A thermosensitive hydrogel-copper meta-organic framework composite improves hindlimb ischemia therapy through synergistically enhancing HIF-1α production and inhibiting HIF-1α degradation
A thermosensitive hydrogel-copper meta-organic framework composite improves hindlimb ischemia therapy through synergistically enhancing HIF-1α production and inhibiting HIF-1α degradation
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DOI：
10.1016/j.matdes.2024.112638
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发表时间：
2024-01-23
影响因子：
8.4
通讯作者：
Xiao，Jisheng
中科院分区：
文献类型：
--
作者：
Cheng，Jinmei;Dou，Yushun;Xiao，Jisheng
严重肢体缺血（critical limb ischemia，CLI）是临床上的一个重大挑战，具有较高的发病率和死亡率.考虑到缺氧诱导因子1α（HIF-1α）在缺氧部位通过调节生长因子的表达诱导血管生成的关键作用，我们将叶酸修饰的铜基MOFs（F-HKUST-1）与温敏水凝胶（PPCN）混合，制备了一种协同复合物（P-F-HKUST-1），用于后肢缺血治疗。P-F-HKUST-1在后肢肌肉中的凝胶化产生了更严重的缺血环境，随后诱导了HIF-1α的表达，而P-F-HKUST-1缓慢释放的Cu 2+通过失活抑制因子缺氧诱导因子1（FIH-1）来增加HIF-1α的稳定性，协同诱导下游生长因子的产生，最终快速恢复血液灌注。此外，P-F-HKUST-1水凝胶具有较长的体内滞留时间，对HIF-1α具有持续作用，可减少给药次数。P-F-HKUST-1具有良好的生物相容性和快速的血流恢复能力，有望成为一种新型的联合治疗（HIF-1α刺激和稳定）严重肢体缺血的药物。
Critical limb ischemia (CLI) remains a significant clinical challenge with high morbidity and mortality. Considering the critical role of hypoxia-inducible factor 1α (HIF-1α) in hypoxic site to induce angiogenesis by regulating the expression of growth factors, we prepared a cooperative composite (P-F-HKUST-1) by mixing thermo-responsive hydrogel (PPCN) with folic acid modified copper-based MOFs (F-HKUST-1) for the hindlimb ischemia therapy. The gelation of P-F-HKUST-1 in hindlimb muscle generated a more serious ischemia environment and subsequently induced the expression of HIF-1α, while the slowly released Cu2+from P-F-HKUST-1 increased HIF-1α stability by inactivating the factor-inhibiting hypoxia-inducible factor 1 (FIH-1), which synergistically induced the productions of downstream growth factors and finally restored the blood perfusion rapidly. In addition, P-F-HKUST-1 hydrogel exhibited a longin vivoretention time, which endowed the sustaining action on HIF-1α to reduce the frequency of administration. The rapid blood flow recovery, together with the good biocompatibility suggested that P-F-HKUST-1 could be a potential novel combined therapy (HIF-1α stimulation and stabilization) for critical limb ischemia.