The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China.
Department of Chemical and Biological Engineering, University of Colorado Boulder 3415 Colorado Ave, Boulder, CO 80303, USA.
Acta Biomater. 2024 Sep 15;186:354-368. doi: 10.1016/j.actbio.2024.07.054. Epub 2024 Aug 6.
Therapeutic options for addressing inflammatory bowel disease (IBD) include the administration of an enema to reduce intestinal inflammation and alleviate associated symptoms. However, uncontrollable retention of enemas in the intestinal tract has posed a long-term challenge for improving their therapeutic efficacy and safety. Herein we have developed a protease-labile hydrogel system as an on-demand enema vehicle with tunable degradation and drug release rates in response to varying matrix metalloproteinase-9 (MMP-9) expression. The system, composed of three tailored hydrogel networks, is crosslinked by poly (ethylene glycol) (PEG) with 2-, 4- and 8-arms through dynamic hydrazone bonds to confer injectability and generate varying network connectivity. The retention time of the hydrogels can be tuned from 12 to 36 h in the intestine due to their different degradation behaviors induced by MMP-9. The drug-releasing rate of the hydrogels can be controlled from 0.0003 mg/h to 0.278 mg/h. In addition, injection of such hydrogels in vivo resulted in significant differences in therapeutic effects including MMP-9 consumption, colon tissue repair, reduced collagen deposition, and decreased macrophage cells, for treating a mouse model of acute colitis. Among them, GP-8/5-ASA exhibits the best performance. This study validates the effectiveness of the tailored design of hydrogel architecture in response to pathological microenvironment cues, representing a promising strategy for on-demand therapy of IBD. STATEMENT OF SIGNIFICANCE: The uncontrollable retention of enemas at the delivery site poses a long-term challenge for improving therapeutic efficacy in IBD patients. MMP-9 is highly expressed in IBD and correlates with disease severity. Therefore, an MMP-9-responsive GP hydrogel system was developed as an enema by linking multi-armed PEG and gelatin through hydrazone bonds. This forms a dynamic hydrogel characterized by in situ gelation, injectability, enhanced bio-adhesion, biocompatibility, controlled retention time, and regulated drug release. GP hydrogels encapsulating 5-ASA significantly improved the intestinal phenotype of acute IBD and demonstrated notable therapeutic differences with increasing PEG arms. This method represents a promising on-demand IBD therapy strategy and provides insights into treating diseases of varying severities using endogenous stimulus-responsive drug delivery systems.
治疗炎症性肠病（IBD）的方法包括灌肠以减轻肠道炎症和缓解相关症状。然而，灌肠剂在肠道内不可控的保留一直是提高其治疗效果和安全性的长期挑战。在此，我们开发了一种蛋白酶可降解的水凝胶系统，作为一种按需灌肠载体，可根据基质金属蛋白酶-9（MMP-9）表达的变化，调节其降解和药物释放速率。该系统由三种定制的水凝胶网络组成，通过动态腙键交联聚乙二醇（PEG）的 2-、4-和 8-臂，赋予可注射性并产生不同的网络连接。由于 MMP-9 诱导的不同降解行为，水凝胶在肠道中的保留时间可从 12 小时调节至 36 小时。水凝胶的药物释放速率可从 0.0003 mg/h 至 0.278 mg/h 控制。此外，体内注射这种水凝胶在治疗急性结肠炎的小鼠模型中，在治疗效果方面产生了显著差异，包括 MMP-9 消耗、结肠组织修复、胶原沉积减少和巨噬细胞减少。其中，GP-8/5-ASA 表现最好。该研究验证了水凝胶结构的定制设计在响应病理微环境信号方面的有效性，代表了按需治疗 IBD 的一种有前途的策略。
在治疗部位不可控的保留灌肠剂对提高 IBD 患者的治疗效果构成了长期挑战。MMP-9 在 IBD 中高度表达，与疾病严重程度相关。因此，通过腙键将多臂 PEG 和明胶连接起来，开发了一种 MMP-9 响应的 GP 水凝胶系统作为灌肠剂。这形成了一种具有原位凝胶化、可注射性、增强的生物粘附性、生物相容性、可控保留时间和调节药物释放的动态水凝胶。封装 5-ASA 的 GP 水凝胶显著改善了急性 IBD 的肠道表型，并随着 PEG 臂的增加显示出显著的治疗差异。这种方法代表了一种有前途的按需 IBD 治疗策略，并为使用内源性刺激响应药物输送系统治疗不同严重程度的疾病提供了见解。
