BRIGE: Reprogramming tumor associated macrophages: Engineering polymer surface properties to discriminately deliver drugs

巨噬细胞可以被经典激活，也可以被选择性地产生促炎分子或促血管生成分子。肿瘤相关巨噬细胞（tam）是促进肿瘤生长的选择性活化细胞。tam可以通过药物传递到经典活化的巨噬细胞中，从而杀死肿瘤细胞。选择性给药是一种非常有吸引力的癌症治疗方法，其中选择性活化的巨噬细胞可以被修复以破坏恶性细胞。因此，我们的长期目标是为tam提供有区别的药物，促进肿瘤消退。该提案的目标是确定哪些表面特性允许选择性靶向选择性活化的巨噬细胞，这是我们追求这一目标的下一步。这一建议的理论是，通过工程微粒组成可以实现对tam的歧视性靶向，这样在选择性活化的巨噬细胞中优先增强吞噬作用。提出这项研究的基本原理是，一旦知道了哪些材料参数会影响选择性活化巨噬细胞的选择性吞噬，就会发现设计抗癌疗法的新的创新策略。这一假设将通过以下目的进行验证：1)确定哪些微粒特性导致体内选择性吞噬的促进；2)设计聚合物系统，以确定选择性地向tam输送重编程药物的最佳条件。拟议的研究有望有助于深入了解如何最好地设计药物输送载体，使tam被重新编程以破坏癌细胞。这项工作将产生关于聚合物参数和颗粒结构增加巨噬细胞药物递送的信息。这一贡献意义重大，因为它有望通过利用聚合物特性和颗粒组成来区分靶向tam，从而产生对肿瘤有毒的分子，从而彻底改变抗癌药物的输送。更广泛的影响开发新的抗癌疗法将对癌症患者产生巨大的影响。此外，这项研究有望提高有关如何最好地设计药物递送载体以靶向选择性活化的巨噬细胞的知识。这有可能对心血管疾病患者、抗逆转录病毒治疗患者和自身免疫性疾病患者产生积极影响。这项研究和其中包含的目标是理想的积极参与学生-从高中到研究生-在实验室。通过与科学与工程女性项目（PWSE）的合作，高中女生将被引入这项研究。此外，通过PWSE计划，目前正在从事该项目的本科生已被招募。我们生活在一个无线世界，其中大量的通信都是数字化的。为了充分利用这个现代世界，在这个建议中所做的研究，以及从文献中获得的知识，将被结合起来形成一个iPad/iPhone应用程序。这个应用程序将传播通过这项研究收集到的知识给所有类型的学生，对于那些在这些类型的课程和专业人士不容易获得的国家/世界地区的学生来说，可能特别有影响力。

PI: Bratlie, KaitlinProposal Number: 1227867Intellectual MeritMacrophages 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 selectivephagocytosis 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 ImpactsDeveloping 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.