Albumin-Encapsulated Rare Earth Nanoprobes for Multifunctional Tissue Imaging

描述(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给社会造成了惊人的损失。目前区分这些病理的方法受到其侵袭性、成本以及无法使用实时跟踪方法针对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，使用发射红外线的分子靶向光学成像纳米探测器来解析和监测组织病理。红外线很有吸引力，因为它可以很容易地透过厚厚的生物组织。我们的纳米探测器由稀土掺杂的陶瓷纳米颗粒组成，在一个新颖的发射窗口中明亮地发射红外光。这些颗粒被白蛋白纳米壳包裹，以提供细胞相容性和水分散体，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，以建立具有体内高生物利用度、改善生物相容性和针对疾病靶点的功能靶向的纳米探针。提出的一个特别创新的终点是通过静脉注射纳米探针鸡尾酒的体内成像来跟踪疾病表型进展，这些纳米探针跨越不同的红外波长发射，并作用于疾病表型的四个不同标记物。提出了两个具体目标。在目标1中，该项目将使用小鼠转移性黑色素瘤模型来研究稀土纳米探针的纳米尺寸和生物功能化对疾病部位的生物分布和聚集的作用。体内分布将使用活体动物的红外成像进行检测，并使用高分辨率电感耦合质谱仪与传统的组织图谱进行比较。因此，将建立用于活体成像的纳米探针的最佳配方。在目标2中，纳米探针稀土掺杂纳米颗粒将被量身定做，以发射不同波长的光，从而创建一系列多色纳米颗粒。这些将被功能化，以同时报告肿瘤生长、侵袭和转移潜力的四个关键标志。多重纳米探针的相对积累将用于跟踪在已确定的药物治疗后肿瘤的进展/稳定。这将作为R21项目基础的概念验证，并成为开发这项针对不同分子表型的更广泛疾病状态的纳米技术的基础。

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.