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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Antitumor effect of nuclear factor-κB decoy transfer by mannose-modified bubble lipoplex into macrophages in mouse
Yusuke Kono1, Shigeru Kawakami, Yuriko Higuchi
1Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
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.
Insights
Targeted delivery of a nuclear factor-κB (NF-κB) decoy into tumor-associated macrophages (TAMs) using ultrasound-responsive liposomes effectively reduced malignant ascites (MA) in mice. This novel approach reprogrammed TAMs, suppressed tumor growth, and improved survival rates.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Malignant ascites (MA) significantly reduces patient quality of life due to symptoms like dyspnea and nausea.
- Tumor-associated macrophages (TAMs) with a pro-tumor M2 phenotype are key drivers of MA progression.
- Nuclear factor-κB (NF-κB) is a critical regulator of macrophage polarization, making it a potential therapeutic target.
Purpose of the Study:
- To develop a targeted delivery system for transferring an NF-κB decoy into TAMs.
- To investigate the efficacy of this method in reprogramming TAMs and treating malignant ascites in a preclinical model.
- To evaluate the impact on tumor progression and survival rates.
Main Methods:
- Development of ultrasound (US)-responsive, mannose-modified liposome/NF-κB decoy complexes (Man-PEG bubble lipoplexes).
- Targeted delivery of the NF-κB decoy into TAMs in a mouse model of peritoneal dissemination of Ehrlich ascites carcinoma using US exposure.
- Analysis of cytokine expression (IL-10, IL-12, TNF-α, IL-6), vascular endothelial growth factor (VEGF) levels, peritoneal angiogenesis, ascitic volume, tumor cell count, and mouse survival rates.
Main Results:
- Efficient transfer of the NF-κB decoy into TAMs was achieved using Man-PEG bubble lipoplexes and US.
- Transfection significantly decreased M2-associated IL-10 and increased M1-associated cytokines (IL-12, TNF-α, IL-6) in TAMs.
- Suppressed VEGF expression, reduced peritoneal angiogenesis, decreased ascitic volume, lowered tumor cell burden, and prolonged survival in treated mice.
Conclusions:
- Man-PEG bubble lipoplexes combined with US exposure provide an effective method for targeted NF-κB decoy delivery into TAMs.
- This strategy shows promise as a novel therapeutic approach for treating malignant ascites by reprogramming TAMs.
- The findings suggest a potential new avenue for improving outcomes in patients with malignant ascites.
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