title: High systemic availability of core-crosslinked polymeric micelles after subcutaneous administration.
abstract: Covalent entrapment of drug molecules within core-crosslinked polymeric micelles (CCPM) represents an attractive approach to improve their therapeutic index. As an alternative to the most commonly employed intravenous (i.v.) route, subcutaneous (s.c.) administration offers the possibility of self-administration and thereby may reduce healthcare costs. The aim of this work was to assess the pharmacokinetic profile and systemic availability of drug-containing CCPM following s.c. injection. We here derivatised dexamethasone (DMS) with three different linkers, which enabled covalent attachment of this drug to the core of CCPM. The obtained DMS-containing CCPM exhibited varying drug release kinetics in vitro. Remarkably, a single dose of DMS-containing CCPM resulted in high systemic availability of about 30% following s.c. injection into the flank of healthy mice, as evidenced by an AUC between 26-37% relative to the AUC attained following i.v. injection. Although different linkers resulted in moderate variations in pharmacokinetic parameters, the overall pharmacokinetic profiles of these i.v. or s.c. administered nanomedicines were not substantially different. Next to DMS, we covalently attached paclitaxel (PTX) to the core of CCPM. Similarly, a single s.c. dose of PTX-containing CCPM resulted in high systemic availability of about 40% compared to i.v. injection and PTX (entrapped plus released) was detected in the blood for at least 3days. Importantly, the systemic availability of s.c. administered drug-containing CCPM is substantially higher than that of other nanoformulations as reported in the literature (e.g. 3% in rodents). These results demonstrate that s.c. administration is a promising route to attain high systemic availability of CCPM, enabling a potentially more patient-friendly and cost-effective treatment approach than the i.v. route.
authors.affiliation: Department of Biomaterials Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, 7500AE, The Netherlands; Cristal Therapeutics, Oxfordlaan 55, Maastricht, 6229EV, The Netherlands.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Biomaterials Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, 7500AE, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.affiliation: Cristal Therapeutics, Oxfordlaan 55, Maastricht, 6229EV, The Netherlands.
authors.forename: Cristianne J F
authors.initials: CJ
authors.lastname: Rijcken
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584CG, 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, 7500AE, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584CG, The Netherlands. Electronic address: g.storm@uu.nl.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003907:Dexamethasone / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D011108:Polymers / Q000737:chemistry*; D012646:Self Administration; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D003907:Dexamethasone; D017239:Paclitaxel
keywords: Dexamethasone; Paclitaxel; Pharmacokinetics; Polymeric micelle; Subcutaneous; Systemic availability