Zhang Ying, Lei Hengyu, Wang Pengchong, Zhou Qinyuan, Yu Jie, Leng Xue, Ma Ruirui, Wang Danyang, Dong Kai, Xing Jianfeng, Dong Yalin
Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Department of Pharmaceutics, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Biomater Res. 2023 Jul 28;27(1):75. doi: 10.1186/s40824-023-00412-8.
Reactive oxygen species (ROS) overproduction and excessive hypoxia play pivotal roles in the initiation and progression of ulcerative colitis (UC). Synergistic ROS scavenging and generating O could be a promising strategy for UC treatment.
Ceria nanozymes (PEG-CNPs) are fabricated using a modified reverse micelle method. We investigate hypoxia attenuating and ROS scavenging of PEG-CNPs in intestinal epithelial cells and RAW 264.7 macrophages and their effects on pro-inflammatory macrophages activation. Subsequently, we investigate the biodistribution, pharmacokinetic properties and long-term toxicity of PEG-CNPs in mice. PEG-CNPs are administered intravenously to mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis to test their colonic tissue targeting and assess their anti-inflammatory activity and mucosal healing properties in UC.
PEG-CNPs exhibit multi-enzymatic activity that can scavenge ROS and generate O, promote intestinal epithelial cell healing and inhibit pro-inflammatory macrophage activation, and have good biocompatibility. After intravenous administration of PEG-CNPs to colitis mice, they can enrich at the site of colonic inflammation, and reduce hypoxia-induced factor-1α expression in intestinal epithelial cells by scavenging ROS to generate O, thus further promoting disrupted intestinal mucosal barrier restoration. Meanwhile, PEG-CNPs can effectively scavenge ROS in impaired colon tissues and relieve colonic macrophage hypoxia to suppress the pro-inflammatory macrophages activation, thereby preventing UC occurrence and development.
This study has provided a paradigm to utilize metallic nanozymes, and suggests that further materials engineering investigations could yield a facile method based on the pathological characteristics of UC for clinically managing UC.
活性氧（ROS）的过度产生和过度缺氧在溃疡性结肠炎（UC）的发生和发展中起关键作用。协同清除ROS并产生氧气可能是治疗UC的一种有前景的策略。
采用改进的反相微乳液法制备二氧化铈纳米酶（PEG-CNPs）。我们研究了PEG-CNPs在肠上皮细胞和RAW 264.7巨噬细胞中减轻缺氧和清除ROS的作用及其对促炎性巨噬细胞活化的影响。随后，我们研究了PEG-CNPs在小鼠体内的生物分布、药代动力学特性和长期毒性。将PEG-CNPs静脉注射到2,4,6-三硝基苯磺酸诱导的结肠炎小鼠体内，以测试其结肠组织靶向性，并评估其在UC中的抗炎活性和黏膜愈合特性。
PEG-CNPs具有多种酶活性，可清除ROS并产生氧气，促进肠上皮细胞愈合，抑制促炎性巨噬细胞活化，且具有良好的生物相容性。将PEG-CNPs静脉注射到结肠炎小鼠体内后，它们可在结肠炎症部位富集，并通过清除ROS产生氧气来降低肠上皮细胞中缺氧诱导因子-1α的表达，从而进一步促进受损肠黏膜屏障的恢复。同时，PEG-CNPs可有效清除受损结肠组织中的ROS，缓解结肠巨噬细胞缺氧，抑制促炎性巨噬细胞活化，从而预防UC的发生和发展。
本研究提供了一种利用金属纳米酶的范例，并表明进一步的材料工程研究可能会基于UC的病理特征产生一种简便的方法用于临床管理UC。
