Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer.

Folate receptor (FR) overexpression occurs in a variety of cancers, including pancreatic cancer. In addition, enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer. Furthermore, the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer. In this study, a novel FR-directed, macropinocytosis-enhanced, and highly cytotoxic bioconjugate folate (F)-human serum albumin (HSA)-apoprotein of lidamycin (LDP)-active enediyne (AE) derived from lidamycin was designed and prepared. F-HSA-LDP-AE consisted of four moieties: F, HSA, LDP, and AE. F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells. Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells. By in vivo optical imaging, F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice, showing clear and lasting tumor localization for 360 h. In the MTT assay, F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines. It also induced apoptosis and caused G2/M cell cycle arrest. F-HSA-LDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice. At well-tolerated doses of 0.5 and 1 mg/kg, (i.v., twice), the inhibition rates were 91.2% and 94.8%, respectively (