Smith Bryan R, Heverhagen Johannes, Knopp Michael, Schmalbrock Petra, Shapiro John, Shiomi Masashi, Moldovan Nicanor I, Ferrari Mauro, Lee Stephen C
Department of Biomedical Engineering, Ohio State University, 1080 Carmack Road, Columbus, OH 43210, USA.
Biomed Microdevices. 2007 Oct;9(5):719-27. doi: 10.1007/s10544-007-9081-3.
Annexin V recognizes apoptotic cells by specific molecular interaction with phosphatidyl serine, a lipid that is normally sequestered in the inner leaflet of the cell membrane, but is translocated to the outer leaflet in apoptotic cells, such as foam cells of atherosclerotic plaque. Annexin V could potentially deliver carried materials (such as superparamagnetic contrast agents for magnetic resonance imaging) to sites containing apoptotic cells, such as high grade atherosclerotic lesions, so we administered biochemically-derivatized (annexin V) superparmagnetic iron oxide particles (SPIONs) parenterally to two related rabbit models of human atherosclerosis. We observe development of negative magnetic resonance imaging (MRI) contrast in atheromatous lesions and but not in healthy artery. Vascular targeting by annexin V SPIONs is atheroma-specific (i.e., does not occur in healthy control rabbits) and requires active annexin V decorating the SPION surface. Targeted SPIONs produce negative contrast at doses that are 2,000-fold lower than reported for non-specific atheroma uptake of untargeted superparamagnetic nanoparticles in plaque in the same animal model. Occlusive and mural plaques are differentiable. While most of the dose accumulates in liver, spleen, kidneys and bladder, annexin V SPIONs also partition rapidly and deeply into early apoptotic foamy macrophages in plaque. Contrast in plaque decays within 2 months, allowing MRI images to be replicated with a subsequent, identical dose of annexin V SPIONs. Thus, biologically targeted superparamagnetic contrast agents can contribute to non-invasive evaluation of cardiovascular lesions by simultaneously extracting morphological and biochemical data from them.
膜联蛋白V通过与磷脂酰丝氨酸的特异性分子相互作用来识别凋亡细胞，磷脂酰丝氨酸是一种脂质，通常隔离在细胞膜的内小叶中，但在凋亡细胞（如动脉粥样硬化斑块的泡沫细胞）中会转移到外小叶。膜联蛋白V有可能将携带的物质（如用于磁共振成像的超顺磁性造影剂）递送至含有凋亡细胞的部位，如高度动脉粥样硬化病变处，因此我们将经生化衍生的（膜联蛋白V）超顺磁性氧化铁颗粒（SPIONs）经肠胃外途径给予两种相关的人类动脉粥样硬化兔模型。我们观察到动脉粥样硬化病变处出现磁共振成像（MRI）负性造影，而健康动脉中未出现。膜联蛋白V修饰的SPIONs的血管靶向作用具有动脉粥样硬化特异性（即健康对照兔中不会发生），且需要活性膜联蛋白V修饰SPION表面。靶向SPIONs产生负性造影的剂量比同一动物模型中未靶向的超顺磁性纳米颗粒在斑块中非特异性动脉粥样硬化摄取所报道的剂量低2000倍。闭塞性斑块和壁内斑块是可区分的。虽然大部分剂量积聚在肝脏、脾脏、肾脏和膀胱中，但膜联蛋白V修饰的SPIONs也能迅速且深入地分布到斑块中早期凋亡的泡沫巨噬细胞中。斑块中的造影剂在2个月内衰减，使得后续给予相同剂量的膜联蛋白V修饰的SPIONs时MRI图像能够重复。因此，生物靶向超顺磁性造影剂可通过同时从心血管病变中提取形态学和生化数据，有助于对其进行非侵入性评估。
