Design of RNA-triggered Disassembly Mechanisms in Multi-responsive Polymer Nanocapsules for Personalized Physiological Profiling and Tailored Therapeutics

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Nontechnical:This award will develop new methods to identify specific genetic profiles in diseased tissues and subsequently release "personalized" drug cocktails or diagnostic molecules only within the targeted tissues. One way to locate and treat diseased tissues is by injecting drug-containing nanoparticles that will circulate through the body until they come into contact with diseased cells. Nanoparticles can be designed to fall apart inside of cells and release encapsulated drugs; however, to protect healthy cells from receiving the drug, it is necessary to design nanoparticles that only fall apart in diseased cells. This research will design and produce polymer nanoparticles linked together by DNA "duplexes" whose sequences are partially complementary. The duplexes will be designed to unbind only in the presence of a fully complementary strand of DNA or RNA, leading to the disassembly of the nanoparticles and the release of any encapsulated compounds. The PIs will produce DNA-linked nanoparticles designed to disassemble in the presence of breast cancer-specific RNA molecules, and will test whether these nanoparticles will selectively release model drugs (dyes) only within cancer cells. Educational efforts, internships and workshops are aimed at increasing participation and enrollment of underrepresented students in research activities at the University of Delaware.Technical:This research addresses the National Academy of Engineering's Grand Challenge to engineer better medicines by developing new approaches that will ultimately allow rapid assessment of the genetic profiles in patients and the release of personalized drug cocktails. The PIs approach is to incorporate DNA "strand displacement" biosensing designs within polymer nanocarriers such that the DNA interface controls nanocarrier stability. Recognition of specific RNA or DNA sequences will result in a strand displacement reaction that destabilizes the nanocarrier and allows the release of encapsulated drugs or diagnostics. The major milestones in this work include the design of DNA strand displacement designs sensitive to breast cancer-specific RNAs; incorporation of these DNA duplexes within block polymer micelles; establishment of the specificity and efficacy of RNA-mediated nanocarrier disassembly; addition of cancer cell-targeting peptides on the surface of the nanocarriers; and establishment of selective cellular uptake and efficient cargo (dye) release in breast cancer cells. Educational activities will include high school internships, graduate recruitment workshops, and mentoring efforts targeted at underrepresented groups, facilitated through the PIs involvement in programs including ACS SEED, SWE, Women in Engineering, and the ACS Scholars Program.