Zhang Huijuan, Wang Chaoqun, Wang Yaning, Ren Yan, Tian Yingmei, Hou Lin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou 450001, China.
ACS Appl Mater Interfaces. 2025 Mar 19;17(11):16696-16707. doi: 10.1021/acsami.5c01658. Epub 2025 Mar 7.
Traditional thrombolytic therapy is limited by low specificity, uncontrollable bleeding complications, and secondary vascular re-embolism. To address this issue, we developed a thrombin-responsive and sequential targeted nanoplatform (MMSN-UK/TI@pep-Fuco) for efficient thrombolysis based on the attack-defense-protection integrated strategy. Herein, the multilevel mesoporous silica nanoparticle with multiple pore sizes was synthesized and modified with fucoidan (Fuco) using the compound peptide (pep) as a bridge to form multifunctional drug carriers MMSN@pep-Fuco. Then, urokinase (UK) and tirofiban (TI) were sequentially loaded into MMSN@pep-Fuco to obtain MMSN-UK/TI@pep-Fuco nano drug delivery systems (NDDS). In vitro and in vivo results demonstrated that MMSN-UK/TI@pep-Fuco maintained stability in the blood circulation to reduce bleeding risk (protection). Once arriving at the thrombus clots, Fuco facilitated NDDS identification and accumulation via P-selectin-mediated active targeting. Thereafter, Fuco coating on the surface of MMSN-UK/TI@pep-Fuco was shed in response to thrombin and then allowed quick release of UK from larger pores to achieve rapid thrombolysis (attack). Next, the exposed LS-MMSN/TI core NPs can continue colonizing at thrombolysis sites, and then TI loaded in smaller pores was released slowly and continuously to prevent re-embolization of blood vessels (defense). Pharmacodynamic results showed that the final thrombus blockage rate of the MMSN-UK/TI@pep-Fuco treatment group was only 4.87% with a relatively low bleeding risk. This nanoplatform provided a new strategy for the treatment of arterial thrombosis and related diseases.
传统溶栓疗法存在特异性低、出血并发症难以控制以及继发性血管再栓塞等局限性。为解决这一问题，我们基于攻防保护一体化策略，开发了一种用于高效溶栓的凝血酶响应性和顺序靶向纳米平台（MMSN-UK/TI@pep-Fuco）。在此，合成了具有多种孔径的多级介孔二氧化硅纳米颗粒，并用岩藻多糖（Fuco）进行修饰，以复合肽（pep）为桥梁，形成多功能药物载体MMSN@pep-Fuco。然后，将尿激酶（UK）和替罗非班（TI）依次负载到MMSN@pep-Fuco中，得到MMSN-UK/TI@pep-Fuco纳米药物递送系统（NDDS）。体外和体内实验结果表明，MMSN-UK/TI@pep-Fuco在血液循环中保持稳定，以降低出血风险（保护）。一旦到达血栓部位，Fuco通过P-选择素介导的主动靶向促进NDDS的识别和积累。此后，MMSN-UK/TI@pep-Fuco表面的Fuco涂层会响应凝血酶而脱落，然后使UK从较大的孔中快速释放，以实现快速溶栓（攻击）。接下来，暴露的LS-MMSN/TI核心纳米颗粒可以继续在溶栓部位聚集，然后负载在较小孔中的TI缓慢持续释放，以防止血管再栓塞（防御）。药效学结果表明，MMSN-UK/TI@pep-Fuco治疗组的最终血栓阻塞率仅为4.87%，出血风险相对较低。这种纳米平台为动脉血栓形成及相关疾病的治疗提供了一种新策略。
