The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma.
The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma.
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作者：
Guerra AD;Yeung OWH;Qi X;Kao WJ;Man K
背景和目的：最近，我们报道了直接注射M1巨噬细胞可显著引起体内肿瘤消退。尽管结果令人鼓舞，但转化这种方法的主要限制是诱导急性炎症反应。为了改进该策略，用于细胞呈递和支持的生物相容性支架对于控制细胞命运至关重要。在这里，我们的目的是阐明的抗肿瘤作用的聚（乙二醇）二丙烯酸酯（PEGdA）和硫醇化明胶聚（乙二醇）（Gel-PEG-Cys）交联的水凝胶封装与M1巨噬细胞在体外和体内疾病模型。方法：以0.5%（w/v）Agrugcure 2959光引发剂、10%（w/v）PEGdA和10%（w/v）Gel-PEG-Cys制备水凝胶。将单核细胞THP-1细胞加载到水凝胶中，并用脂多糖（LPS）和干扰素γ（IFN-γ）分化成M1巨噬细胞。然后将M1水凝胶与肝癌细胞系Hep 3B和MHCC 97 L共培养，以研究体外抗肿瘤能力和相关分子谱。通过建立裸鼠异位肝癌背窗模型和皮下肿瘤模型，验证M1水凝胶的体内应用。结果：与对照相比，M1水凝胶在体外显著降低HCC细胞的存活率（MHCC 97 L：-46%; Hep 3B：-56.9%; P<0.05）。作为对HCC细胞的响应，水凝胶包埋的M1巨噬细胞上调亚硝酸盐和肿瘤坏死因子α（TNF-α）激活caspase-3诱导肿瘤细胞凋亡。在填充有M1水凝胶的DWC中观察到肿瘤坏死增加。此外，与对照组相比，用M1水凝胶处理的小鼠显示皮下HCC肿瘤的信号强度显著降低2.4倍（P=0.036）。结论：M1水凝胶在体内可诱导肝癌细胞凋亡和肿瘤消退。基于支架的癌症免疫治疗的持续发展可能提供针对HCC的替代和创新策略。
Background and Aims: Recently we reported that direct injection of M1 macrophages significantly caused tumor regression in vivo. Despite the promising result, a major limitation in translating this approach is the induction of acute inflammatory response. To improve the strategy, a biocompatible scaffold for cell presentation and support is essential to control cell fate. Here, we aimed to elucidate the anti-tumor effects of a poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) cross-linked hydrogels capsulated with M1 macrophages in both in vitro and in vivo disease models. Methods: Hydrogels were made at 0.5% (w/v) Iragcure 2959 photoinitiator, 10% (w/v) PEGdA, and 10% (w/v) Gel-PEG-Cys. Monocytic THP-1 cells were loaded into hydrogels and differentiated into M1 macrophages with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). The M1 hydrogels were then cocultivated with HCC cell-lines Hep3B and MHCC97L to investigate the anti-tumor capacities and the associated molecular profiles in vitro. A nude mice ectopic liver cancer model with dorsal window chamber (DWC) and a subcutaneous tumor model were both performed to validate the in vivo application of M1 hydrogels. Results: M1 hydrogels significantly decreased the viability of HCC cells (MHCC97L: -46%; Hep3B: -56.9%; P<0.05) compared to the control in vitro. In response to HCC cells, the hydrogel embedded M1 macrophages up-regulated nitrite and tumor necrosis factor alpha (TNF-α) activating caspase-3 induced apoptosis in the tumor cells. Increased tumor necrosis was observed in DWC filled with M1 hydrogels. In addition, mice treated with M1 hydrogels exhibited a significant 2.4-fold decrease in signal intensity of subcutaneous HCC tumor compared to control (P=0.036). Conclusion: M1 hydrogels induced apoptosis in HCC cells and tumor regression in vivo. Continuous development of the scaffold-based cancer immunotherapy may provide an alternative and innovative strategy against HCC.
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