PMID- 27003313
OWN - NLM
STAT- MEDLINE
DCOM- 20170410
LR  - 20181202
IS  - 1804-7521 (Electronic)
IS  - 1213-8118 (Linking)
VI  - 160
IP  - 2
DP  - 2016 Jun
TI  - Biodegradable system for drug delivery of hydrolytically labile azanucleoside 
      drugs.
PG  - 222-30
LID - 10.5507/bp.2016.013 [doi]
AB  - 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.
FAU - Hruby, Martin
AU  - Hruby M
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Agrawal, Khushboo
AU  - Agrawal K
AD  - Institute of Molecular and Translational Medicine, Faculty of Medicine and 
      Dentistry, Palacky University Olomouc, Hnevotinska 5, 779 00 Olomouc, Czech 
      Republic.
FAU - Policianova, Olivia
AU  - Policianova O
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Brus, Jiri
AU  - Brus J
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Skopal, Jan
AU  - Skopal J
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Svec, Pavel
AU  - Svec P
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Otmar, Miroslav
AU  - Otmar M
AD  - Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech 
      Republic, v.v.i., Fleming Sq. 2.166 10 Prague 6, Czech Republic.
FAU - Dzubak, Petr
AU  - Dzubak P
AD  - Institute of Molecular and Translational Medicine, Faculty of Medicine and 
      Dentistry, Palacky University Olomouc, Hnevotinska 5, 779 00 Olomouc, Czech 
      Republic.
FAU - Stepanek, Petr
AU  - Stepanek P
AD  - Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 
      v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
FAU - Hajduch, Marian
AU  - Hajduch M
AD  - Institute of Molecular and Translational Medicine, Faculty of Medicine and 
      Dentistry, Palacky University Olomouc, Hnevotinska 5, 779 00 Olomouc, Czech 
      Republic.
LA  - eng
PT  - Journal Article
DEP - 20160321
PL  - Czech Republic
TA  - Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
JT  - Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, 
      Czechoslovakia
JID - 101140142
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Polymers)
RN  - 776B62CQ27 (Decitabine)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Absorbable Implants
MH  - Antimetabolites, Antineoplastic/*administration & dosage/pharmacology
MH  - Azacitidine/*administration & dosage/*analogs & derivatives/pharmacology
MH  - Cells, Cultured
MH  - Decitabine
MH  - Humans
MH  - Infusion Pumps, Implantable
MH  - Magnetic Resonance Spectroscopy
MH  - Microspheres
MH  - Polymers/chemistry
OTO - NOTNLM
OT  - 5-aza-2'-deoxycytidine
OT  - 5-azacitidine
OT  - diclofenac
OT  - microbeads
OT  - polyanhydride
EDAT- 2016/03/24 06:00
MHDA- 2017/04/11 06:00
CRDT- 2016/03/23 06:00
PHST- 2015/07/23 00:00 [received]
PHST- 2016/03/03 00:00 [accepted]
PHST- 2016/03/23 06:00 [entrez]
PHST- 2016/03/24 06:00 [pubmed]
PHST- 2017/04/11 06:00 [medline]
AID - 10.5507/bp.2016.013 [doi]
PST - ppublish
SO  - Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016 Jun;160(2):222-30. doi: 
      10.5507/bp.2016.013. Epub 2016 Mar 21.