Decisive role of hydrophobic side groups of polypeptides in thermosensitive gelation.

Thermosensitive hydrogels based on PEG and poly(l-glutamate)s bearing different hydrophobic side groups were separately synthesized by the ring-opening polymerization (ROP) of l-glutamate N-carboxyanhydrides containing different alkyl protected groups, that is, methyl, ethyl, n-propyl, and n-butyl, using mPEG(45)-NH(2) as macroinitiator. The resulting copolymers underwent sol-gel transitions in response to temperature change. Interestingly, the polypeptides containing methyl and ethyl showed significantly lower critical gelation temperatures (CGTs) than those bearing n-propyl and butyl side groups. Based on the analysis of (13)C NMR spectra, DLS, circular dichroism spectra, and ATR-FTIR spectra, the sol-gel transition mechanism was attributed to the dehydration of poly(ethylene glycol) and the increase of β-sheet conformation content in the polypeptides. The in vivo gelation test indicated that the copolymer solution (6.0 wt %) immediately changed to a gel after subcutaneous injection into rats. The mass loss of the hydrogel in vitro was accelerated in the presence of proteinase K, and the MTT assay revealed that the block copolymers exhibited no detectable cytotoxicity. The present work revealed that subtle variation in the length of a hydrophobic side group displayed the decisive effect on the gelation behavior of the polypeptides. In addition, the thermosensitive hydrogels could be promising materials for biomedical applications due to their good biocompatibility, biodegradability, and the fast in situ gelation behavior.