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
(PDC-1 to PDC-5) using a 1,3,5-triazine-based
linker to conjugate the camptothecin derivative with the c(RGDfC)
peptide. Among these, PDC-2 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, PDC-2 dually inhibits Survivin protein expression and the
PI3K/AKT/mTOR signaling pathway. In A549 and AsPC-1 xenograft models, PDC-2 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.