Polyglycerin-Based Nanogels for Protein Encapsulation [thesis]

Alexander Oehrl, Universitätsbibliothek Der FU Berlin
Smart and sensitive nanocarriers for the delivery of therapeutic proteins are needed as alternatives for covalent modification with the potentially immunogenic PEG. Nanogels as water swollen, highly hydrophilic polymer networks are promising candidates for protein delivery vehicles. However, scalable production, under sensitive and mild conditions, is still an active area of research. Inverse nanoprecipitation, as one of several production methods, offers the potential for the mild and
more » ... e mild and non-destructive encapsulation of sensitive proteins. The gel networks are preferably formed by crosslinking of biocompatible, hydrophilic, and easily obtainable functionalized polymers. A variety of crosslinking chemistries, such as CuAAC, Thiol-Michael addition, and SPAAC have been studied for this purpose. Most of these chemistries, however, suffer from low biorthogonality, toxic catalysts, or the low synthetic accessibility of the precursors. IEDDA has emerged as an alternative for the other click chemistries, with fast reaction kinetics, high biorthogonality and easily accessible precursors. The goal of this study was to design nanogels in a way that most of the mentioned criteria for a successful nanocarrier system are fulfilled. Nanogels, based on the biocompatible, scalable, hydrophilic and easily functionalizable dPG were presented in this work. Inverse nanoprecipitation was used as a mild gelation method, that lacks toxic surfactants or damaging ultrasound. The bioorthogonal and fast iEDDA click chemistry, based on tetrazines and dienophiles, was established for the first time in the use of nanogel production. The first study focused on the search for suitable dienophiles for the iEDDA crosslinking chemistry. Reactivity and scalability were most important. This was achieved by screening of different iEDDA-reactive dienophile macromonomers. For this, the four different dienophile macromonomers dPG-norbonene, dPG-BCN, dPG-cyclopropene, and dPG-DHP were synthesized. As the tetrazine counterpart, the stable but still reactive [...]
doi:10.17169/refubium-27495 fatcat:27vfabs4vzeapm7qhj2imtsyfy