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，但目前仍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，但目前还没有特定的纳米颗粒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，将装载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很有前途的临床前方法。然而，将药物磁靶到中、大血管的实验尝试非常少。因此，人们对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对内皮细胞的直接体外作用，研究了SPIONs在人体内动脉的磁性靶向性，并在兔模型中建立了血管造影辅助下SPIONs的体内靶向性。此外，我们在兔腹主动脉粥样硬化模型中评估了spion与地塞米松结合对动脉粥样硬化斑块的影响。在这个更新项目中，我们建议将我们的研究重点放在磁药物靶向动脉粥样硬化的方法上，以验证区域特异性SPION在体内和体外积累的可行性。此外，将在兔晚期动脉粥样硬化模型中广泛研究药物偶联SPIONs的治疗效果。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颗粒积累的影响。下一步的任务将是利用载药SPIONs实现磁颗粒积累和药物靶向的体内有效性研究。为此，我们将通过磁共振成像和组织学来评估SPION对动脉粥样硬化斑块的疗效。此外，为了获得先前开发的海洋马伐他汀结合SPIONs和抗vegf抗体结合SPIONs有效性的临床前证据，将使用这些纳米颗粒在动脉粥样硬化兔子中进行磁性药物靶向研究。我们相信，通过增加药物制剂的有效局部剂量，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.