Nanosensor probes for oxygen imaging in vivo

描述（由申请人提供）：磷光的氧依赖性猝灭是一种灵敏且稳健的测量分子氧的方法，特别是在体内组织中。已经证明，当将近红外吸收磷光氧传感器添加到血液中时，可以使用近红外光来实现组织中氧的3D成像。我们建议开发无毒的光学纳米传感器，适用于测量和成像组织微血管中的氧在体内，准备翻译成临床。我们将合成具有近红外吸收和发射以及猝灭常数的生物相容性氧纳米传感器，用于组织中的测量。磷光体将是多层的，即四苯并卟啉的金属络合物，封装在树枝状聚合物内并涂覆有低聚乙二醇（PEG）。近红外吸收发光金属卟啉将作为实际的氧传感器。树枝状聚合物将共价连接到卟啉以形成保护壳，将氧扩散速率调节到组织氧测量的最佳值。树枝状壳还将有助于保护卟啉核心不与血液成分相互作用，并将作为单线态氧的清除剂。然后，通过用PEG涂覆卟啉树枝状聚合物的外表面，卟啉树枝状聚合物将被靶向用于快速排泄（通过肾脏）。PEG将卟啉树枝状聚合物与其他血液成分的相互作用隔离开来。因此，传感器发光强度和寿命将变得对环境中除氧以外的物质完全不敏感。纳米传感器的急性和长期毒性将分别在新生仔猪模型和小鼠模型中进行彻底测试。我们的目标是创建一个适合临床使用的氧气纳米传感器，将其移动到可以转化为临床的程度，即准备进行更大规模的合成和严格的毒理学研究，为临床试验做准备。

DESCRIPTION (provided by applicant): Oxygen dependent quenching of phosphorescence is a sensitive and robust method for measuring molecular oxygen, particularly in tissue in vivo. It has been demonstrated that 3D imaging of oxygen in tissue can be accomplished using near infrared light when near-infrared absorbing phosphorescent oxygen sensors are added to the blood. We propose to develop non-toxic optical nanosensors suitable for measuring and imaging oxygen in tissue microvascualture in vivo, ready for translation into clinics. We will synthesize bio-compatible oxygen nanosensors with near infrared absorption and emission and quenching constants optimized for measurements in tissue. The phosphors will be multi-layered, i.e. metal complexes of tetrabenzoporphyrins, encapsulated inside dendrimers and coated with oligoethyleneglycols (PEG). The near-infrared absorbing luminescent metalloporphyrins will act as the actual sensors for oxygen. Dendrimers will be covalently linked to the porphyrins to form protective shells, tuning oxygen diffusion rates to the values optimal for tissue oxygen measurement. The dendritic shells will also help to protect the porphyrin core from interacting with blood components and will serve as scavengers for singlet oxygen. Porphyrin dendrimers will then be targeted for rapid excretion (via the kidney) by coating their external surfaces with PEGs. PEGs will isolate the porphyrin-dendrimers from interactions with other blood components. Thus, the sensor luminescence intensity and lifetime will become completely insensitive to species in the environment other than oxygen. Acute and long term toxicity of the nanosensors will be exhaustively tested in the newborn piglet model and mice model, respectively. The goal is to create a nanosensor(s) for oxygen that is suitable for clinical use, moving it to the point where it is ready for translation into the clinics i.e. ready for larger scale synthesis and rigorous toxicology studies preparatory to use in clinical trials.