Conjugating 10,11-Dimethoxy-camptothecin with an Integrin αvβ3-Targeting Peptide through a Triazine Linker for Targeted Tumor Treatment in Lung and Pancreatic Carcinoma

Peptide-drug conjugates (PDCs) targeting integrin αvβ3 represent a promising strategy for tumor-targeted therapies. We designed and synthesized a series of integrin αvβ3-selective PDCs (<b>PDC-1</b> to <b>PDC-5</b>) using a 1,3,5-triazine-based linker to conjugate the camptothecin derivative with the c(RGDfC) peptide. Among these, <b>PDC-2</b> exhibited high stability in plasma, selective internalization via integrin αvβ3, efficient cell binding, and potent cytotoxicity. Additionally, it induced apoptosis of A549 and AsPC-1 cells and inhibited their adhesion, migration, and invasion in a concentration-dependent manner. Mechanistically, <b>PDC-2</b> dually inhibits Survivin protein expression and the PI3K/AKT/mTOR signaling pathway. In A549 and AsPC-1 xenograft models, <b>PDC-2</b> demonstrated superior tumor growth inhibition, reduced systemic toxicity, and enhanced tumor specificity compared to FL118. Pharmacokinetically, it enabled a sustained release of FL118, extending its half-life by 3.4-fold and promoting targeted tumor accumulation, positioning it as a promising therapeutic for lung and pancreatic cancers.