BACKGROUND: 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. METHODS: 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. RESULTS: Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R(2) = 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. CONCLUSIONS: 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.

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic v v i Prague Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Prague Czech Republic

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