Albumin-Encapsulated Rare Earth Nanoprobes for Multifunctional Tissue Imaging

描述（由申请人提供）：复杂的疾病状态，如转移性癌症和急性动脉粥样硬化，在死亡率和医疗费用方面对社会造成了惊人的影响。目前鉴别这些病理的方法受到其侵袭性、成本和无法使用实时跟踪方法靶向病理的分子特征的限制。这项探索性的R21研究基于一种创新的纳米级概念，利用发射红外光的分子靶向光学成像纳米探针来解决和监测组织病理。红外光很有吸引力，因为它很容易穿透厚的生物组织。我们的纳米探针由稀土掺杂的陶瓷纳米颗粒组成，它在一个新的发射窗口中发出明亮的红外光。这些颗粒被包裹在白蛋白纳米壳中，以赋予细胞相容性和水分散性，白蛋白与标记物结合以靶向感兴趣的疾病。该项目建议开发一系列包裹在功能化白蛋白纳米壳中的稀土掺杂纳米颗粒，以建立具有高体内生物利用度、提高生物相容性和功能靶向疾病靶点的纳米探针。提出的一个特别创新的终点是通过静脉注射纳米探针混合物的体内成像来跟踪疾病表型进展，这些纳米探针发射不同的红外波长，并功能化到四种不同的疾病表型标记物。提出了两个具体目标。在Aim 1中，该项目将使用小鼠转移性黑色素瘤模型研究稀土纳米探针的纳米尺寸和生物功能在疾病部位的生物分布和积累中的作用。体内分布将使用活体动物的红外成像进行检查，并使用高分辨率电感耦合质谱法与传统组织剖面进行比较。因此，将建立用于体内成像的纳米探针的最佳配方。在Aim 2中，纳米探针稀土掺杂纳米粒子将被定制为在不同波长发射，从而创建一个多色纳米粒子家族。这些将被功能化，以同时报告肿瘤生长、侵袭性和转移潜力的四个关键标志物。多路纳米探针的相对积累将用于跟踪肿瘤在既定药物治疗后的进展/稳定。这将作为R21项目基础的概念证明，并成为开发这种纳米技术用于更广泛的不同分子表型疾病状态的基础。

DESCRIPTION (provided by applicant): Complex disease states such as metastatic cancers and acute atherosclerosis take a staggering toll on society in terms of mortality and health care costs. Current approaches to discriminate these pathologies are limited by their invasive nature, costs, and inability to target molecular features of the pathologies using real-time tracking methods. This exploratory R21 study is based on an innovative nanoscale concept to resolve and monitor tissue pathology using molecularly targeted optical imaging nanoprobes that emit infrared light. Infrared light is attractive because can be easily transmitted through thick biological tissues. Our nanoprobes consist of rare earth doped ceramic nanoparticles, which brightly emit infrared light in a novel window of emission. These particles are encapsulated with albumin nanoshells to impart cytocompatibility and aqueous dispersion and the albumin is conjugated with markers to target the disease of interest. The project proposes to develop a repertoire of rare earth-doped nanoparticles encapsulated in functionalized albumin nanoshells to establish nanoprobes with high biological availability in vivo, improved biocompatibility, and functional targeting to disease targets. A particularly innovative endpoint proposed is that of tracking disease phenotype progression through the in vivo imaging of intravenously injected cocktail of nanoprobes emitting across different infrared wavelengths and functionalized to four different markers of disease phenotypes. Two specific aims are proposed. In Aim 1, the project will investigate the role of nanoscale size and biofunctionalization of the rare earth nanoprobes on the biodistribution and accumulation at disease sites using a murine metastatic melanoma model. The in vivo distribution will be examined using infrared imaging of living animals and compared against conventional tissue profiles using high resolution inductively coupled mass spectrometry. Thus, optimal formulations of nanoprobes for in vivo imaging will be established. In Aim 2, the nanoprobe rare earth doped nanoparticles will be tailored to emit at different wavelengths and thus create a family of multi-chromatic nanoparticles. These will be functionalized to report simultaneously on four key markers for growth, invasiveness, and metastatic potential of tumors . The relative accumulation of the multiplexed nanoprobes will be used to track the progression/stabilization of tumors following established drug treatment. This will serve as a proof of concept for the foundations of this R21 project, and be the basis for developing this nanotechnology for a broader range of disease states of varying molecular phenotypes.