A Fullerene-based Molecular Route towards Designer Nanoparticles

基于富勒烯的设计纳米粒子的分子路线

• 批准号: 10713377
• 负责人: Jianyuan Zhang
• 金额: $ 39.25万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713377
• 关键词: Adopted; Biochemical; Biological; Biology; Biomedical Research; Characteristics; Chemicals; Communities; Contrast Media; Detection; Diagnostic; Diffusion; Dyes; Event; Fluorescent Probes; Fullerenes; Future; Goals; Heavy Metals; Image; Libraries; Ligands; Magnetic Resonance Imaging; Medical; Microscopic; Molecular; Nature; Pharmaceutical Preparations; Photobleaching; Property; Quality Control; RNA; RNA amplification; Reaction; Reproducibility; Research; Resistance; Route; Safety; Series; Shapes; Signal Transduction; Specificity; Surface; Synthesis Chemistry; Technology; Therapeutic; Work; cancer cell; covalent bond; design; fluorescence imaging; fullerene C60; imaging probe; live cell imaging; nanoparticle; nanoprobe; next generation; novel; particle; ratiometric; scaffold; scale up; single-molecule FRET; small molecule; tool

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.

项目摘要 在化学生物学中，精确的自下而上的合成桥接显微镜和宏观世界是一个 最终目标。纳米颗粒的最新进展产生了具有可调整特性的生物医学工具 克服与传统的被动/基于扩散相关的障碍方面的出色力量 诊断和治疗药物。但是，常规的纳米颗粒本质上是多分散的，并且 因此，通常缺乏可靠量化所需的精度和统一性和 生物医学研究的可重复性，以及将来扩大和长期存储的质量控制 申请。富勒烯是NM大小的分子，可以将其大小和形状作为刚性多价核心 像无机颗粒一样，并允许有机反应通过鲁棒引入生物学特性和功能 C-C共价键。在我们的小组中，我们利用富勒烯C60的特征性六角形作为核心脚手架 和模块化平台，以开发一系列具有理想表面功能的精度“分子纳米颗粒”， 多价和大小，用于新型磁共振成像和荧光成像问题。我们的工作 包括四个在概念上独立但技术协同的研究主题。 在第一个主题中，MRI问题具有多价靶向癌细胞的问题，我们将建立在最近的基础上 开发的“ metallobuckytrio”（MBT），以开发具有GD的内膜的精确分子纳米颗粒 用于下一代MRI对比剂的金属氟烷和生化配体。这些MRI问题会检查 未来MRI问题中的所有“愿望清单项目”：GD重金属安全性，高松弛度，结构性精度和 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染料扩增RNA信号，以促进 低丰度RNA分子的检测和数量。在第三个主题中，信号放大和 实时细胞成像和SMFRET成像的抗氧化问题，我们将利用抗氧化特性和 六链甲成富勒烯纳米颗粒的多价，加载有机染料，以发展 耐光彩和信号扩增的成像问题。在第四个主题中，精确的比率计量学 纳米探针，我们将在准确的1：1比例中引入生物增强染料，并“始终使用”参考染料 共定位到抗氧化，多价富勒烯纳米颗粒上，以实现比例计量成像 传感和跟踪生物学事件。 这四个主题将结合我们的合成专业知识，将C60变成精确的分子纳米颗粒 理想的配体以及足智多谋的纳米颗粒和小分子研究图书馆，以嫁给精度 化学生物学中纳米颗粒的分子以及纳米颗粒的多重性和多重性。具有模块化的性质 在我们的合成平台上，我们预计所提出的技术将被更广泛的生物学采用 可以选择许多新的自下而上设计和配体的社区。