The proposed research plan describes the development of a microfluidic device to mimic the delivery of chemotherapeutics to tumors. The goal of the project is to develop a screen that can quickly identify drugs that are able to eliminate tumors and that will be successful in preclinical animal trials. The device will contain perfused three-dimensional tumor tissue and will be constructed using soft lithographic techniques. The research plan is comprised of four Aims: 1) use the tumor-tissue device to measure the diffusion, binding and cytotoxicity of anticancer drugs, 2) optimize drug dosage regimens, 3) measure the effect of liposome encapsulation, and 4) validate the device with a library of chemotherapeutic drugs. For these experiments, chemotherapeutic molecules will be administered to the tumor-tissue device, and time-lapse microscopy will be used to quantify concentration and cell viability as functions of time and positions. These measurements will be interpreted by a computational model that calculates rates of diffusion, cell binding and cytotoxicity. The predictive power of the device will be validated with a library of chemotherapeutic drugs that have dramatically different behaviors in cell culture and in xenograft tumors.
Intellectual merit The proposed research will change our understanding of why cancer drugs fail. Currently, drug screens focus on identifying compounds that kill cancer cells in culture and eliminate tumor in mice with minimal toxicity. The proposed research will show that cancer drugs also fail because of limited exposure of all cancer cells within tumors. Proposed experiments will show that the two mechanisms that control exposure are diffusion and cell binding. Counterintuitively, these mechanisms can both increase and decrease cellular exposure to drugs. The proposed research has intellectual merit because it will show that quantification of these mechanisms can be used to predict which drugs will pass and fail preclinical animal studies. These experiments will also show that if the causes of drug failure can be determined, the properties of a drug can be modified to improve its transport behavior.
Broader Impacts The proposed research will have significant impact on the scientific community and society. As a screen for experimental anticancer therapeutics the device will increase the number of potential drugs and decrease the time from discovery to clinical trials. Ultimately, an increase in successful drug would have a positive effect on cancer mortality. The proposed project will foster undergraduate participation in research by supporting a team of undergraduate researchers and REU students, and encouraging authorship in top journals. The project will also promote involvement of high school students from Amherst Regional High School, who will receive academic credit for their participation. These students will be exposed to bioengineering and medical research by participating in programs at UMass and at Baystate Medical Center. Involvement of women and underrepresented minorities will be encouraged at all levels with targeted recruiting of high school students, undergraduate researchers and graduate students. Graduates will be recruited as part of the Northeast Alliance for Graduate Education and the Professoriate (NEAGEP).
