%0 journal article
%@ 1438-7492
%A Folikumah, M.Y.,Behl, M.,Lendlein, A.,Neffe, A.T.

%D 2023
%J Macromolecular Materials and Engineering
%N 11
%P 2300146 
%R doi:10.1002/mame.202300146
%T A 4-Arm PEG-Thiodepsipeptide Precursor Enables Gelatinase-promoted Hydrogel Formation
%U https://doi.org/10.1002/mame.202300146
11 
%X In situ hydrogelation of injectable precursors upon biological stimulus is relevant to generate hydrogels under mild conditions and, potentially, at a biological side of interest. Here, it is shown that hydrolytic enzymes can be used to initiate the formation of covalent hydrogel networks, realizing a cleavage-leading-to-gelation strategy. For this purpose, a two-component system is used, consisting of a 4-arm polyethylene glycol-thiodepsipeptide conjugate, PEG4TDPo containing the matrix metalloproteinases MMP-2- and MMP-9-cleavable Ac-Pro-Leu-Gly#SLeu-Leu-Gly- thiodepsipeptide sequence releasing a thiol upon hydrolysis, and a maleimide functionalized 4-armed PEG (PEG4MAL). PEG4TDPo is synthesized in a PEG-functionalization protocol involving convergent and divergent synthetic steps without the need for rigorous purification procedures. In a fluorometric assay, it is shown that the construct is in fact cleaved by both investigated MMPs. PEG4TDPo in the presence of 10 wt.% PEG4MAL formed hydrogels upon addition of MMP-2 or -9 with average gelation times of 28 and 40 min, respectively, as is investigated by rheology. The much faster gelation times compared to the enzyme-free system showed the specific input of the enzymatic reactions. The MMP-assisted activation and crosslinking strategy can potentially become useful by targeting tissues showing an increased expression of MMPs, such as cancers, or to detect MMPs.