A Fullerene-based Molecular Route towards Designer Nanoparticles - 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.
