Antitumor effect of nuclear factor‐κB decoy transfer by mannose‐modified bubble lipoplex into macrophages in mouse malignant ascites. Issue 8 (31st July 2014) - Kono, Yusuke
Abstract Patients with malignant ascites (MAs) display several symptoms, such as dyspnea, nausea, pain, and abdominal tenderness, resulting in a significant reduction in their quality of life. Tumor‐associated macrophages (TAMs) play a crucial role in MA progression. Because TAMs have a tumor‐promoting M2 phenotype, conversion of the M2 phenotypic function of TAMs would be promising for MA treatment. Nuclear factor‐κB (NF‐κB) is a master regulator of macrophage polarization. Here, we developed targeted transfer of a NF‐κB decoy into TAMs by ultrasound (US)‐responsive, mannose‐modified liposome/NF‐κB decoy complexes (Man‐PEG bubble lipoplexes) in a mouse peritoneal dissemination model of Ehrlich ascites carcinoma. In addition, we investigated the effects of NF‐κB decoy transfection into TAMs on MA progression and mouse survival rates. Intraperitoneal injection of Man‐PEG bubble lipoplexes and US exposure transferred the NF‐κB decoy into TAMs effectively. When the NF‐κB decoy was delivered into TAMs by this method in the mouse peritoneal dissemination model, mRNA expression of the Th2 cytokine interleukin (IL)‐10 in TAMs was decreased significantly. In contrast, mRNA levels of Th1 cytokines (IL‐12, tumor necrosis factor‐α, and IL‐6) were increased significantly. Moreover, the expression level of vascular endothelial growth factor in ascites was suppressed significantly, and peritoneal angiogenesis showed a reduction. Furthermore, NF‐κB decoy transfer into TAMs significantly decreased the ascitic volume and number of Ehrlich ascites carcinoma cells in ascites, and prolonged mouse survival. In conclusion, we transferred a NF‐κB decoy efficiently by Man‐PEG bubble lipoplexes with US exposure into TAMs, which may be a novel approach for MA treatment.