A Cathepsin B-Sensitive Gemcitabine Prodrug for Enhanced Pancreatic Cancer Therapy.

Although gemcitabine (GEM) is a first-line chemotherapeutic drug in treating pancreatic cancer, the therapeutic efficacy of GEM is relatively poor. One main reason is that GEM can be easily deaminated to inactive 2',2'-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA). In order to improve the antitumor activity of GEM, a polypeptide modified GEM prodrug RGDGFLG-GEM (GEM-RGD) is designed. Because the amino group of GEM is protected by RGDGFLG peptide sequence, the in vivo stability of GEM-RGD can be significantly improved since the deamination of GEM can be avoided. GEM-RGD shows enhanced uptake by pancreatic cancer cells due to the active targeting RGD group. The cathepsin B-sensitive GFLG sequence endows GEM-RGD with specific release of GEM in pancreatic cancer cells. Compared to free GEM and non-targeted GEM prodrug RDGGFLG-GEM (GEM-RDG), GEM-RGD exhibits enhanced antitumor activity and reduced systemic toxicity. These results implies that GEM-RGD is a promising candidate in treating pancreatic cancer.