Enzyme-responsive oncolytic polypeptide for tumor therapy.

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Cancer Therapeutics

Background:

• Host defense peptide-mimicking cationic oncolytic polymers are promising for cancer treatment.
• Existing cationic polymers face challenges with rapid clearance and off-target toxicity.
• Need for tumor-selective and safer oncolytic polymer strategies is critical.

Purpose of the Study:

• To develop an enzyme-responsive oncolytic polypeptide precursor for enhanced in vivo cancer therapy.
• To design a polymer that selectively activates within the tumor microenvironment.
• To mitigate the toxicity associated with highly cationic polymers.

Main Methods:

• Synthesis of an alkaline phosphatase (ALP)-responsive polypeptide precursor (C12-PLL/PA).
• Hydrolysis of C12-PLL/PA by extracellular ALP in tumors to yield active C12-PLL.
• Evaluation of membrane-lytic activity, cancer cell destruction, and in vivo tumor inhibition in a 4T1 breast tumor model.

Main Results:

• C12-PLL/PA selectively converts to the active, membrane-lytic C12-PLL form via tumor-specific ALP activity.
• The activated polypeptide effectively disrupts cancer cell membranes, inducing rapid necrosis.
• Significant inhibition of tumor growth was observed in the 4T1 orthotopic breast tumor model with negligible side effects.

Conclusions:

• Shielding cationic groups with phosphate moieties creates a secure and effective oncolytic polypeptide precursor.
• Enzyme-responsive activation offers a promising strategy for tumor-specific delivery and reduced systemic toxicity.
• This approach provides a valuable reference for designing next-generation enzyme-activated oncolytic polymers for cancer therapy.