Rational Design of Short Peptide-Based Hydrogels with MMP-2 Responsiveness for Controlled Anticancer Peptide Delivery

Molecular self-assembly makes it feasible to harness the structures and properties of advanced materials via initial molecular design. To develop short peptide-based hydrogels with stimuli responsiveness, we designed here short amphiphilic peptides by engineering protease cleavage site motifs into self-assembling peptide sequences. We demonstrated that the designed Ac-I₃SLKG-NH₂ and Ac-I₃SLGK-NH₂ self-assembled into fibrillar hydrogels and that the Ac-I₃SLKG-NH₂ hydrogel showed degradation in response to MMP-2 but the Ac-I₃SLGK-NH₂ hydrogel did not. The cleavage of Ac-I₃SLKG-NH₂ into Ac-I₃S and LKG-NH₂ was found to be mechanistically responsible for the enzymatic degradation. Finally, when an anticancer peptide G(IIKK)₃I-NH₂ (G3) was entrapped into Ac-I₃SLKG-NH₂ hydrogels, its release was revealed to occur in a "cell-demanded" way in the presence of HeLa cells that overexpress MMP-2, therefore leading to a marked inhibitory effect on their growth on the gels.