This project will continue work on the use of controlled radical polymerizations to synthesize well-defined protein-polymer conjugates. Many proteins exist as multimers in the active state, yet most conjugates contain only one protein due to the lack of high yielding, efficient synthetic strategies to make the polymers. In this research, a straightforward method to synthesize biocompatible polymers with protein-reactive groups at one or both ends will be developed. The polymers will then be applied to produce conjugates of a growth factor that is critical in wound healing. Because this growth factor exists as a dimer in the active state, the growth factor conjugate is expected to be more bioactive. Conjugates containing polymers that mimic polysaccharides in the body will also be prepared to form growth factors resistant to denaturation upon application and storage.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Heather D. Maynard of the Department of Chemistry and Biochemistry at the University of California, Los Angeles. Professor Maynard's research focuses on the synthesis of well-defined multimeric protein-polymer conjugates by controlled radical polymerizations. This work will contribute to the synthesis of active and stable conjugates for therapeutic applications. Successful development of the methodology will have an impact on the polymer, biomedical and materials communities.
Proteins control and regulate a lot of the processes that go on in the human body. As a result, proteins have been used as therapeutics for specific diseases, for example to replace a natural protein that is not functioning properly. A well-known example is insulin, which is used by people with diabetes to help regulate blood sugar levels. However, one of the difficulties with proteins is that they rapidly degrade in the body. It is known that if a polymer chain (a plastic) is attached to the protein, it can enhance the lifetime of proteins. In this report synthetic methods to make new polymers that can be attached to these proteins were created. The research was applied to an important protein that is critical in wound healing, cardiac protection, and bone repair. It was shown that polymers made by the synthetic methods that were developed could be used to stabilize this particular protein, when attached to it. The protein is otherwise easily destroyed during shipping or handling. This result is important, because it could allow the protein to be more easily transported and stored, thus reducing costs of shipping and handling. Many proteins come together (i.e. there are more than one protein) in order to be active. It is also known that by attaching two or more proteins to a single polymer chain, the activity can be much greater than having a single protein. This funding was used to develop synthetic methods to create polymers that can bring together two or more proteins. The syntheses are easy to carry out and allow people to make many different types of polymers for this purpose. A unique way to characterize these so-called protein-polymer conjugates, in order to accurately determine the number of proteins attached, was created. In addition, a systematic investigation of the toxicity of the polymers prepared via the synthetic methods was carried out. This was done in order to be able to compare and contrast the synthetic methods that were used in order to determine which ones lead to non-toxic polymers. The study also was used to determine how to best purify the materials. This research provided an excellent training ground for students. Two undergraduate students, eight graduate students and three postdoctoral researchers worked on this project. Both undergraduates went on to graduate school. Four of the graduate students already received their PhD or MS degrees. All finishing students and postdoctoral researchers received jobs in academics or industry. In addition, close to 50% of the people trained are female and 23% are underrepresented minorities. Thus, this research contributed significantly to human resources in the field, particularly to underrepresented groups. Finally, this work was discussed in many different public venues for non-scientists, K-12 students, and minorities, providing a broader impact for the work.
