A Fullerene-based Molecular Route towards Designer Nanoparticles

项目摘要 在化学生物学中，连接微观和宏观世界的精确自下而上的合成是一种 终极目标纳米粒子的最新进展已经产生了具有可定制特性的生物医学工具 以及在克服与传统的被动/扩散型 诊断和治疗药物。然而，常规纳米颗粒固有地是多分散的，并且 因此通常缺乏稳健量化所需的精确度和均匀性， 生物医学研究的重现性，以及未来规模扩大和长期储存的质量控制 应用.富勒烯是一种纳米级的分子，它的大小和形状与刚性多价核一样 像无机颗粒，并允许有机反应，以引入生物特性和功能，通过强大的 C-C共价键。在我们的小组中，我们利用富勒烯C60的特征六加合物作为核心支架， 和模块化平台，开发一系列具有理想表面功能的精密“分子纳米颗粒”， 多价性和大小，用于新型磁共振成像和荧光成像探针。我们的工作 包括四个概念上独立，但技术上协同的研究主题。 在第一个主题中，具有多价靶向癌细胞的MRI探针，我们将建立在我们最近的 开发了“金属巴基三重奏”（MBT），以开发具有含Gd的内配体的精确分子纳米颗粒 用于下一代MRI造影剂的金属富勒烯和生物化学配体。这些核磁共振探针会检查 未来MRI探头中的所有“愿望清单项目”：Gd重金属安全性、高弛豫率、结构精度，以及 生化特异性在第二个主题中，具有快速和定量信号放大的FullerFISH，我们将 合成多价分子构建体以用10-30种染料扩增RNA-FISH信号，以促进 检测和定量缺乏低丰度RNA分子。在第三个主题中，信号放大和 抗氧化探针用于活细胞成像和smFRET成像，我们将利用抗氧化特性， 多价的六加合物富勒烯纳米粒子，负载有机染料，以开发 抗光漂白和信号放大成像探针。在第四个主题中， 纳米探针，我们将引入生物响应染料和“永远”的参考染料在准确的1：1的比例和准确的 共定位到抗氧化的多价富勒烯纳米颗粒上，以实现用于 感知和跟踪生物事件。 这四个主题将联合收割机结合我们的合成专业知识，将C60转化为精确的分子纳米颗粒， 理想的配体，与纳米粒子和小分子研究的资源库，以配合精确的 以及化学生物学中纳米粒子的多价性和多重性。随着模块化的本质 我们的合成平台，我们预计提出的技术将被更广泛的生物 有许多新的自下而上的设计和选择配体的社区。

Project Summary In chemical biology, precise bottom-up synthesis bridging the microscopic and macroscopic world is an ultimate goal. Recent advancements in nanoparticles have yielded biomedical tools with tailorable properties and exceptional strength in overcoming the hurdles associated with conventional passive/diffusion-based diagnostic and therapeutic drugs. However, conventional nanoparticles are inherently polydisperse, and therefore generally lack the precision and uniformity that are needed for the robust quantification and reproducibility in biomedical research, and for the quality control in scaling up and long-term storage in future applications. Fullerenes are nm-sized molecules that would hold their size and shape as a rigid multivalent core like inorganic particles, and allow for organic reactions to introduce biological properties and functions via robust C-C covalent bonds. In our group, we utilize a characteristic hexakisadduct of fullerene C60 as a core scaffold and modular platform to develop a series of precise “molecular nanoparticles” with desirable surface function, multivalency, and size, for novel magnetic resonance imaging and fluorescence imaging probes. Our work comprises four conceptually independent, but technically synergistic Research Themes. In the first Theme, MRI probes with multivalent targeting to cancer cells, we will build on our recently developed “metallobuckytrio” (MBT), to develop precise molecular nanoparticles with Gd-containing endohedral metallofullerene and biochemical ligands for next-generation MRI contrast agents. These MRI probes will check all the “wish list items” in future MRI probes: Gd heavy-metal safety, high relaxivity, structural precision, and biochemical specificity. In the second Theme, FullerFISH with fast and quantitative signal amplification, we will synthesize multivalent molecular constructs to amplify RNA-FISH signals with 10-30 dyes, to facilitate the detection and quantification of short of low-abundance RNA molecules. In the third Theme, signal amplifying and antioxidative probes for live cell imaging and smFRET imaging, we will exploit the anti-oxidative property and multivalency of the hexakisadduct fullerene nanoparticles, load them with organic dyes, to develop photobleaching-resistant and signal-amplifying imaging probes. In the fourth Theme, precise ratiometric nanoprobes, we will introduce bioresponsive dyes and “always on” reference dyes in accurate 1:1 ratio and exact colocalization onto the antioxidative, multivalent fullerene nanoparticles to achieve ratiometric imaging for sensing and tracking biological events. These four Themes will combine our synthetic expertise to turn C60 into precise molecular nanoparticles with desirable ligands, with the resourceful library of nanoparticle and small-molecule research, to marry the precision of molecules and the multivalency and multiplexity of nanoparticles in chemical biology. With the modular nature of our synthetic platform, we anticipate the proposed technology will be adopted by broader biological communities with many new bottom-up designs and ligands by choice.