Research Project
9373531
Project Summary Traditional methods to deliver drugs to bones for the treatment of mineralization diseases, such as Osteoporosis, can also disrupt homeostasis in other tissues. To overcome this important problem it is critical to develop novel drug delivery methods that precisely deliver drugs exclusively to the bones. One novel method of drug delivery uses Carbon nanodots (C-dots), an emerging class of nanoparticles with high stability and excellent biocompatibility. Our work in zebrafish has identified a particular class of C-dots that bind with high affinity and specificity to larval and adult bones, without binding to other tissues. Based on this and additional preliminary evidence, here we seek to develop C-dots as a novel method for the precise delivery of drugs exclusively to bones. By systematically defining the chemical properties of C-dots that are essential for bone binding and drug delivery, we will determine the mechanism of C-dot's binding specificity and affinity to bones, while developing a novel and versatile set of carriers for delivering drugs precisely to bones. As proof of principle that C-dots can be used as novel therapeutic drug delivery system, we are targeting the Retinoic Acid signaling pathway involved in the homeostatic regulation of bone mineralization. Rare mutations in humans have identified Retinoic Acid as a key regulator of bone mineralization. These mutations, which can be faithfully recapitulated in the zebrafish, cause excessive Retinoic Acid accumulation, promote excessive osteocyte cell differentiation, and trigger bone fusions. Thus, recruiting the Retinoic Acid signaling pathway to regulate osteocyte production represents a novel and largely unexplored approach to regulating bone mineralization for disease treatment. We are combining our expertise in carbon-based material chemistry and Retinoic Acid signaling in zebrafish to determine the mechanisms of C-dots binding to bones, and improve their efficiency as a bone-specific drug delivery system. The aims of this project are: 1) to determine C-dots' range of function as bone-specific, drug delivery agents; by loading C-dots with a variety of Retinoic Acid activator and inhibitor drugs and measuring changes in osteocyte cell differentiation and bone mineralization in developing, mature, and regenerating bones; 2) to increase the repertoire of drugs that C-dots can deliver to bones; by chemically changing the linkers and functional groups on the C-dots surface and testing their activity in our osteocyte cell differentiation and bone mineralization paradigm. The development of C-dots as tools for the study and precise treatment of bone mineralization diseases will help increase our understanding of the function of cell signaling in promoting and preventing osteocyte differentiation. By expanding the repertoire of drugs that C-dots can carry, this novel drug-delivery platform will also allow, in future work, to target other processes altering bone homeostasis, including cancer. Thus, cellular and molecular data emerging from the use of C-dot-based reagents will lead to new biological insights and the development of innovative bone therapies.
