Testing the therapeutic potential of carbon nanodots in bone mineralization diseases - 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.
