Design, Synthesis and Biological Evaluation of Novel SN38 Based Albumin-Binding Peptide-Drug Conjugates in Pancreatic Ductal Adenocarcinoma.

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense extracellular matrix (ECM) with overexpression of extra domain B fibronectin (EDB-FN). Methods: Herein, we investigated novel albumin-binding peptide-drug conjugates, Mc-ZD2-SN38 and SSC-ZD2-SN38, which integrate the prolonged circulation properties of albumin with the active targeting capability of the ZD2 peptide toward EDB-FN. Covalent and noncovalent albumin-binding strategies extended the half-life by approximately 100-fold and 15-fold, respectively, compared with the non-albumin-binding peptide-drug conjugate (PDC) (ZD2-SN38). Results: Notably, ZD2-mediated targeting markedly reduced payload accumulation in major organs, resulting in an improved safety profile. In a BxPC-3 xenograft model, Mc-ZD2-SN38 and SSC-ZD2-SN38 demonstrated potent and sustained antitumor efficacy. Conclusions: These findings establish a long circulation and active targeting drug delivery strategy, providing an ideal framework for the development of PDCs with enhanced therapeutic indices.