ROS-Activated Peptide-Based Prodrug for Chemoselective Covalent Targeting in Cancer Cells

Area of Science:

• Drug Delivery
• Nanomedicine
• Cancer Therapeutics

Background:

• Covalent drugs offer high selectivity but face challenges with off-target reactivity.
• Developing targeted therapies is crucial for minimizing systemic toxicity in cancer treatment.

Purpose of the Study:

• To design and evaluate IRS1, a novel peptide-based prodrug for targeted cancer inhibition.
• To investigate the self-assembly, tumor targeting, and drug release mechanisms of IRS1.

Main Methods:

• IRS1 synthesis incorporating an RGD motif, ROS-responsive unit, and chlorambucil warhead.
• Characterization of IRS1 self-assembly into nanoparticles and transformation into nanofibrils.
• In vitro evaluation of cancer cell death induction and in vivo assessment in uveal melanoma xenograft models.

Main Results:

• IRS1 self-assembles into nanoparticles, targeting uveal melanoma cells via integrin mediation.
• ROS-triggered transformation of IRS1 nanoparticles to nanofibrils exposes the covalent warhead.
• IRS1 induces cancer cell death by disrupting membrane integrity and activating apoptosis, showing potent antitumor efficacy in vivo with reduced toxicity.

Conclusions:

• IRS1 represents a promising peptide-reconfiguration strategy for tumor-selective covalent therapeutics.
• The developed prodrug demonstrates efficient cancer inhibition through targeted drug delivery and controlled release.