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Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs
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SYSNO ASEP 0460868 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs Author(s) Hrubý, Martin (UMCH-V) RID, ORCID
Agrawal, K. (CZ)
Policianová, Olivia (UMCH-V) RID
Brus, Jiří (UMCH-V) RID, ORCID
Skopal, Jan (UMCH-V)
Švec, Pavel (UMCH-V) RID, ORCID
Otmar, Miroslav (UOCHB-X) RID
Dzubak, P. (CZ)
Štěpánek, Petr (UMCH-V) RID, ORCID
Hajduch, M. (CZ)Source Title Biomedical Papers. - : Univerzita Palackého v Olomouci - ISSN 1213-8118
Roč. 160, č. 2 (2016), s. 222-230Number of pages 9 s. Language eng - English Country CZ - Czech Republic Keywords 5-azacitidine ; 5-aza-2'-deoxycytidine ; diclofenac Subject RIV EE - Microbiology, Virology Subject RIV - cooperation Institute of Organic Chemistry and Biochemistry - Genetics ; Molecular Biology R&D Projects FR-TI4/625 GA MPO - Ministry of Industry and Trade (MPO) 7F14009 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA14-03636S GA ČR - Czech Science Foundation (CSF) Institutional support UMCH-V - RVO:61389013 ; UOCHB-X - RVO:61388963 UT WOS 000379360500007 EID SCOPUS 84976433840 DOI 10.5507/bp.2016.013 Annotation The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback. Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the time-course dissolution of the microbeads, using an in vitro developed cell based reporter system. Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R2 = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads. The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2017
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