Tuning of Peptide Cytotoxicity with Cell Penetrating Motif Activatable by Matrix Metalloproteinase-2

Abstract

Although diverse cell penetrating motifs not only from naturally occurring proteins but also from synthetic peptides have been discovered and developed, the selectivity of cargo delivery connected to these motifs into the desired target cells is generally low. Here, we demonstrate the selective cytotoxicity tuning of an anticancer KLA peptide with a cell penetrating motif activatable by matrix metalloproteinase-2 (MMP2). The anionic masking sequence introduced at the end of the KLA peptide through an MMP2-cleavable linker is selectively cleaved by MMP2 and the cationic cell penetrating motif is activated. Upon treatment of the peptide to H1299 cells (high MMP2 level), it is selectively internalized into the cells by MMP2, which consequently induces membrane disruption and cell death. In contrast, the peptide shows negligible cytotoxicity toward A549 cancer cells with low MMP2 levels. Furthermore, the selective therapeutic efficacy of the peptide induced by MMP2 is also corroborated using in vivo study.

Interaction of KLAKLAK-NH2 and Analogs with Biomimetic Membrane Models

“…The amide I band indicates a strong hydrogen bonding in the α-helical peptide, which is sensitive to membrane fluidity, i.e., to the lipid chain mobility discussed above [ 52 ]. Several distinct structures of the peptide–lipid binding have been observed, suggesting that the peptides undergo functionally relevant changes in their conformation and membrane alignment [ 53 , 61 , 62 , 63 , 64 ]. More generally, surface S-states and transmembrane T-states have been reported, respectively, with a parallel and oblique direction of the helix axis toward the normal to the bilayer surface.…”

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

“…These hurdles were initially ameliorated by topical use of Tat conjugated to a therapeutic [ 25 , 26 , 27 ], or in a compartment-restricted manner such as intra-articular [ 28 , 29 , 30 ] or intra-ocular administration [ 31 , 32 , 33 ]. Another use of non-specific CPP was the use of activatable peptides given a certain tissue milieu in oncological applications [ 34 , 35 , 36 , 37 , 38 ] or enzyme-activatable cell penetrating peptides [ 39 , 40 , 41 ]. Phage display to identify specific tumor- or tissue-targeting CPPs was yet another strategy in attempts to harness CPP’s transduction abilities for clinical application [ 9 , 42 , 43 , 44 ].…”

Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies

“…MMP2 and MMP9 play an important role in tumor invasion and metastasis by degrading fibrillar collagen after cleavage by collagenase [ 142 ]. The short peptide sequence PLGLAG is an MMP2/MMP9-sensitive linker fragment that breaks in tumor tissue [ 144 ].…”