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

Abstract

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-ISLKG-NH and Ac-ISLGK-NH self-assembled into fibrillar hydrogels and that the Ac-ISLKG-NH hydrogel showed degradation in response to MMP-2 but the Ac-ISLGK-NH hydrogel did not. The cleavage of Ac-ISLKG-NH into Ac-IS and LKG-NH was found to be mechanistically responsible for the enzymatic degradation. Finally, when an anticancer peptide G(IIKK)I-NH (G3) was entrapped into Ac-ISLKG-NH 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.

Tuning the matrix metalloproteinase-1 degradability of peptide amphiphile nanofibers through supramolecular engineering

“…sequence modification of MMP substrates). 23,24 Recently, Ulijn and coworkers reported a peptide design approach to tune the degradation kinetics of supramolecular peptide nanostructures by MMP-9. 25 Peptides were designed with systematically modified amino acid sequences to control overall charge and order in the MMP-9 substrate region.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…The SPH could retain in the tumor for a prolonged period, and release G3 in a "cell-demanded" way due to the MMP-2 responsiveness of SPH. [122] In contrast to this study, Mo and colleagues used enzyme WQ9-2 to initiate SPH formation. [170] The enzyme-catalyzed a condensation reaction between two precursors Fmoc-F and FF-Dopa to form hydrogelator Fmoc-FFF-Dopa, which entrapped hirudin (an antiangiogenic protein), and TRAIL (an apoptosis-inducing cytokine) in the hydrogel.…”

“…[20] Xu and colleagues designed an MMP-2 responsive peptide hydrogelator (Ac-I 3 SLKG-NH 2 ) by incorporating MMP-2 substrate sequence into molecule design. [122] Upon exposure to MMP-2 overexpressing HeLa cells, the selfassembled nanofibers and the entangled hydrogel network can be significantly disrupted. A similar design was reported by Cui and colleagues, and the hydrogel filaments could rapidly break into fragments prior to reassembling into spherical micelles upon MMP-2 exposure.…”

Supramolecular Hydrogels for Protein Delivery in Tissue Engineering

“…Enzymatic cleavage of certain peptide sequence was also used as a strategy to achieve hydrogel degradation [83]. Ac-I 3 SLKG-NH 2 is an amphiphilic peptide able to self-assemble into fibrillar hydrogels [77]. This peptide hydrogel was able to be degraded into Ac-I 3 S-OH and H-LKG-NH 2 in response to MMP-2.…”