Controlling Protein Release via Intermolecular Hybridization

0967512

Wang

Protein drugs hold great promise for the treatment of various human diseases. However, efficient and safe delivery of protein drugs is a long-standing challenge in the field of drug delivery. Many protein delivery systems still suffer from problems including the rapid release of protein drugs, the inefficiency of controlling the release of multiple proteins, and the involvement of toxic molecules and/or harsh conditions during the preparation of protein delivery systems. This project is proposed to address these issues.

Intellectual merits:

The objectives of the proposed research are to thoroughly understand the mechanisms of complementary oligonucleotide-mediated protein-aptamer dissociation, and based on this understanding, to develop a novel protein delivery method using nucleic acid aptamers, complementary oligonucleotides, and alginate hydrogels. Our novel hypotheses are: 1) aptamers can efficiently entrap one or multiple proteins in the alginate matrix because of their high binding affinity and specificity; 2) complementary oligonucleotides can be used as a molecular trigger to modulate protein release via hybridization with the aptamers; and 3) proteins can maintain a high level of bioactivity due to the mild procedure for hydrogel preparation and the protection by the aptamers. To test these hypotheses, preliminary studies have been carried out, showing that complementary oligonucleotides are capable of accelerating protein-aptamer dissociation. Encouraged by the compelling preliminary results, we will perform three tasks involving both experiments and mathematical modeling. The tasks are: 1) to investigate complementary oligonucleotide-mediated protein-aptamer dissociation, 2) to investigate the release of proteins from hydrogels in the presence or absence of complementary oligonucleotides, and 3) to develop a mathematical model to simulate the protein release process. We anticipate the outcomes of this study will be a deeper understanding of molecular recognition and a transformative method for protein delivery.

Broader impacts:

The success of the proposed research will make several broad scientific and economical impacts. First, it will open a new avenue for the development of drug delivery systems. Second, it will enrich the knowledge of molecular recognition and provide valuable information for nucleic acid research. Third, the success of protein delivery will tremendously improve the treatments of various human diseases and save billions of dollars in healthcare costs. The broader impacts of this program will also be evident in our strong commitment to education and human resource development, which will have direct impacts on graduate, undergraduate, and K-12 students. First, this project will provide students with a unique intellectual environment to learn drug delivery, hydrogel synthesis, biomolecular engineering, kinetic analysis, cell characterization, and mathematical modeling. All participating students will

have modularized scientific questions to study and will discuss their research findings in regular group meetings. The students will be able to not only acquire hands-on research skills, but also learn analytical, communication, collaboration, and innovation skills. In addition, the PI will incorporate the results acquired from the proposed research into the Drug Delivery course that

is offered to both graduate and senior undergraduate students every spring semester. Second, we will initiate a new outreach program by collaborating with local high schools to teach the concepts of biomedical engineering in the Advanced Biology course. The results acquired by the participating students will be presented to high school students during the visits. In addition,

we will continuously participate in the established outreach programs at UConn. These outreach efforts will raise high school students' interests in science and engineering and facilitate the development of a viable, sustainable science and engineering workforce. Third, the students' research findings will be widely disseminated through publications in peer-refereed journals and presentations at national/international conferences.