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

The development of covalent drugs has renewed interest
in strategies
that achieve high selectivity while minimizing off-target reactivity.
Herein, we report IRS1, a peptide-based prodrug comprising an integrin-targeting
RGD motif, an ROS-responsive thiomorpholine unit, and a chlorambucil-derived
covalent warhead for efficient cancer inhibition. Under physiological
conditions, IRS1 self-assembles into nanoparticles and preferentially
accumulates in uveal melanoma (UM) cells via integrin-mediated targeting.
Within the tumor microenvironment, ROS-triggered oxidation of thiomorpholine
induces a hydrophobic-to-hydrophilic transition, driving the nanoparticle-to-nanofibril
transformation and exposing the chlorambucil moiety. This enables
covalent conjugation with the thiol groups of DR4/DR5 on the cell
membrane. IRS1 effectively disrupts membrane integrity, activates
extrinsic apoptosis, and induces cancer cell death in vitro. In UM xenograft models, IRS1 shows potent antitumor efficacy with
reduced systemic toxicity, highlighting a peptide-reconfiguration
strategy for tumor-selective covalent therapeutics.