ABSTRACT

Proposal: 1554508
PI: Nguyen, Hung D.

Dynamic nanomaterials that can change their shape and structure in response to environmental stimuli hold promise to revolutionize medicine and biotechnology. However, the current discovery process of such smart materials is slow and often serendipitous due to the enormously large design space and lack of systematic knowledge as well as predictive models. Indeed, a quantitative understanding of their self-assembly and disassembly processes, and how the solution condition and chemical structure govern their morphological transition, has remained elusive. To tackle these challenges and harness the full potential of smart materials, the PIs will build an integrated platform of computer-aided design using peptide-polymer conjugates by performing molecular simulations in collaboration with experimentalists in facilitating rapid development of novel stimuli-responsive nanomaterials for different biomedical applications in cancer and gene therapy. The proposed research will provide timely and invaluable tools and knowledge to move the community towards expedited discovery of smart materials that help improve lives. Specifically, the valuable insights gained from the simulation studies could lead to the development of a cancer-specific diagnostic agent and targeted gene delivery system.

The specific objectives of the proposed CAREER research program are: 1) elucidate the sequence-structure-property relationships in solution for de novo design of PEG-conjugated peptide amphiphiles as delivery vehicles of drugs or bioimaging agents; 2) examine the crowding effects of the blood serum and in vivo conditions on stimuli-responsive self-assembly by peptide amphiphiles; 3) understand the relationship between peptide-polymer conjugate sequence and structure of siRNA complexes and mechanisms of siRNA complexation by different conjugates for gene delivery; and 4) investigate the mechanisms of intracellular trafficking of siRNA complexes and siRNA disassembly by peptide-polymer conjugates. By integrating multi-scale modeling techniques, the proposed platform will innovate and accelerate the materials discovery process in two transformative ways. First, the development of new models and simulations tools will push the boundary of multi-scale modeling and pave the way for computer-aided design of novel biomaterials. Second, the integrated in silico and in vitro and in vivo studies of sequence-structure-properties relationships and assembly/disassembly processes will generate novel, systematic knowledge that will be applied to design novel stimuli-responsive delivery vehicles for improved pharmaco-kinetic properties.

To broaden the impact of the planned research, the PI will integrate research into the undergraduate curricula by developing a new course on biomaterial design and offering research opportunities for undergraduate students. Furthermore, the PI will launch a summer research program for high school students to perform simple simulations in his laboratory for one week and will play an active role in training middle and high school teachers to integrate engineering concepts and hands-on experiential learning methodologies into their science curriculum.

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