Abstract:
The development of new multi-target combination treatment strategies to tackle ischemic stroke (IS) remains to be challenging. Herein, a proof-of-concept demonstration of an advanced nanomedicine formulation composed of macrophage membrane (MM)-camouflaged phosphorous dendrimer (termed as AK137)/fibronectin (FN) nanocomplexes (NCs) loaded with antioxidant edaravone (EDV) to modulate both microglia and neurons for effective IS therapy is showcased. The created MM@AK137-FN/EDV (M@A-F/E) NCs with a mean size of 260 nm possess good colloidal stability, sustained EDV release kinetics, and desired cytocompatibility. By virtue of MM decoration, the M@A-F/E NCs can cross blood-brain barrier, act on microglia to exert the anti-inflammatory (AK137 and FN) and antioxidative (FN and EDV) effects in vitro for oxidative stress alleviation, microglia M2 polarization, and reduction of pro-inflammatory cytokine secretion, and act on neuron cells to be anti-apoptotic. In a transient middle cerebral artery occlusion rat model, the developed M@A-F/E NCs can exert enhanced antioxidant/anti-inflammatory/anti-apoptotic therapeutic effects to comprehensively regulate the brain microenvironment and promote vascular regeneration to collaboratively restore the blood flow after ischemia-reperfusion. The designed MM-coated NCs composed of all-active ingredients of phosphorous dendrimers, FN, and EDV that can fully regulate the brain inflammatory microenvironment may expand their application scope in other neurodegenerative diseases.
摘要:
开发新的多靶点联合治疗策略来应对缺血性卒中(IS)仍然具有挑战性。在这里,展示了一种先进的纳米药物制剂的概念验证,该制剂由巨噬细胞膜(MM)伪装的磷树状聚合物(称为AK137)/纤连蛋白(FN)纳米复合物(NCs)组成,负载有抗氧化剂依达拉奉(EDV),可调节小胶质细胞和神经元以进行有效的IS治疗。所制备的MM@AK137-FN/EDV(M@A-F/E)NCs平均粒径为260nm,具有良好的胶体稳定性,EDV持续释放动力学,和所需的细胞相容性。凭借MM的装修,M@A-F/ENC可以穿越血脑屏障,作用于小胶质细胞在体外发挥抗炎(AK137和FN)和抗氧化(FN和EDV)作用以缓解氧化应激,小胶质细胞M2极化,和减少促炎细胞因子的分泌,并作用于神经元细胞以抗凋亡。短暂性大脑中动脉闭塞大鼠模型,开发的M@A-F/ENCs可发挥增强的抗氧化/抗炎/抗凋亡治疗作用,全面调节脑微环境,促进血管再生,协同恢复缺血再灌注后的血流。设计的MM涂层NC由磷树枝状聚合物的所有活性成分组成,FN,EDV能充分调节脑内炎症微环境,有可能扩大其在其他神经退行性疾病中的应用范围。