Release, Partitioning, and Conjugation Stability of Doxorubicin in Polymer Micelles Determined by Mechanistic Modeling

Andrei Ponta, Kyle D. Fugit, Bradley D. Anderson, Younsoo Bae

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Purpose: 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. Conclusion: These results illustrate the potential utility of mechanistic modeling to better assess release characteristics intrinsic to a particular drug/nanoparticle system.

Original languageEnglish
Pages (from-to)1752-1763
Number of pages12
JournalPharmaceutical Research
Volume32
Issue number5
DOIs
StatePublished - May 1 2015

Bibliographical note

Funding Information:
This work is partially supported by the Kentucky Lung Cancer Research Program and the University of Kentucky Cancer Nanotechnology Training Center (UK-CNTC), grant R25CA153954 from the National Cancer Institute. The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Publisher Copyright:
© 2014 Springer Science+Business Media.

Keywords

  • controlled drug release
  • doxorubicin
  • hydrazone
  • mechanistic modeling
  • nanoparticles

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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