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Biomacromolecules. 2019 Oct 14;20(10):3786-3797. doi: 10.1021/acs.biomac.9b00868. Epub 2019 Sep 19.

HPMA-Based Nanoparticles for Fast, Bioorthogonal iEDDA Ligation.

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Johannes Gutenberg University Mainz , Institute of Organic Chemistry , Duesbergweg 10-14 , 55128 Mainz , Germany.
TU Wien , Institute of Applied Synthetic Chemistry , Getreidemarkt 9 , 1060 Vienna , Austria.
Max Planck Institute for Polymer Research , Physics of Interfaces , Ackermannweg 10 , 55128 Mainz , Germany.
Tagworks Pharmaceuticals BV, Radboud University Medical Center , Department of Nuclear Medicine and Radiology , 6500 HB Nijmegen , The Netherlands.


Fast and bioorthogonally reacting nanoparticles are attractive tools for biomedical applications such as tumor pretargeting. In this study, we designed an amphiphilic block copolymer system based on HPMA using different strategies to introduce the highly reactive click units 1,2,4,5-tetrazines (Tz) either at the chain end (Tz-CTA) or statistical into the hydrophobic block. This reactive group undergoes a rapid, bioorthogonal inverse electron-demand Diels-Alder reaction (iEDDA) with trans-cyclooctenes (TCO). Subsequently, this polymer platform was used for the preparation of different Tz-covered nanoparticles, such as micelles and colloids. Thereby it was found that the reactivity of the polymeric micelles is comparable to that of the low molar mass tetrazines. The core-cross-linked micelles can be successfully conjugated at rather low concentrations to large biomacromolecules like antibodies, not only in physiological buffer, but also in human blood plasma, which was confirmed by fluorescence correlation spectroscopy (FCS).

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