title: Core-Crosslinked Polymeric Micelles: Principles, Preparation, Biomedical Applications and Clinical Translation.
abstract: Polymeric micelles (PM) are extensively used to improve the delivery of hydrophobic drugs. Many different PM have been designed and evaluated over the years, and some of them have steadily progressed through clinical trials. Increasing evidence suggests, however, that for prolonged circulation times and for efficient EPR-mediated drug targeting to tumors and to sites of inflammation, PM need to be stabilized, to prevent premature disintegration. Core-crosslinking is among the most popular methods to improve thein vivostability of PM, and a number of core-crosslinked polymeric micelles (CCPM) have demonstrated promising efficacy in animal models. The latter is particularly true for CCPM in which (pro-) drugs are covalently entrapped. This ensures proper drug retention in the micelles during systemic circulation, efficient drug delivery to pathological sites via EPR, and tailorable drug release kinetics at the target site. We here summarize recent advances in the CCPM field, addressing the chemistry involved in preparing them, theirin vitroandin vivoperformance, potential biomedical applications, and guidelines for efficient clinical translation.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Immunology and Oncology and NanoBiomedicine Initiative, Centro Nacional de Biotecnología (CNB)/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Talelli
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barz
authors.affiliation: Cristal Therapeutics, Oxfordlaan 55, 6229 EV Maastricht, the Netherlands.
authors.forename: Cristianne J
authors.initials: CJ
authors.lastname: Rijcken
authors.affiliation: Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
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 Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.|Department of Controlled Drug Delivery, University of Twente and MIRA Institute for Biomedical Technology and Technical Medicine, Enschede, The Netherlands.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
keywords: Core-crosslinking; Drug targeting; EPR; Micelle; Nanomedicine; Polymer