PROJECT SUMMARY Breast cancer is by far the most common type of cancer and is the second most deadly cancer in women. Breast cancer mammography screening programs for early detection are widespread. Mammography screening reduces mortality from breast cancer and is cost-effective. However, it has emerged that mammography is not very effective in women with dense breasts (about 10% of women), with sensitivity of 30- 60%. Moreover, independent of the lower chance of tumor detection, women with dense breasts are at a higher risk of breast cancer. Therefore to reduce mortality from breast cancer in this population, better screening techniques are needed. Dual-energy mammography has recently emerged as a technique that is highly sensitive and specific for detecting cancer in women with dense breasts. A contrast agent for dual-energy mammography that can identify tumors would be highly beneficial in women with dense breasts, as well as in selected high-risk populations. Currently available iodine-based contrast agents have poor pharmacokinetics, low tumor accumulation and are contraindicated in many patients. While other techniques such as contrast-enhanced MRI can be used for screening women with dense breasts, the high costs and practical obstacles prevent the use of those techniques. We herein propose to develop novel, biodegradable silver-based nanoparticles (SBNP) to allow safe detection of tumors in patients at higher risk of breast cancer. We have found that silver is an element that produces excellent contrast in dual-energy mammography a new variation of mammography where two images are acquired at different x-ray energies. We have found methods that make the nanoparticles stable and biocompatible. We have chosen a comparatively simple, yet flexible nanoparticle design in order to improve the likelihood of translation. The nanoparticles should quickly accumulate in tumors, rendering them conspicuous on mammography, before gradually breaking down into their components for renal excretion. This proposal addresses a key challenge in the use of nanoparticles in cancer: excretion. As part of this proposal we will develop a biodegradable carrier system that can deliver small, highly hydrophilic nanoparticles to tumors, before breakdown and renal excretion. This carrier system could have a broad impact, since it could be applied to numerous different nanoparticle types and anti-cancer approaches.