Pancreatic cancer (PC) is one of the most dangerous
cancers with less than 5% survival rate in 5 years. This study was to evaluate the antitumor activities of dFv-LDP-AE and dFv-R-LDP-AE, two energized fusion
protein targeting
gelatinases, on
pancreatic cancer. The fusion
protein dFv-LDP-AE consists of two tandem anti-gelatianses scFv and an enediyne
antibiotic lidamycin (LDM) for receptor binding and cell killing. To improve the penetration capability, the fusion
protein dFv-LDP-AE was integrated with an
arginine-rich
cell penetrating peptide (Arg)9 and then generated the fusion
protein dFv-R-LDP-AE. The current study demonstrated that dFv-LDP and dFv-R-LDP had high affinity with the
antigen gelatinases and PC cells, the integration of (Arg)9 could increase the penetration rate of fusion
protein in SW-1990 and PANC-1 cells. After enediyne-energized with chromophore of
lidamycin, the energized fusion
protein dFv-LDP-AE and dFv-R-LDP-AE showed potent cytotoxicity to PC cells and could induced the robust cell apoptosis and
necrosis in vitro. Western blot showed that dFv-R-LDP-AE could increase PARP cleavage, and inhibited the expression of
VEGF,
Cyclin D1, Cox-2 and Bcl-2 in SW-1990 and PANC-1 cells. In vivo, at a tolerated dosage, dFv-LDP, dFv-LDP-AE and dFv-R-LDP-AE inhibited
tumor growth by 20.42%, 56.31% (P < 0.01, compared to that of control) and 74.2% (P < 0.05, compared to that of dFv-LDP-AE) in
pancreatic cancer SW-1990 xenografted mice, respectively. Moreover, the results of in vivo optical imaging showed that fusion
protein dFv-R-LDP displayed prominent accumulation in the
tumor in SW-1990 xenografted mice and Capan-2 orthotopic transplanted mice. These results showed that dFv-R-LDP-AE possessed potent antitumor efficacy on PC, which indicating it could be a promising candidate for targeting
therapy of PC.