归巢肽修饰Tβ4纳米颗粒靶向治疗急性心肌损伤的实验研究

Regenerative capacity of heart is limited after myocardial injury. Using active factor to promote endogenous repair has become a hotspot recently. Thymosinβ4（Tβ4）which is expressed in the embryonic heart, has great clinical conversion value, since it plays a key role in promotion cardiac precursor cells proliferation, migration and differentiation. However, the conventional administration route of Tβ4 lead to short plasma half-life and unsufficient drug accumulation in the injured heart, severely compromising the therapeutic benefits. After myocardial infarction, fibrin was specifically and predominantly expressed in the infarcted area. The time frame of fibrin expression is nearly coincident with the effective acting time of Tβ4. The spatiotemporal characteristics of fibrin expression after injury render fibrin a perfect target for Tβ4 delivery. Based on these rationales, here we tried to develop a novel targeting drug delivery system of Tβ4, with nanoparticles as the drug carriers, peptide CREKA with special high affinity for fibrin as the targeting moiety, and fibrin as the therapeutic target to delivery Tβ4 for acute heart injury region. It is expected to extend the plasma half-life of Tβ4, improve the drug concentration and retention in the infarct zone, subsequently prompt the activation of cardiac precursor cells , and finally augment the therapeutic benefits of Tβ4. Our study offers a new method for drug delivery in endogenous repair of heart and provides new perspective for targeting drug therapy of other tissues injury.

心肌损伤后自我修复能力有限，导入活性因子激活心脏内源性修复是近年研究热点。Thymosin β4（Tβ4）是胚胎心脏发育过程中特异性表达的多肽，可促进成体心脏前体细胞的增生、迁移和分化，具有临床转化价值。但Tβ4常规给药存在药物半衰期短、心脏损伤部位浓度低下二大局限性，严重削弱其疗效。由于心肌损伤后纤维蛋白在心梗区特异性表达，表达时间与 Tβ4作用时间一致，由此推断，纤维蛋白可作为药物靶向治疗的新靶点。基于此，本研究拟构建一个新型的Tβ4靶向递药平台：利用纳米颗粒（NP）作为载体，特异性靶向纤维蛋白的归巢短肽CREKA作为靶头，针对心肌损伤区细胞外基质纤维蛋白靶向递送Tβ4，从而延长药物半衰期，提高损伤区药物浓度，动员心脏自身前体细胞，实现Tβ4心肌修复能力的最大化。本研究旨在为心脏内源性修复提供新的给药策略，并为其他组织损伤的药物靶向治疗提供新视角。

心肌损伤后自我修复能力有限，Thymosin β4（Tβ4）可促进成体心脏前体细胞的增生、迁移和分化，具有临床转化价值。但Tβ4常规给药存在药物半衰期短、心脏损伤部位浓度低下二大局限性，严重削弱其疗效。本研究构建了一个新型的Tβ4靶向递药平台，利用纳米颗粒NP作为载体，归巢短肽CREKA作为靶头，针对心肌损伤区细胞外基质纤维蛋白靶向递送Tβ4，从而延长药物半衰期，提高Tβ4在心梗区的药物浓度，动员心脏自身EPDC细胞，提高Tβ4修复心肌损伤的疗效，为心脏内源性修复提供了新的给药策略，并为其他组织损伤的药物靶向治疗提供新视角。