Wang Siyu, Guo Xixi, Ren Lili, Wang Bo, Hou Lixin, Zhou Hao, Gao Qinchang, Gao Yu, Wang Lianhui
Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, China.
Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, China.
Ultrason Sonochem. 2020 Oct;67:105188. doi: 10.1016/j.ultsonch.2020.105188. Epub 2020 May 25.
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.
支架置入是治疗动脉粥样硬化的有效方法，但会受到支架机械损伤导致的支架内再狭窄（ISR）的影响。传统的ISR治疗方法，如药物洗脱支架（DES），面临着治疗效果低、并发症严重、个体药物剂量不可变以及药物在血管组织中渗透有限等挑战。我们假设通过磁导向和超声刺激的磁靶向和深度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-共-乙交酯）（PLGA）纳米颗粒（PLGA-PTX）被嵌入磁纳米颗粒包被的微泡（MMB-PLGA-PTX）的壳内。一旦在磁场作用下靶向到支架，施加低强度聚焦超声（LIFU）以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穿透增厚的血管组织，并增强平滑肌细胞（SMC）对它们的摄取，从而减少血流清除。在体外实验中，磁靶向使MMB-PLGA-PTX的积累量提高了10倍，而LIFU促进了释放的PLGA-PTX穿透猪冠状动脉的中膜区域，导致在支架血管组织中的保留时间延长。通过这些联合作用，该策略在将抗增殖药物精确递送至支架血管组织以治疗ISR方面具有很大的前景。
