Tumor-Targeted Membrane Lysing Mediated by Tumor-Associated Protease

We previously developed a polymer-lytic peptide conjugate that could effectively lyse cell membrane. The lysing activity largely depends on the electrostatic interaction between cationic peptides and polar head groups of phospholipids. In this project, we fused a poly-γ-glutamate sequence to the cationic lytic peptide, with an attempt to suppress the lysing activity by neutralizing the important positive charge. Poly-γ-glutamate is the natural substrate of PSMA, a membrane exopeptidase overexpressed by prostate cancer cells and neovasculature of many solid tumors. As a result, the suppressing segment can be removed and the lytic peptide can regain activity upon enzymatic digestion. The conjugate will be subject to in vitro test to examine the specificity. We expect the conjugate could be activated on PSMA positive cell membrane and exert specific cytotoxicity.