Development of amine protecting group chemistry for long chain nucleic acids

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"Smart" drugs or drug delivery vehicles that can selectively deliver a target therapeutic to the exact site desired have attracted significant research interest over the last several years. However, no truly smart drug has yet to come to market due to a lack of available efficient delivery vehicles. One widely-investigated candidate for the creation of marketable, effective smart drug delivery vehicles are liposomes, nanoparticles comprised of self-assembled lipids that mimic natural cell membranes. However, liposomes have traditionally been plagued by poor control over size, low drug loading, poor long-term storage stability, and low delivery efficiency to their target(s). While other researchers have identified ingenious but incompatible solutions to these problems, our partner SP-Nanobiotech is the first to use DNA nanotechnology to overcome these challenges. Using DNA as an organizing scaffold, liposomes can be self-assembled with a pre-defined size, drug loading, and storage resilience using a combination of the directing DNA and lipid to single stranded (ss)DNA adducts. The key step to the success of this method is thus being able to form well-defined lipid-ssDNA adducts. This is, however, inherently challenging since as many as 100 competing amine groups may be present (aside from the terminal amine group targeted for modification) in the native ssDNA chains, requiring protection of the non-terminal amine groups that is unlikely to go to completion using conventional chemistries. To overcome this problem, we plan to leverage the Hoare lab's extensive experience in the synthesis and tailored modification of nanoscaled hydrogels called nanogels. We propose that nanogels can be used as physical protecting groups for the non-target amines on ssDNA, sterically blocking reactions with non-terminal amines while also avoiding costly and time-consuming protecting group chemistry. Successful completion of this project is expected to lead to a commercial product in the shorter term that SP-Nanobiotech could sell to other researchers (allowing the company to continue its growth) as well as take a key step forward to the longer-term design of truly smart drug delivery vehicles with the potential to significantly improve health outcomes.