title: Release, partitioning, and conjugation stability of doxorubicin in polymer micelles determined by mechanistic modeling.
abstract: OBJECTIVE
  To better understand the mechanistic parameters that govern drug release from polymer micelles with acid-labile linkers.
  
  
  METHODS
  A mathematical model was developed to describe drug release from block copolymer micelles composed of a poly(ethylene glycol) shell and a poly(aspartate) core, modified with drug binding linkers for pH-controlled release [hydrazide (HYD), aminobenzoate-hydrazide (ABZ), or glycine-hydrazide (GLY)]. Doxorubicin (Dox) was conjugated to the block copolymers through acid-labile hydrazone bonds. The polymer drug conjugates were used to prepare three polymer micelles (HYD-M, ABZ-M, and GLY-M). Drug release studies were performed to identify the factors governing pH-sensitive release of Dox. The effect of prolonged storage of copolymer material on release kinetics was also observed.
  
  
  RESULTS
  Biphasic drug release kinetics were observed for all three micelle formulations. The developed model was able to quantify observed release kinetics upon the inclusion of terms for unconjugated Dox and two populations of conjugated Dox. Micelle/water partitioning of Dox was also incorporated into the model and found significant in all micelles under neutral conditions but reduced under acidic conditions. The drug binding linker played a major role in drug release as the extent of Dox release at specific time intervals was greater at pH 5.0 than at pH 7.4 (HYD-M > ABZ-M > GLY-M). Mathematical modeling was also able to correlate changes in release kinetics with the instability of the hydrazone conjugation of Dox during prolonged storage.
  
  
  CONCLUSIONS
  These results illustrate the potential utility of mechanistic modeling to better assess release characteristics intrinsic to a particular drug/nanoparticle system.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky, 40536-0596, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Ponta
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Fugit
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Younsoo
authors.initials: Y
authors.lastname: Bae
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D065546:Drug Liberation; D004355:Drug Stability; D006835:Hydrazones / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008823:Micelles; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D006835:Hydrazones; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin