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 (P<0.01). The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.

叶酸受体 (FR) 过表达发生在多种癌症中，包括胰腺癌。此外，K-Ras 突变胰腺癌中存在增强的巨胞饮作用。此外，密集结缔组织增生的发生导致胰腺癌中的低氧微环境。在这项研究中，设计并制备了一种新型的 FR 导向、巨胞饮作用增强和高细胞毒性的生物共轭叶酸 (F)-人血清白蛋白 (HSA)-利达霉素 (LDP) 的载脂蛋白 (LDP)-活性烯二炔 (AE)。F-HSA-LDP-AE 由四个部分组成：F、HSA、LDP 和 AE。F-HSA-LDP 与 FR 和胰腺癌细胞具有高结合效率。它在野生型细胞中的摄取比在 K-Ras 突变型细胞中更广泛。通过活体光学成像，F-HSA-LDP 在携带胰腺癌异种移植物的小鼠中表现出显着的肿瘤特异性生物分布，在 360 小时内显示出清晰持久的肿瘤定位。在 MTT 测定中，F-HSA-LDP-AE 在三种类型的胰腺癌细胞系中表现出有效的细胞毒性。它还诱导细胞凋亡并导致 G2/M 细胞周期停滞。F-HSA-LDP-AE 显着抑制无胸腺小鼠中 AsPc-1 胰腺癌异种移植物的肿瘤生长。在 0.5 和 1 mg/kg 的良好耐受剂量（iv，两次）下，抑制率分别为 91.2% 和 94.8%（F-HSA-LDP-AE 显着抑制无胸腺小鼠中 AsPc-1 胰腺癌异种移植物的肿瘤生长。在 0.5 和 1 mg/kg 的良好耐受剂量（iv，两次）下，抑制率分别为 91.2% 和 94.8%（F-HSA-LDP-AE 显着抑制无胸腺小鼠中 AsPc-1 胰腺癌异种移植物的肿瘤生长。在 0.5 和 1 mg/kg 的良好耐受剂量（iv，两次）下，抑制率分别为 91.2% 和 94.8%（P <0.01）。本研究结果表明，F-HSA-LDP 多功能生物偶联物可能对治疗 K-Ras 突变型胰腺癌有效。