Stent placement is an effective treatment for atherosclerosis, but is suffered from in-stent restenosis (ISR) caused by stent mechanical damage. Conventional ISR treatment such as drug-eluting stents (DES) is challenged by the low therapeutic efficacy and severe complications, unchangeable drug dosage for individuals, and limited drug penetration in the vascular tissue. We hypothesize that magnetic targeting and deep-penetrating delivery strategy by magnetic guidance and ultrasound stimulation might be an effective approach for ISR treatment. In the present study, antiproliferative drug (paclitaxel, PTX) loaded poly (lactide-co-glycolide) (PLGA) nanoparticles (PLGA-PTX) were embedded within the shells of the magnetic nanoparticle coated microbubbles (MMB-PLGA-PTX). Once being targeted to the stent under a magnetic field, a low intensity focused ultrasound (LIFU) is applied to activate stable microbubble oscillations, thereby triggering the release of PLGA-PTX. The generated mechanical force and microstreaming facilitate the penetration of released PLGA-PTX into the thickened vascular tissue and enhance their internalization by smooth muscle cells (SMCs), thereby reducing the clearance by blood flow. In an ex vivo experiment, magnetic targeting improved the accumulation amount of MMB-PLGA-PTX by 10 folds, while the LIFU facilitated the penetration of released PLGA-PTX into the tunica media region of the porcine coronary artery, resulting in prolonged retention time at the stented vascular tissue. With the combination effects, this strategy holds great promise in the precision delivery of antiproliferative drugs to the stented vascular tissue for ISR treatment.

放置支架是治疗动脉粥样硬化的有效方法，但会遭受支架机械损伤引起的支架内再狭窄（ISR）。常规的ISR治疗（例如药物洗脱支架（DES））受到治疗效率低，并发症严重，药物剂量不变以及血管组织药物渗透受限等挑战。我们假设通过磁引导和超声刺激进行磁靶向和深穿透递送策略可能是治疗ISR的有效方法。在本研究中，负载抗增殖药物（紫杉醇，PTX）的聚丙交酯-乙交酯共聚物（PLGA）纳米颗粒（PLGA-PTX）被嵌入磁性纳米颗粒包被的微泡（MMB-PLGA-PTX）的壳中。一旦在磁场下对准支架，使用低强度聚焦超声（LIFU）激活稳定的微泡振荡，从而触发PLGA-PTX的释放。产生的机械力和微流有助于释放的PLGA-PTX进入增厚的血管组织，并通过平滑肌细胞（SMC）增强其内在化，从而减少血流清除。在离体实验中，磁性靶向将MMB-PLGA-PTX的积累量提高了10倍，而LIFU促进了释放的PLGA-PTX渗透到猪冠状动脉的中膜区域，从而延长了保留时间。支架血管组织。具有联合作用，该策略在将抗增殖药物精确递送至带支架的血管组织进行ISR治疗方面具有广阔的前景。