title: A novel approach for the intravenous delivery of leuprolide using core-cross-linked polymeric micelles.
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.
authors.affiliation: 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.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Cristal Therapeutics, Maastricht, The Netherlands.
authors.forename: Ethlinn V B
authors.initials: EV
authors.lastname: van Gaal
authors.affiliation: Cristal Therapeutics, Maastricht, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Brundel
authors.affiliation: Department of Biochemistry and CARIM, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Ippel
authors.affiliation: Department of Biochemistry and CARIM, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Tilman
authors.initials: T
authors.lastname: Hackeng
authors.affiliation: Cristal Therapeutics, Maastricht, The Netherlands.
authors.forename: Cristianne J F
authors.initials: CJ
authors.lastname: Rijcken
authors.affiliation: 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.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: 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.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004952:Esters / Q000737:chemistry; D006207:Half-Life; D006868:Hydrolysis; D007275:Injections, Intravenous; D016729:Leuprolide / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008823:Micelles; D011108:Polymers / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013739:Testosterone / Q000097:blood
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004952:Esters; D008823:Micelles; D011108:Polymers; D013739:Testosterone; D016729:Leuprolide
keywords: Leuprolide; Pharmacokinetics; Polymeric micelles; Sustained release; Therapeutic peptide