Thompson John W, Suon Jennifer, Knott Maxon V, Corsaletti Gina, Hamad Naser, Hanna Joshua, Rodrigues Pedro Barkevitch, Sanikommu Sai, Hernandez-Cuervo Helena, Haniff Rianna, Hataoka Shunsuke, Chen Stephanie H, Abdelsalam Ahmed, Toledo Jayro, Eatz Tiffany, Bhattacharya Sanjoy K, Hare Joshua M, Toborek Michal, Vazquez-Padron Roberto I, Burks Joshua D, Luther Evan M, Starke Robert M
Department of Neurological Surgery, Radiology and the University of Miami Cerebrovascular Initiative.
Department of Molecular and Cellular Pharmacology; University of Miami, Miller School of Medicine.
bioRxiv. 2025 Jun 27:2025.06.24.661344. doi: 10.1101/2025.06.24.661344.
Cerebral aneurysm occlusion with coils and flow diverting stents has become the first line treatment for both unruptured and ruptured cerebral aneurysms. As these technologies have advanced, there have been changes in device shape and surface coating to enhance aneurysm embolization while reducing stent thrombogenicity. Drug eluting stents have been used with great success in the targeted delivery of rapamycin, a mTOR complex 1 inhibitor to prevent restenosis in coronary and peripheral artery disease. However, few studies have investigated the use of coils and stents as delivery platforms for sustained drug release to cerebral aneurysm tissue. In this study, we used the bio-compatible and degradable polymers, gelatin and PLGA and a simple evaporative coating technique to investigate the release of rapamycin over time from coated platinum coils and Pipeline flow diverting stents. Rapamycin coated coils were incubated with human vascular endothelial cells to confirm therapeutic levels of rapamycin release. The rate of rapamycin release was similar in both gelatin and PLGA coated coils and was sustained for more than three weeks. Rapamycin was bioactive, at a therapeutic dose and inhibited mTOR complex 1 in human brain endothelial cells treated with a rapamycin coated coil. The relative degree of mTOR complex 1 inhibition was greater in PLGA compared to gelatin coated coils. Coating flow diverting stents with a rapamycin-PLGA coating demonstrated continuous rapamycin release over a 35 day period. Reducing the percent PLGA polymer concentration caused a robust and sustainable release of rapamycin. The PLGA coating was resilient enough to allow device recapturing without affecting rapamycin eluting rates or device deployment and expansion. This work provides a simple, feasible and tunable method to coat occlusion devices for preclinical studies investigating targeted drug delivery for improved parent vessel healing and aneurysm obliteration.
使用弹簧圈和血流导向支架闭塞脑动脉瘤已成为未破裂和破裂脑动脉瘤的一线治疗方法。随着这些技术的进步,设备形状和表面涂层发生了变化,以增强动脉瘤栓塞,同时降低支架的血栓形成性。药物洗脱支架已成功用于靶向递送雷帕霉素,一种mTOR复合物1抑制剂,以预防冠状动脉和外周动脉疾病的再狭窄。然而,很少有研究调查使用弹簧圈和支架作为向脑动脉瘤组织持续释放药物的递送平台。在本研究中,我们使用生物相容性和可降解的聚合物、明胶和聚乳酸-羟基乙酸共聚物(PLGA)以及一种简单的蒸发涂层技术来研究雷帕霉素从涂层铂弹簧圈和Pipeline血流导向支架中的随时间释放情况。将雷帕霉素涂层弹簧圈与人血管内皮细胞一起孵育,以确认雷帕霉素的治疗水平释放。雷帕霉素在明胶和PLGA涂层弹簧圈中的释放速率相似,并且持续超过三周。雷帕霉素具有生物活性,在治疗剂量下可抑制用雷帕霉素涂层弹簧圈处理的人脑内皮细胞中的mTOR复合物1。与明胶涂层弹簧圈相比,PLGA中mTOR复合物1的相对抑制程度更大。用雷帕霉素-PLGA涂层对血流导向支架进行涂层,结果表明雷帕霉素在35天内持续释放。降低PLGA聚合物浓度百分比会导致雷帕霉素强劲且持续的释放。PLGA涂层具有足够的弹性,允许重新捕获装置,而不会影响雷帕霉素的洗脱速率或装置的展开和扩张。这项工作提供了一种简单、可行且可调节的方法来为闭塞装置涂层用于临床前研究,以研究靶向药物递送,从而改善母血管愈合和动脉瘤闭塞。