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The Washington Research Foundation Fellowship

Fan Lee, Bioengineering - 2008-09 WRFF

Fan Lee. 2008 WRFF recipient.Growing up, I have always had an interest in science, more specifically, in what science can do for the human body. At the University of Washington, I had the opportunity to participate in a variety of research areas before finding my interest in the field of bioengineering. I was fascinated with the integration of engineering and medicine and the role of biotechnology in the medical field. In the summer of 2008, I was given an opportunity through a NIH fellowship to explore the clinical side of research. I spent my summer working with Dr. Corinna Palanca-Wessles at the Fred Hutchinson Cancer Research Center and shadowing her at the Oncology clinic at Harborview Medical Center. The excitement of being able to alternate between the forefront of research and the forefront of patient care helped me bridge the gap between the laboratory and the clinic. The close interrelationship between the two environments that was introduced to me by my mentor also gave me new perspectives on my goals for the future. In my current project, I hope to bring the engineering side of polymer design and synthesizes into the clinical setting by using it to delivery cancer therapeutics to tumor cells. In the future, I hope to be the person that is able to bridge that gap between research and clinical practice. I hope to be pursuing higher education through a MD/PhD program so that I can have a unique understanding and appreciation of both sides of the medical work and to be able to bring it together elegantly in daily practice.

Mentor: Patrick Stayton, Bioengineering and Corinna Palanca-Wessels, Medicine

Project Title: A Novel Design for a Tumor-Specific Polymer Carrier for Systemic Delivery of siRNA

Abstract: Cancer contributes to a large portion of mortality rates both in the US and many parts of the world. More than 25% of deaths in the US and 12% of death worldwide are attributed to cancer. However, new discoveries in the last decade on cellular and molecular pathways has improved the understanding of tumor cell growth mechanisms, leading to innovations in drug development that has extended survival rates and prolonged the quality of life for people around the world. The important discovery of the RNA interference pathway has lead to the development of a promising tool in cancer treatment:  siRNA to silence genes that contribute to tumor development. However, the application of siRNA therapeutics has been limited by cellular pathways that prevent cell penetration and cause enzymatic degradation of biomolecules. This project aims to design and synthesize a novel carrier system for siRNA therapeutics that consists of a tumor-specific targeting component and a pH-responsive membrane disruptive polymer component to protect the therapeutic from degradation and enhance uptake of the delivery system into the cell. Antibody targeting tumor-specific receptors will be attached to the polymer via streptavidin-biotin technology. The polymer will be synthesized using RAFT polymerization and biotinylated. This project explores methods to conjugate streptavidin to antibody and optimizes the method to biotinylate the polymer carrier. The end result will be an immunopolymer carrier system for siRNA that targets tumor cells through surface antigens and penetrates the cell via receptor-mediated endocytosis. Once synthesized and characterized, the delivery system will be tested in vitro to enhance cellular uptake of GAPD siRNA. The specificity of the tumor targeting will be analyzed using flow cytometry. The pathway of the polymer uptake will be verified using fluorescent microscopy, and the efficacy of gene knockdown by siRNA therapeutics will be evaluated using quantitative RT-PCR, Western Blot and cell viability tests. The results will be evaluated and the delivery system will be optimized to reduce cytotoxicity and enhance siRNA delivery.