Nontoxic Si Nanoprobes for Mulitple Biomarker Imaging

描述（由申请人提供）：斑块组成是预防急性冠状动脉综合征的重要评估点。比斑块大小更重要的是，斑块的组成和特定标志物的存在表明斑块是否有破裂的危险。破裂可导致血栓形成事件，导致死亡或发病率。许多斑块成分已被确定与斑块稳定性相关，包括与炎症相关的细胞类型和细胞因子，但这些很难在体内研究。此外，没有单一的标志物是斑块破裂风险的绝对预测因子，临床医生对多种标志物的评估越来越感兴趣。因此，需要一种能够对许多斑块成分进行临床评估的成像方法。磁共振成像（MRI）和正电子发射断层扫描（PET）等非侵入性方法能够使用靶向造影剂成像标志物表达，但不能同时评估多个标志物。如果临床医生有兴趣检查多个标记物，则必须连续进行研究，并在之前的靶向造影剂清除（MRI）或衰减（PET）之间等待一段时间。本提案的总体目标是开发合成方法并进行成像研究，从而在人类冠状动脉疾病的管理中使用无毒，半导体，纳米颗粒，成像探针（量子点，QDs）。我们建议开发发光和顺磁性的硅量子点，以允许光学和磁共振成像。与传统的镉基量子点不同，硅纳米粒子有望无毒，即使是游离硅也相对无毒。可以针对量子点来识别在心血管预防医学中重要的特定生物标志物，然后使用磁共振和光学成像来评估斑块组成——MRI用于检测生物标志物表达的区域，而光学方法用于询问这些区域以识别存在的生物标志物类型。在本文中，我们描述了合成特定尺寸和成像特性的Si量子点的方法，表征了这些纳米颗粒在细胞培养中的毒性和摄取，并证明了这些量子点在动物模型中标记斑块稳定性的多种生物标志物的实用性。这项提议的工作开发了一种新的成像材料，使医生能够评估动脉斑块是否有破裂的危险。斑块破裂对健康的威胁比斑块的大小更严重。医生可以利用这些信息来决定患者的治疗计划，并确定需要更仔细监测的斑块。

DESCRIPTION (provided by applicant): Plaque composition is an important assessment point in the prevention of acute coronary syndrome. More so than plaque size, the composition of a plaque and presence of specific markers indicate if a plaque is at risk for rupture. Rupture can lead to thrombotic events that cause mortality or morbidity. A number of plaque components have been identified that correlate with plaque stability, including cell types and cytokines associated with inflammation, but these are difficult to study in vivo. In addition, no single marker is an absolute predictor for plaque risk to rupture clinicians are increasingly interested in multiple marker assessment. Therefore a need exists for imaging methods that will allow for clinical assessment of many plaque components. Noninvasive methods such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are capable of imaging marker expression using targeted contrast agents, but multiple markers cannot be assessed simultaneously. If a clinician is interested to examine more than one marker, studies must be done serially, with a wait time in between for the previous targeted contrast agent to clear (for MRI), or decay (for PET). The overall goal of this proposal is to develop synthetic methods and conduct imaging studies leading toward the use of nontoxic, semiconductor, nanoparticle, imaging probes (quantum dots, QDs) in the management of human coronary artery disease. We propose to develop silicon QDs that are luminescent and also paramagnetic to allow both optical and MR imaging. Unlike traditional cadmium based QDs, silicon nanoparticles have the promise to be nontoxic as even free silicon relatively nontoxic. The QDs can be targeted to identify specific biomarkers important in cardiovascular preventative medicine and both magnetic resonance and optical imaging are then employed to assess plaque composition--MRI is used to detect regions where biomarkers are expressed, while optical methods are employed to interrogate these regions to identify the types of biomarkers present. In this proposal we describe methods to synthesize Si QDs of specific size and imaging properties, characterize the toxicity and uptake of these nanoparticles in cell cultures, and demonstrate the utility for these QDs to label multiple biomarkers of plaque stability in an animal model. The proposed work develops a new imaging material that would allow physicians to assess whether an arterial plaque was at risk to rupture. Plaque rupture is a graver threat to health than the size of the plaque. The physician can use this information to decide on treatment plans for the patient and to identify plaques that need to be more carefully monitored.