Antitumor effect of nuclear factor-κB decoy transfer by mannose-modified bubble lipoplex into macrophages in mouse malignant ascites.
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.
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Yusuke
Y
Kono
Shigeru
S
Kawakami
Yuriko
Y
Higuchi
Kazuo
K
Maruyama
Fumiyoshi
F
Yamashita
Mitsuru
M
Hashida
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D037181:Lectins, C-Type / Q000378:metabolism; D008081:Liposomes; D008264:Macrophages / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014465:Ultrasonics
D037181:Lectins, C-Type; D008081:Liposomes; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D011956:Receptors, Cell Surface
Drug targeting; Ehrlich ascites carcinoma; nuclear factor-κB decoy; sonoporation; tumor-associated macrophages