Poly( <scp>dl</scp> -Alanine- <i>co</i> -Glycine): Peptide Analogue of Poly( <scp>dl</scp> -Lactide- <i>co</i> -Glycolide)

We report poly(dl-alanine-<i>co</i>-glycine)s (dl-PAGs) as peptide-based analogues of the extensively studied ester-based poly(dl-lactide-<i>co</i>-glycolide)s (dl-PLGA)s. In contrast to the hydrophobic and water-insoluble dl-PLGAs, dl-PAGs containing less than 22 mol % glycine were water-soluble. Notably, their aqueous solutions exhibited a sol-to-gel transition upon heating at concentrations ranging from 7.0 to 16.0 wt %. Spectroscopic analyses─including ¹H NMR, FTIR, and circular dichroism─suggest that this thermoresponsive behavior is driven by partial dehydration of the randomly coiled dl-PAG chains, akin to the mechanism observed in poly(<i>N</i>-isopropylacrylamide). dl-PAGs were stable in phosphate-buffered saline but underwent enzymatic degradation in the presence of proteolytic enzymes, such as collagenase and elastase. When injected subcutaneously into rats, the aqueous dl-PAG solutions formed in situ gels, with gel duration controllable from 7 to 15 days by adjusting the polymer composition. dl-PAGs elicited only mild inflammatory tissue responses, indicating good tissue compatibility. As an injectable, poly(ethylene glycol) (PEG)-free thermogelling system, dl-PAGs show a strong potential for diverse biomedical applications.