The effect of the linker on the hydrolysis rate of drug-linked ester bonds

Ronald G. Schoenmakers, Petra Van De Wetering, Donald L. Elbert, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2 ± 0.1 to 14.0 ± 0.2 days. Drug-containing hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylbutyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs.

Original languageEnglish (US)
Pages (from-to)291-300
Number of pages10
JournalJournal of Controlled Release
Volume95
Issue number2
DOIs
StatePublished - Mar 5 2004

Keywords

  • Conjugate addition
  • Drug release
  • Hydrogels
  • Poly(ethylene glycol)
  • Prodrugs

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Schoenmakers, R. G., Van De Wetering, P., Elbert, D. L., & Hubbell, J. A. (2004). The effect of the linker on the hydrolysis rate of drug-linked ester bonds. Journal of Controlled Release, 95(2), 291-300. https://doi.org/10.1016/j.jconrel.2003.12.009