In Situ Synthesis of an Anticancer Peptide Amphiphile Using Tyrosine Kinase Overexpressed in Cancer Cells

Area of Science:

• Biochemistry
• Biotechnology
• Cancer Therapy

Background:

• Molecular self-assemblies offer a promising strategy for cancer therapy.
• Current methods often lack cell selectivity due to non-specific hydrolysis.
• Targeting intracellular enzymes presents an opportunity for enhanced drug specificity.

Purpose of the Study:

• To develop a cell-selective molecular self-assembly triggered by cancer-specific enzymes.
• To investigate the potential of in situ synthesized self-assemblies for cancer treatment.

Main Methods:

• Designed a tyrosine-containing peptide amphiphile (C16-E4Y).
• Utilized tyrosine kinase, overexpressed in cancer cells, for in situ phosphorylation to C16-E4pY.
• Investigated self-assembly, cytotoxicity, and mechanism of cell death (endoplasmic reticulum stress, apoptosis).
• Evaluated antitumor activity in animal models.

Main Results:

• C16-E4Y was selectively phosphorylated to C16-E4pY by cancer cell tyrosine kinase.
• Phosphorylated C16-E4pY self-assembled into nanofibers within cancer cells.
• C16-E4Y demonstrated selective cytotoxicity against tyrosine kinase-overexpressing cancer cells.
• Self-assembled C16-E4pY induced endoplasmic reticulum stress, leading to apoptotic cell death and exhibiting antitumor effects in vivo.

Conclusions:

• Enzymes overexpressed in cancer cells can be leveraged for intracellular synthesis of self-assembling drugs.
• This approach enables cell-selective drug delivery and enhanced therapeutic efficacy.
• The developed self-assembling peptide amphiphile (C16-E4Y) shows significant potential as a targeted cancer therapeutic.