中国神经再生研究(英文版) ›› 2024, Vol. 20 ›› Issue (2): 503-517.doi: 10.4103/NRR.NRR-D-23-01322

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

基质金属蛋白酶响应性水凝胶靶向递送血管生成肽修复脑缺血再灌注损伤

  


  • 出版日期:2025-02-15 发布日期:2024-06-18
  • 基金资助:
    山东省自然科学基金项目(ZR2023MC168);国家自然科学基金项目(31670989);山东省重点研发计划项目(2019GSF107037)

A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

Qi Liu1, 2, #, Jianye Xie3, #, Runxue Zhou1, Jin Deng1, 2, Weihong Nie1, Shuwei Sun1, Haiping Wang2, *, Chunying Shi1, *   

  1. 1Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; 2Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 3Department of General Practice, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
  • Online:2025-02-15 Published:2024-06-18
  • Contact: Chunying Shi, PhD, schy1116@163.com; Haiping Wang, PhD, wanghaiping999@163.com.
  • Supported by:
    This work was supported by the Natural Science Foundation of Shandong Province, No. ZR2023MC168; the National Natural Science Foundation of China, No. 31670989; and the Key R&D Program of Shandong Province, No. 2019GSF107037 (all to CS).

摘要:

血管内皮生长因子及其模拟肽KLTWQELYQLKYKGI(QK)作为最有效的血管生成因子已被广泛用于治疗多种缺血性疾病,但传统的局部给药往往会导致药物的突然释放,造成体内短暂滞留(无效)和不良扩散(毒性)。因此,如何响应组织再生微环境的变化,控制其释放是血管内皮生长因子在缺血性脑卒中治疗中发挥作用的重要问题。此次实验基于基质金属蛋白酶2在脑缺血后逐步上调的特性,将血管内皮生长因子模拟肽QK与基质金属蛋白酶2特异性剪切肽PLGLAG(TIMP)及可定制肽两亲分子(PA)自组装,构建了PA-TIMP-QK纳米自组装多肽水凝胶。该水凝胶可响应基质金属蛋白酶2的变化以控制血管生成肽QK的释放,且在体外与血管内皮生长因子具有相似的生物活性。将PA-TIMP-QK纳米自组装多肽水凝胶置入到脑缺血再灌注损伤大鼠的损伤部位,可实现响应微环境中基质金属蛋白酶2上调以控制血管生成肽QK的逐步释放,从而显著促进神经元存活,重建局部血运循环,减少血脑屏障通透性,并最终有效恢复其运动功能。这一结果表明,这种新型PA-TIMP-QK纳米自组装多肽水凝胶可作为一种响应微环境的智能药物递送系统,实现促进脑缺血再灌注损伤再生修复的效果。

https://orcid.org/0000-0002-5710-8966 (Chunying Shi); https://orcid.org/0009-0005-1083-7511 (Qi Liu)

关键词: 自组装纳米纤维水凝胶, 控制释放, 基质金属蛋白酶2, 血管内皮生长因子模拟肽, 血管生成, 血脑屏障, 神经保护, 炎症, 脑缺血再灌注损伤, 生物材料

Abstract: Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI (QK) are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases. However, conventional topical drug delivery often results in a burst release of the drug, leading to transient retention (inefficacy) and undesirable diffusion (toxicity) in vivo. Therefore, a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke. Matrix metalloproteinase-2 (MMP-2) is gradually upregulated after cerebral ischemia. Herein, vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG (TIMP) and customizable peptide amphiphilic (PA) molecules to construct nanofiber hydrogel PA-TIMP-QK. PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro. The results indicated that PA-TIMP-QK promoted neuronal survival, restored local blood circulation, reduced blood-brain barrier permeability, and restored motor function. These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

Key words: angiogenesis, biomaterial, blood–brain barrier, cerebral ischemia/reperfusion injury, control release, drug delivery, inflammation, QK peptides, matrix metalloproteinase-2, neuroprotection, self-assembling nanofiber hydrogel