Multifunctional methionine based materials for therapeutic use

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Technical: There is a need for polymeric drug carriers that can be prepared using a versatile method that allows fine tuning of chemical composition and structure, and use building blocks that are biocompatible and easily functionalized. The goal of this project is to develop and study multifunctional amphiphilic block copolypeptides containing modified poly(L-methionine) segments, MMOD, that can be assembled into vehicles for intracellular drug delivery. Recent synthetic advances in this lab now allow the development of entirely new polypeptide amphiphiles utilizing MMOD domains that are designed so that individual segments can play unprecedented multiple functional roles in the resulting nanocarrier assemblies. This innovative approach provides a new method for introducing functionality into polymeric nanocarriers and will develop and test a new class of methionine based biomaterials. The incorporation of methionine segments and their subsequent modification is a straightforward, scalable process, and allows unprecedented control in the ability to add complex functionality and biological activity to polypeptides. Some MMOD residues also occur naturally in biological systems and these will be used strategically to promote release of therapeutics, and may also provide other therapeutic benefits. The MMOD segments will be utilized as new, functional hydrophilic domains capable of providing multiple combinations of solubility, biocompatibility, therapeutic binding, cell uptake, enzyme-response, pH response, and chemoselective bioconjugation. Specifically, the project will design, prepare, and characterize vesicle forming block copolypeptides containing MMOD segments as carriers for therapeutics with low cytotoxicity and capability for cell uptake, endosomal release and intracellular carrier disruption. In addition, it will test the capabilities of these carriers using in vitro cell culture and trafficking studies. The knowledge gained from these studies will allow fine tuning of carrier properties for downstream specific uses in encapsulation and delivery of drugs, and will lay groundwork for development of a new class of functional biomaterials for medical applications.Non-Technical: In this project, the PIs will continue their successful inclusion of underrepresented groups, teaching and training of graduate and undergraduate students, and dissemination of their research findings in publications and presentations. Some examples of these efforts from the previous grant period are: development and improvement of bioengineering courses incorporating concepts from the project such as intracellular trafficking and bioconjugation methods; recruitment of a Hispanic female student (Ph.D. granted in March 2013) and an African American female student for this project (1st year); PI and student presentations of research results at national and local meetings (ACS, BMES, MRS, Society for Advancement of Hispanics, Chicanos, and Native Americans in Science (SACNAS) national meeting); and presentations incorporating this research by the PI to encourage students to pursue careers in science (2010 UCSB Summer School on materials synthesis; 2011 NAE Grand Challenges Summit for graduate students; 2012 International Young Scientist Symposium, Bordeaux, France). Professor Kamei has also made annual visits to elementary and high schools in East Los Angeles (one is 90% Hispanic) to inspire youth in this system to become scientists and engineers. Ph.D. students trained under this program are valuable in the industrial job force (both pharmaceutical and materials science areas) since they will learn fundamentals of polymer synthesis using catalysis and self-assembly, cell culture and drug trafficking, as well as more applied areas of materials characterization and property evaluation. These undergraduate students have also done well by being admitted into prestigious Ph.D. (Washington, MIT, UCSB) and MD (Cornell, Texas A&M) programs, and obtaining NSF graduate fellowships.