1. A novel approach for the intravenous delivery of leuprolide using core-cross-linked polymeric micelles
- Author
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Hu, Qizhi, Van Gaal, Ethlinn V B, Brundel, Paul, Ippel, Hans, Hackeng, Tilman, Rijcken, Cristianne J F, Storm, Gert, Hennink, Wim E., Prakash, Jai, Sub Drug delivery, UIPS - Utrecht Institute for Pharmaceutical Sciences, Sub General Pharmaceutics, Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R3 - Vascular biology, Sub Drug delivery, UIPS - Utrecht Institute for Pharmaceutical Sciences, Sub General Pharmaceutics, and Biomaterials Science and Technology
- Subjects
Male ,Metabolic Clearance Rate ,Polymers ,Chemistry, Pharmaceutical ,Kinetics ,Pharmaceutical Science ,Peptide ,Pharmacology ,Micelle ,Rats, Sprague-Dawley ,Pharmacokinetics ,In vivo ,Therapeutic peptide ,Animals ,Technology, Pharmaceutical ,Testosterone ,Micelles ,chemistry.chemical_classification ,Drug Carriers ,Chemistry ,Hydrolysis ,METIS-308682 ,Esters ,Biological activity ,IR-95553 ,Cross-Linking Reagents ,Solubility ,Covalent bond ,Area Under Curve ,Delayed-Action Preparations ,Injections, Intravenous ,Polymeric micelles ,Leuprolide ,Drug carrier ,Half-Life ,Sustained release - 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 (14.4 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.
- Published
- 2015
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