Dittrich, Milan (referee) ; Kalendová, Andrea (referee)
The aim of this dissertation thesis was preparation of drug delivery systems for polyene antimycotics, especially amphtoricin B(AmB). Series of pH-sensitive conjugates of AmB with substituated poly(ethylene glycols) (PEG) have been synthesized and characterized for this purpose. The intermediate PEGs possess a 1,4-disubstituted benzene ring with aldehyde group at the end of the chain. The benzene ring is connected with PEG at its 4-position (with respect to the aldehyde group) by various functional groups (ether, amide, ester). Reaction of terminal aldehyde group of the substituted PEGs with AmB gave conjugates containinga pH-sensitive imine linkage, which can be presumed to exhibit antimycotic effect at sites with lowered pH value. The stability of prepared conjugates under the different physiological conditions was studied. Phosphate buffers (pH = 7,4 or 5,5) were used as model media. Stability of conjugates in human blood plasma and human blood serum was examinated. The imine linkage is split to give free AmB with half-lives of 2-45 min. The rate of acid catalysed hydrolysis depends upon substitution of the benzene ring; however, it does not depend on molecular weights ofthe PEGs used. The conjugates with ester linkage undergo enzymatic splitting in human blood plasma and/or blood serum at pH 7.4...
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Substituated Poly(ethylene Glycols) as Drugs Carriers
Pravda, Martin ; Hrabálek, Alexandr (advisor) ; Dittrich, Milan (referee) ; Kalendová, Andrea (referee)
The aim of this dissertation thesis was preparation of drug delivery systems for polyene antimycotics, especially amphtoricin B(AmB). Series of pH-sensitive conjugates of AmB with substituated poly(ethylene glycols) (PEG) have been synthesized and characterized for this purpose. The intermediate PEGs possess a 1,4-disubstituted benzene ring with aldehyde group at the end of the chain. The benzene ring is connected with PEG at its 4-position (with respect to the aldehyde group) by various functional groups (ether, amide, ester). Reaction of terminal aldehyde group of the substituted PEGs with AmB gave conjugates containinga pH-sensitive imine linkage, which can be presumed to exhibit antimycotic effect at sites with lowered pH value. The stability of prepared conjugates under the different physiological conditions was studied. Phosphate buffers (pH = 7,4 or 5,5) were used as model media. Stability of conjugates in human blood plasma and human blood serum was examinated. The imine linkage is split to give free AmB with half-lives of 2-45 min. The rate of acid catalysed hydrolysis depends upon substitution of the benzene ring; however, it does not depend on molecular weights ofthe PEGs used. The conjugates with ester linkage undergo enzymatic splitting in human blood plasma and/or blood serum at pH 7.4...
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