Nanomedical approach to prevention and treatment of atherosclerosis

心血管疾病是全球最大的健康问题之一，但仍然缺乏有效的靶向治疗方法。纳米技术在心血管疾病管理方面的潜在临床影响是巨大的，但还没有特定的基于纳米颗粒的系统被批准用于人类动脉粥样硬化的诊断或治疗。在动脉粥样硬化领域，将负载Spion的细胞磁靶向血管支架，以防止血栓形成和再狭窄，是一种有希望的临床前方法。然而，将药物磁性靶向大中型血管的实验尝试非常少见。因此，对于磁性药物靶向治疗动脉粥样硬化的可行性知之甚少。在最初的项目中，我们分析了SPIONS对血管内皮细胞的直接作用，利用人动脉体外研究了SPIONS的磁靶向性，并在兔模型上建立了血管造影术辅助的SPIONS体内靶向性。进一步，我们评估了SPION与地塞米松结合对腹主动脉粥样硬化兔模型中动脉粥样硬化斑块的影响。在这个更新项目中，我们建议将重点放在针对动脉粥样硬化的磁性药物靶向方法上，以验证体内和体外区域特异性Spion蓄积的可行性。此外，药物偶联SPION的治疗效果将在晚期动脉粥样硬化的兔模型中进行广泛的研究。为了实现这些目标，我们将首先分析血液成分对体外流动下磁粉聚集的影响。进一步的任务将被设计成实现关于磁性粒子积累和使用载药SPION的药物靶向的有效性研究的在体证明。为此，我们将使用磁共振成像和组织学来评估Spion给药对动脉粥样硬化斑块的疗效。此外，为了获得先前开发的马拉马司马汀结合的SPION和抗血管内皮生长因子抗体偶联的SPION的临床前有效性证明，将使用这些纳米粒子在动脉粥样硬化兔身上进行磁性药物靶向研究。我们相信，通过增加药物的有效局部剂量，磁性药物靶向可能是改善斑块稳定性和减少炎症反应的有用工具。

Cardiovascular diseases represent one of the biggest global healthproblems, but effective approaches to targeted therapies are stillmissing. The potential clinical impact of nanotechnology in terms ofcardiovascular diseases management is enormous, but no specificnanoparticle-based system has been approved for diagnosis ortherapy of atherosclerosis in humans. In the field of atherosclerosis,magnetic targeting of SPION-loaded cells to vascular stents in orderto prevent thrombosis and restenosis constitutes a promisingpreclinical approach. However, the experimental attempts tomagnetically target drugs to medium and large vessels are veryscarce. Consequently, little is known about the feasibility of magneticdrug targeting approach in atherosclerosis. In the original project, weanalyzed the direct in vitro effect of SPIONs on endothelium,investigated the magnetic targeting of SPIONs using human arteriesex vivo, and established angiography-aided in vivo targeting ofSPIONs in rabbit model. Further, we evaluated the effects of SPIONsconjugated with dexamethasone on atherosclerotic plaques in a rabbitmodel of abdominal aortic atherosclerosis. In this renewal project, wepropose to focus our investigations on magnetic drug targetingapproach to atherosclerosis in order to validate the feasibility ofregion-specific SPION accumulation ex vivo and in vivo. Furthermore,the therapeutic efficacy of the drug-conjugated SPIONs will beextensively investigated in a rabbit model of advancedatherosclerosis. To achieve these objectives, we will at first analysethe effects of blood components on magnetic particle accumulationunder flow ex vivo. The further tasks will be designed to achieve an invivo proof of efficacy studies on magnetic particle accumulation anddrug targeting using drug-loaded SPIONs. For this purpose, we willevaluate the efficacy of SPION delivery to atherosclerotic plaquesusing magnetic resonance imaging and histology. Furthermore, toobtain the preclinical proof of efficacy of the previously developedmarimastat-bound SPIONs and anti-VEGF antibody-conjugatedSPIONs, the magnetic drug targeting studies in atherosclerotic rabbitswill be performed using these nanoparticles. We are convinced thatby increasing the effective local doses of pharmaceutical agents,magnetic drug targeting may represent a useful tool to improve theplaque stability and reduce inflammatory responses.