Nanosensor probes for oxygen imaging in vivo

描述（由申请人提供）：氧依赖性磷光猝灭是一种灵敏而可靠的测量分子氧的方法，特别是在体内组织中。研究表明，当在血液中加入近红外吸收磷光氧传感器时，可以利用近红外光完成组织中氧的三维成像。我们建议开发无毒的光学纳米传感器，用于测量和成像体内组织微血管培养中的氧气，准备转化为临床。我们将合成具有近红外吸收、发射和淬灭常数的生物相容性氧纳米传感器，以优化其在组织中的测量。荧光粉将是多层的，即四苯并卟啉的金属配合物，包裹在树状大分子内并涂有聚乙二醇（PEG）。近红外吸收发光金属卟啉将作为氧气的实际传感器。树状大分子将共价连接到卟啉形成保护壳，调整氧扩散率的值最适合组织氧测量。树突壳也将有助于保护卟啉核心免受与血液成分的相互作用，并将作为单线态氧的清道夫。然后，卟啉树状大分子将通过在其外表面涂上聚乙二醇（peg）来快速排泄（通过肾脏）。聚乙二醇将分离卟啉树状大分子与其他血液成分的相互作用。因此，传感器的发光强度和寿命将变得完全不敏感的物种以外的环境中的氧气。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详尽的测试。我们的目标是创造一种适合临床使用的氧气纳米传感器，将其推向临床应用的阶段，即准备用于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.