Macrophages can be activated classically or alternatively to produce pro-inflammatory or pro-angiogenic molecules, respectively. Tumor associated macrophages (TAMs) are alternatively activated cells that promote tumor growth. TAMs can be reprogrammed through drug delivery to classically activated macrophages, which kill neoplastic cells. Discriminatory drug delivery to TAMs presents a very attractive cancer therapeutic in which alternatively activated macrophages could be reconditioned to destroy malignant cells. Therefore, our long term goal is to deliver drugs discriminately to TAMs that will promote tumor regression. The objective of this proposal, which is the out next step in pursuit of that goal, is to determine what surface properties allow for selective targeting to alternatively activated macrophages. This proposal theorizes that discriminatory targeting to TAMs can be achieved through engineering microparticle compositions such that phagocytosis is preferentially enhanced in alternatively activated macrophages. The rationale for the proposed research is that, once it is known what material parameters influence selective phagocytosis in alternatively activated macrophages, new and innovative strategies for designing anti-cancer therapeutics will be uncovered. This hypothesis will be tested through the following aims: 1) Determine what microparticle properties result in the facilitation of selective phagocytosis in vivo; 2) Engineer polymeric systems to determine the best conditions for selectively delivering reprogramming drugs to TAMs. The proposed research is expected to contribute in-depth understanding of how best to engineer the drug delivery vehicle such that TAMs are reprogrammed to destroy cancerous cells. This work will generate information on what polymer parameters and particle configurations augment drug delivery to macrophages. This contribution is significant, because it is expected to revolutionize anti-cancer drug delivery through exploiting polymer properties and particle compositions to discriminately target TAMs, such that they produce molecules that are toxic to tumors.
Broader Impacts Developing novel anti-cancer therapeutics will have a tremendous impact on cancer patients. In addition, this research is expected to be able to improve knowledge pertaining to how to best engineer a drug delivery vehicle to target alternatively activated macrophages. This has the potential to positively impact people stricken with cardiovascular disease, people on antiretroviral therapy, and patients with autoimmune diseases. This research and the goals contained within are ideal for actively involving students - from high school to graduate students - in the lab. Through collaboration with the Program for Women in Science and Engineering (PWSE), high school girls will be introduced to this research. In addition, an undergraduate currently working on this project has been recruited through the PWSE program. We live in a wireless world in which large amount of communications are digital. To take full advantage of this modern world, the research done in this proposal, along with the knowledge obtained from the literature, will be combined to form an iPad/iPhone app. This app will disseminate the knowledge gleaned through this study to all types of students, and may be particularly impactful for students in areas of the country/world in which these sorts of classes and professionals are not readily available.