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。纳米颗粒的最新进展已经产生了具有可定制特性的生物医学工具 以及在克服与传统被动/扩散相关的障碍方面的非凡实力 诊断和治疗药物。然而，传统的纳米颗粒本质上是多分散的，并且 因此，通常缺乏稳健量化所需的精确度和一致性 在生物医学研究中的重复性，以及在未来的放大和长期储存中的质量控制 申请。富勒烯是纳米大小的分子，其大小和形状将保持刚性的多价核心。 像无机颗粒一样，并允许有机反应通过健壮的 C-C共价键。在我们团队中，我们使用了富勒烯C60的特征六加成物作为核心支架 和模块化平台，开发出一系列具有理想表面功能的精准分子纳米粒子， 用于新型磁共振成像和荧光成像探针的多价性和尺寸。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核磁共振探针，我们将在最近的基础上 开发出含Gd内面体的精密分子纳米粒子 下一代核磁共振造影剂的金属富勒烯和生化配体。这些核磁共振探头将检查 所有未来核磁共振探头的“愿望清单”：GD重金属安全性、高弛豫度、结构精确度和 生化特异性。在第二个主题中，FullerFISH通过快速和定量的信号放大，我们将 合成多价分子结构，用10-30种染料放大RNA-FISH信号，以促进 缺乏低丰度RNA分子的检测和定量。在第三个主题中，信号放大和 用于活细胞成像和smFRET成像的抗氧化探针，我们将利用其抗氧化特性和 六加成富勒烯纳米粒子的多价性，负载有机染料，以显影 抗光漂白和信号放大成像探头。在第四个主题中，精确比率测量 纳米探针，我们将推出生物响应性染料和“永远在线”的参考染料，以准确的1：1比例和准确 共聚焦到抗氧化剂多价富勒烯纳米颗粒上以实现比率成像 感知和跟踪生物事件。 这四个主题将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，与资源丰富的纳米颗粒和小分子研究库结合在一起，达到了精确度 以及纳米粒子在化学生物学中的多价性和多重性。具有模块化的特性 在我们的合成平台上，我们预计拟议的技术将被更广泛的生物学采用 具有许多新的自下而上设计和选择的配体的社区。

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.