LRG1-TargetedCamptothecin Nanomicelles with SimultaneousDelivery of Olaparib for Enhanced Colorectal Cancer Chemotherapy

Camptothecin (CPT), an effective topoisomerase I inhibitor used in colorectal cancer chemotherapy, often faces limitations due to severe toxicities. Addressing this, we developed OCE^NM, a nanomedicine featuring the CPT–ET conjugatecomprising a cathepsin B-sensitive linker and CPT linked to the ET peptide targeting leucine-rich alpha-2-glycoprotein 1 (LRG1) and encapsulating Olaparib, a potent poly ADP-ribose polymerase (PARP) inhibitor. OCE^NM aims for precise CPT delivery to colorectal cancer sites overexpressing LRG1, while Olaparib disrupts compromised DNA repair pathways, enhancing DNA damage and promoting increased tumor cell apoptosis. Our results show OCE^NM accumulates preferentially in colorectal cancer models through LRG1 targeting and triggers synergistic tumor cell apoptosis through the dual action of enhanced DNA damage and inhibited repair mechanisms. This study not only highlights the potential of LRG1 as a strategic target for nanomedicine delivery but also underscores the therapeutic promise of combining CPT with Olaparib for colorectal cancer treatment.