Polymer micelles with hydrazone-ester dual linkers for tunable release of dexamethasone

Melissa D. Howard, Andrei Ponta, Allison Eckman, Michael Jay, Younsoo Bae

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Purpose: To develop polymer micelles for the tunable release of Dexamethasone (DEX) in tumors. Methods: DEX was conjugated to poly(ethylene glycol)-poly(aspartate) block copolymers using hydrazone, ester, or hydrazone-ester dual linkers. Ketonic acids containing 3, 4, and 5 methylene groups were used as spacers to separate the dual linkers. Polymer micelles from the DEX-conjugated polymers were tested for drug release at different pH values and carboxylesterase activity levels. Results: DLS measurements and 1H-NMR analysis confirmed all DEX-loaded micelles were <100 nm with core-shell structure. Single linker micelles appeared unsuitable to release DEX preferentially in acidic tumor tissues. Hydrazone linkages between DEX and polymers were non-degradable at both pH 7.4 and 5.0. Ester linkages stable at pH 5.0 were unstable at pH 7.4. Hydrazone-ester dual linkers suppressed DEX release at pH 7.4 while accelerating drug release at pH 5.0. DEX release decreased at pH 5.0 as the length of ketonic acid increased but was independent of spacer length at pH 7.4. Dual linker micelles were stable in the presence of carboxylesterases, suggesting DEX release was primarily due to pH-dependent hydrolysis. Conclusion: Tunable release of DEX was achieved using pH-sensitive polymer micelles with hydrazone-ester dual linkers.

Original languageEnglish
Pages (from-to)2435-2446
Number of pages12
JournalPharmaceutical Research
Volume28
Issue number10
DOIs
StatePublished - Oct 2011

Bibliographical note

Funding Information:
Authors acknowledge financial support provided by the Kentucky Lung Cancer Research Program.

Keywords

  • dexamethasone
  • drug delivery
  • ester
  • hydrazone
  • polymer micelles

ASJC Scopus subject areas

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

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