Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction.
Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction.
复制标题
受肾素-血管紧张素系统启发的双配体超分子纳米纤维用于心肌梗死的靶向和协同治疗
作者：
Wen Z;Zhan J;Li H;Xu G;Ma S;Zhang J;Li Z;Ou C;Yang Z;Cai Y;Chen M
基本原理：心肌梗死（MI）后肾素-血管紧张素系统（RAS）的代偿性激活在心力衰竭的发病机制中起着至关重要的作用。现有的研究多集中于阻断RAS的单药或双药治疗，其疗效有限，且常引起严重不良反应。很少有研究已经进行了基于激活RAS的MI后的靶向治疗。因此，开发具有同时靶向能力和对RAS的协同治疗作用的多功能纳米药物可能在改善MI后的心脏功能方面显示出巨大的前景。研究方法：我们利用协同自组装策略构建超分子纳米纤维-替米沙坦掺杂的共组装纳米纤维（TDCNfs），通过靶向递送和联合治疗来反调节RAS。通过溶剂交换、加热孵育、凝胶化、离心和冻干等一系列步骤制备TDCNfs，其中替米沙坦掺杂在Ang1 - 7的自组装过程中，以获得共组装纳米纤维，其中它们充当治疗剂和靶向导向剂。结果：TDCNfs对两种不同的受体AT1R和MasR表现出所需的结合亲和力。通过双重配体-受体相互作用介导同时发生的下游途径，TDCNfs不仅对缺氧心肌细胞表现出良好的靶向特性，而且在体外和体内发挥减少细胞凋亡、缓解炎症反应和抑制纤维化的协同治疗作用，显着保护心脏功能并减轻心肌梗死后的不良后果。结论：成功开发了双配体纳米平台，实现了对MI后心脏恶化的靶向和协同治疗。我们设想，通过超分子自组装整合多种治疗药物将为心血管疾病的系统和靶向治疗提供新的见解。
Rationale: The compensatory activation of the renin-angiotensin system (RAS) after myocardial infarction (MI) plays a crucial role in the pathogenesis of heart failure. Most existing studies on this subject focus on mono- or dual-therapy of blocking the RAS, which exhibit limited efficacy and often causes serious adverse reactions. Few studies have been conducted on targeted therapy based on the activated RAS post-MI. Thus, the development of multiple-functional nanomedicine with concurrent targeting ability and synergistic therapeutic effect against RAS may show great promise in improving cardiac function post-MI. Methods: We utilized a cooperative self-assembly strategy constructing supramolecular nanofibers— telmisartan-doped co-assembly nanofibers (TDCNfs) to counter-regulate RAS through targeted delivery and combined therapy. TDCNfs were prepared through serial steps of solvent exchange, heating incubation, gelation, centrifugation, and lyophilization, in which the telmisartan was doped in the self-assembly process of Ang1-7 to obtain the co-assembly nanofibers wherein they act as both therapeutic agents and target-guide agents. Results: TDCNfs exhibited the desired binding affinity to the two different receptors, AT1R and MasR. Through the dual ligand-receptor interactions to mediate the coincident downstream pathways, TDCNfs not only displayed favorably targeted properties to hypoxic cardiomyocytes, but also exerted synergistic therapeutic effects in apoptosis reduction, inflammatory response alleviation, and fibrosis inhibition in vitro and in vivo, significantly protecting cardiac function and mitigating post-MI adverse outcomes. Conclusion: A dual-ligand nanoplatform was successfully developed to achieve targeted and synergistic therapy against cardiac deterioration post-MI. We envision that the integration of multiple therapeutic agents through supramolecular self-assembly would offer new insight for the systematic and targeted treatment of cardiovascular diseases.
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