Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

Area of Science:

• Biomedical Engineering
• Cancer Therapeutics
• Molecular Self-Assembly

Background:

• Alkaline phosphatases (ALP) promote tumor immunosuppression and are considered
• Purpose_of_the_Study

Purpose of the Study:

• To develop a novel therapeutic strategy for solid tumors overexpressing alkaline phosphatases (ALP).
• To leverage enzyme-instructed molecular self-assembly for targeted cancer cell death.
• To create peptide-based therapeutics that avoid direct inhibition of ALP.

Main Methods:

• Design of a precursor molecule comprising amphiphilic self-assembling peptides linked to a tyrosine phosphate moiety.
• Enzyme-instructed assembly triggered by ALP cleavage of the phosphate group on osteosarcoma cells.
• In vivo evaluation in an orthotopic osteosarcoma mouse model.

Main Results:

• Selective cleavage of the precursor by ALP on and within osteosarcoma cells (Saos-2).
• Formation of peptide assemblies specifically at the tumor site, inducing cancer cell death.
• Significant inhibition of tumor growth and improved survival rates in metastatic tumor-bearing mice without systemic toxicity.

Conclusions:

• Enzyme-instructed peptide self-assembly offers a promising new approach for targeted cancer therapy.
• This method effectively generates therapeutic peptide fibrils in situ, bypassing the challenge of targeting "undruggable" enzymes like ALP.
• The developed strategy demonstrates potential for treating solid tumors, including osteosarcoma, with improved efficacy and safety.