DESCRIPTION: Nanoparticles carrying dyes and drugs that can be targeted to a wide variety of cancers have shown great promise in the treatment of this disease. However, most if not all of the mouse models that test the effectiveness of nanoparticles in eradicating cancers take place in lean, young mice whereas the vast majority of humans that will develop cancers and thus potentially be treated with nanoparticle technologies will be obese and have additional metabolic imbalances. We hypothesize that the metabolic condition of cancer patients will play a crucial role in the effectiveness of chemotherapies that are delivered via nanoparticles. In fact, we have compelling preliminary data showing that excessive white adipose tissue (WAT) is a major sink for nanoparticles in obese mice. We have created a unique nanoparticle library that spans both the geometries and chemistries of previously successful nanoparticles that we propose to administer to prescient mouse models of human metabolic conditions with a main focus on 1) excessive WAT, 2) fatty/enlarged livers, 3) varying lipoprotein levels, 4) atherosclerosis, and 5) the first-ever combinations of metabolic conditions and oncogene mutations. The dynamic biodistribution of the nanoparticles - the main assay for future efficacy in treating cancers - wil be assessed using cutting edge organ imaging. Results generated from in vivo experiments will be confirmed in reductionist in vitro experiments for the purpose of fleshing out nanoparticle localization mechanisms at the cellular level. The overall approach differs from the standard model of synthesis of a single nanoparticle and administration to lean rodents, which tends to provide nanoparticle-specific insights in idealized physiological settings. Instead, the proposed fundamental methodologies eliminate dependence upon the success of a single nanoparticle and provide a general and novel gateway toward complete understanding of nanoparticle-patient interactions that will be elucidated in enough detail as to drastically improve nanoparticl efficacy for a plethora of targeting applications with a special focus on cancer.

PUBLIC HEALTH RELEVANCE: Nanoparticles have received much attention over the past twenty years because of their exciting potential to augment current treatments, especially in regards to drug and dye delivery for certain diseases such as cancer. However, most of the live animal work that tests the efficacy of nanoparticles occurs in mice that are lean and metabolically healthy. Since the vast majority of human patients that will potentially be administered nanoparticles will have non-ideal metabolisms, we are focused on determining how these metabolic states impact nanoparticle effectiveness. Such improvement of the delivery of dyes and drugs to identify and ultimately eradicate tumors is one of the major goals of the NIH.