Polycation Beacons for Multiscale and Multimodal Imaging of Nucleic Acid Delivery

ID: MPS/DMR/BMAT(7623) 1105895 PI: Reinecke, Theresa ORG: University of Minnesota

Title: Polycation Beacons for Multiscale and Multimodal Imaging of Nucleic Acid Delivery

INTELLECTUAL MERIT: The PI proposes to develop a novel family of twelve polycations that form nanoparticle complexes with nucleic acids that are nontoxic and effective at cellular entry, and to develop methods to track these nanoparticles via luminescence imaging (for intracellular trafficking on the nm/ìm scale) and magnetic resonance imaging (MRI, for bulk cell and tissue tracking/imaging on the ìm/mm scale). The specific objectives are: (1) To synthesize and characterize a novel family of twelve polymer structures that contain lanthanide chelates. The PI will systematically vary the following chemical properties of these polymer beacons: number of ethyleneamine groups, absence, presence, and size of the carbohydrates within the repeat unit, and polymer molecular weight. (2) To characterize water proton relaxivity, toxicity, and delivery efficiency for twelve polymer structures (chelated with Gd3+) and statistically compare the results to select three highly effective vehicles for delivery and imaging of pDNA and siRNA. (3) To examine the selected delivery beacons for pDNA and siRNA cellular trafficking via confocal microscopy (with the Eu3+ chelates) and MRI (with the Gd3+ chelates) in cultured cells to optimize the balance between imaging capability and delivery efficiency. (4) To establish an interactive mentoring and learning environment that successfully attracts undergraduate chemistry students to the McNair Scholars Program in an effort to unite teaching and scholarship with the excitement of performing interdisciplinary research and thus increase retention of disadvantaged students in the sciences.

BROADER IMPACTS: This research is critical to advance many areas in need of delivery beacons, such as studies involving gene and epigenetic function, cellular signaling, therapeutic development, and regenerative medicine. The work will pave the way for higher information content imaging for therapeutic tracking in the lab and in the clinic, as well as aid development of specific medical therapies involving cellular-based genetic delivery. Students involved in this interdisciplinary program will gain uniquely broad and deep experience in fields ranging from synthetic chemistry and polymer science to molecular biology and imaging. Training students at this interface of different fields is essential to foster creative and innovative developments in research, increase the skills of our future workforce, and keep our country at the forefront of technological advancement. Involvement of the co-PI in the McNair Scholars Program targets current undergraduate students from disadvantaged backgrounds at Virginia Tech and prepares them to earn an advanced degree via formal graduate school preparation courses and mentoring. This program is designed to encourage and prepare financially disadvantaged and first generation college students and those from groups currently underrepresented to enter graduate education programs, primarily at the PhD level. The results from this project will be disseminated widely to the general public by the PIs, graduate and undergraduate and students involved in this work through publications, conference presentations, the web, to promote the research, mentoring, and educational programs are presented here.