Tetrafluoroaryl azide as an N-Terminal capping group for click-To-dissolve diphenylalanine hydrogels

Abstract

The synthesis of a bioorthogonal-responsive low molecular weight diphenylalanine (PhePhe)-based hydrogel that is capped with a 4-Azido-2,3,5,6-Tetrafluorobenzyl carbamate self-immolative linker is reported. The hydrogelator (AzF4-PhePhe) generates a stable hydrogel at 0.1 wt%, and rapidly reacts with the bioorthogonal reagent trans-cyclooctene (TCO), inducing a gel-To-solution transition. The critical gel concentration is five-fold lower than our previously synthesized non-fluorinated hydrogelator (Az-PhePhe), and the minimum concentration of TCO required for visible gel-To-solution transition in 24 hours is 1 mM. Doxorubicin can be encapsulated in the hydrogel and TCO-Triggered dissolution results in 76% and 89% release after 10 and 24 hours, respectively. Compared with our non-substituted aryl azide capping group used for Az-PhePhe, the tetrafluorinated aryl azide group improves the stability of the hydrogel in unbuffered water at a lower critical gel concentration, while improving sensitivity towards the bioorthogonal reagent TCO.