A novel approach for the intravenous delivery of leuprolide using core-cross-linked polymeric micelles

Qizhi Hu, Ethlinn V. B. van Gaal, Paul Brundel, Hans Ippel, Tilman Hackeng, Cristianne J. F. Rijcken, Gert Storm, Wim E. Hennink, Jai Prakash*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Therapeutic peptides are highly attractive drugs for the treatment of various diseases. However, their poor pharmacokinetics due to rapid renal elimination limits their clinical applications. In this study, a model hormone peptide, leuprolide, was covalently linked to core-cross-linked polymeric micelles (CCL-PMs) via two different hydrolysable ester linkages, thereby yielding a nanoparticulate system with tuneable drug release kinetics. The ester linkage that provided the slowest peptide release kinetics was selected for in vivo evaluation. Compared to the soluble peptide, the leuprolide-entrapped CCL-PMs showed a prolonged circulation half-life (14.4 h) following a single intravenous injection in healthy rats and the released leuprolide was detected in blood for 3 days. In addition, the area under the plasma concentration-time curve (AUC) value was >100-fold higher for leuprolide-entrapped CCL-PMs than for soluble leuprolide. Importantly, the released peptide remained biologically active as demonstrated by increased and long-lasting plasma testosterone levels. This study shows that covalent linkage of peptides to CCL-PMs via hydrolytically sensitive ester bonds is a promising approach to achieving sustained systemic levels of peptides after intravenous administration.
Original languageEnglish
Pages (from-to)98-108
JournalJournal of Controlled Release
Publication statusPublished - 10 May 2015


  • Polymeric micelles
  • Therapeutic peptide
  • Leuprolide
  • Pharmacokinetics
  • Sustained release

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