INTELLECTUAL MERIT: A select group of bacterial pathogens secrete proteins called effectors during infection, which enable them to survive and grow in a hostile host. Some of these effectors have the capability to interfere with the same pathways that are altered in breast cancer. The goal of this proposal is to use these effector proteins as novel breast cancer therapies. In order for these proteins to be used as anticancer drugs, the normal bacterial delivery mechanisms must be replaced by a drug delivery system able to deliver biologically active protein to breast cancer cells. To achieve this, the effector proteins will be linked together into nano-sized clusters that can enter breast cancer cells and then fall apart to allow the individual proteins to act inside the cells. The proposed work will fabricate effector nanoclusters and assess their ability to restore normal behaviors in breast cancer cells, such as increased apoptotic cell death, decreased proliferation, decreased metastasis, or increased sensitivity to chemotherapeutics. Four technical objectives have been established to achieve this goal: (1) Identify candidate effector proteins with therapeutic potential. (2) Fabricate effector nanoclusters with controlled disassembly and effector protein release. (3) Assess nanocluster delivery efficiency and therapeutic effects on breast cancer cell lines. (4) Assess immunologic potential by measurement of nanocluster uptake and cytokine activation by macrophages. The results of these objectives will establish the feasibility of using bacterial proteins as breast cancer drugs and the capability to deliver these molecules to breast cancer cells with positive therapeutic outcomes. The nanoclusters described here are unique assemblies that protect proteins and increase delivery load over traditional polymer-drug nanoparticles. The result is a new type of protein therapeutic, mimicked from nature, which serves as both the bioactive agent and delivery vehicle, all in one, for the treatment of breast cancer.
BROADER IMPACTS: Given that breast cancer is the most common cancer in U.S. women and the 2nd leading cause of cancer death, many people could benefit from the development of effector nanoclusters. This work validates the idea of using bacterial proteins for therapeutic applications and the concept can be expanded for a variety of drug development and delivery needs for other diseases. Beyond the anticipated scientific results, the PI has planned a variety of activities to educate non-engineers as well as to recruit and retain women in chemical engineering. This proposal will support one female under-represented minority graduate student. The PI will actively mentor this student to encourage her to continue her career in engineering and serve as a role model for the next generation of potential female engineers. The PI is also active in the Women in Engineering program at Georgia Tech (GT), and she will participate in outreach programs such as "Introduce a Girl to Engineering Day." These programs are aimed at Atlanta-area middle and high school girls. The objective is to get them excited and interested in the important projects that chemical engineers work on through interactions with women engineers such as the PI. In addition to scientific publications and presentations, results from this proposal will be shared with GT alumni through a homecoming cancer research panel and with all Atlantans on the GT science-comedy radio show "Inside the Black Box."