Innovative Materials

Bioorthogonal Preparation of dPG - based Nano - and Microgels Using a IEDDA Linking Strategy

Alexander Oehrl1, Svenja Ehrmann1,2, Era Kapourani1 and Rainer Haag1

1Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195, Berlin, GER

2Research Center of Electron Microscopy, Freie Universität Berlin, Fabeckstr. 36A, 14195, Berlin, GER

The development of nanocarrier systems for targeted therapeutics and improvement of plasma half-lifes and immune evasion of proteins includes the necessity of a suitable linker strategy for the synthesis of the carrier and for conjugation of targeting ligands. Click chemistry is playing a major role in this field due to reaction rates, selectivity and orthogonality to biological systems. Especially strain-promoted azide-alkyne cycloaddition (SPAAC), introduced by BERTOZZI et al. 1, was and still is one of the most important coupling strategies within biological systems, e.g. cell staining or antibody conjugates. However, this strategy suffers from specific drawbacks, as the strained alkynes are obtained through tedious synthesis and show some reactivity towards free thiols of proteins 2, rendering SPAAC not completely bioorthogonal. Recently, another click approach utilizing inverse electron-demand Diels Alder (iEDDA) has emerged 3 4 5. Based on electron-deficient tetrazine derivatives and electron-rich olefins, it is used in this work as a linker strategy for the formation of nanogels from functionalized dendritic polyglycerol (dPG) scaffolds by the nanoprecipitation method. Therefore, some novel dPG-olefin derivatives as well as literature known derivatives are synthesized and compared regarding their ability to allow fast and stable nanogel formation. The strategy is also currently employed to evaluate the bioorthogonal encapsulation of therapeutic proteins.

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