Enzyme-responsive oncolytic polypeptide for tumor therapy

Abstract

Host defense peptide-mimicking cationic oncolytic polymers have attracted increasing attention for cancer treatment in recent years. However, polymers with large amounts of positive charge may cause rapid clearance and severe off-target toxicity. To facilitate in vivo application, an alkaline phosphatase (ALP)-responsive oncolytic polypeptide precursor (C₁₂-PLL/PA) has been reported in this work. C₁₂-PLL/PA could be hydrolyzed into the active form of the oncolytic polypeptide (C₁₂-PLL) by the extracellular alkaline phosphatase within solid tumors, thereby resulting in the conversion of the negative charge to positive charge and restoring its membrane-lytic activity. Detailed mechanistic studies showed that C₁₂-PLL/PA could effectively destroy cancer cell membranes and subsequently result in rapid necrosis of cancer cells. More importantly, C₁₂-PLL/PA significantly inhibited the tumor growth in the 4T1 orthotopic breast tumor model with negligible side effects. In summary, these findings demonstrated that the shielding of the amino groups with phosphate groups represents a secure and effective strategy to develop cationic oncolytic polypeptide, which represents a valuable reference for the design of enzyme-activated oncolytic polymers.

Statement of significance

Recently, there has been a growing interest in fabricating host defense peptide-mimicking cationic oncolytic polymers for cancer therapy. However, there remain concerns about the tumor selectivity and off-target toxicity of these cationic polymers. In this study, an alkaline phosphatase-responsive oncolytic polypeptide precursor (C₁₂-PLL/PA) has been developed to selectively target cancer cells while sparing normal cells. Mechanistic investigations demonstrated that C₁₂-PLL/PA effectively disrupted cancer cell membranes, leading to rapid necrosis. Both in vitro and in vivo experiments showed promising anticancer activity and reliable safety of C₁₂-PLL/PA. The findings suggest that this synthetic enzyme-responsive polypeptide holds potential as a tumor-specific oncolytic polymer, paving the way for future applications in cancer therapy.