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J Control Release. 2015 May 10;205:98-108. doi: 10.1016/j.jconrel.2014.12.023. Epub 2015 Jan 10.

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

Author information

1
Department of Biomaterials Science and Technology, section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands; Cristal Therapeutics, Maastricht, The Netherlands.
2
Cristal Therapeutics, Maastricht, The Netherlands.
3
Department of Biochemistry and CARIM, University of Maastricht, Maastricht, The Netherlands.
4
Department of Biomaterials Science and Technology, section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
5
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
6
Department of Biomaterials Science and Technology, section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands. Electronic address: j.prakash@utwente.nl.

Abstract

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 (14.4h) following a single intravenous injection in healthy rats and the released leuprolide was detected in blood for 3days. 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.

KEYWORDS:

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

PMID:
25583642
DOI:
10.1016/j.jconrel.2014.12.023
[Indexed for MEDLINE]

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