Engineering Effector Protein Nanoclusters for Breast Cancer Therapy

ID: MPS/DMR/BMAT(7623) 1105248 PI：冠军，朱莉ORG：乔治亚州技术标题：工程效应蛋白纳米簇乳腺癌治疗知识优点：一组选定的细菌病原体在感染期间分泌称为效应蛋白的蛋白质，使它们能够在敌对宿主中生存和生长。其中一些效应物有能力干扰乳腺癌中改变的相同途径。这项提议的目标是利用这些效应蛋白作为新的乳腺癌治疗方法。为了将这些蛋白质用作抗癌药物，正常的细菌传递机制必须被一种能够向乳腺癌细胞传递生物活性蛋白质的药物传递系统所取代。为了实现这一目标，效应蛋白将被连接在一起，形成纳米级的簇，这些簇可以进入乳腺癌细胞，然后分解，让单个蛋白在细胞内发挥作用。这项工作将制造效应纳米团簇，并评估其恢复乳腺癌细胞正常行为的能力，如增加凋亡细胞死亡，减少增殖，减少转移，或增加对化疗药物的敏感性。为了实现这一目标，已经建立了四个技术目标：(1)鉴定具有治疗潜力的候选效应蛋白。(2)通过控制分解和释放效应蛋白来制备效应纳米团簇。(3)评估纳米簇传递效率及其对乳腺癌细胞系的治疗作用。(4)通过测量巨噬细胞对纳米簇的摄取和细胞因子的激活来评估免疫潜能。这些目标的结果将确定使用细菌蛋白作为乳腺癌药物的可行性，以及将这些分子输送到乳腺癌细胞并取得积极治疗效果的能力。这里描述的纳米团簇是一种独特的组合，可以保护蛋白质，并比传统的聚合物药物纳米颗粒增加递送负荷。结果是一种新型的蛋白质治疗药物，模仿自然，既可以作为生物活性剂，又可以作为传递载体，集所有功能于一体，用于治疗乳腺癌。更广泛的影响：鉴于乳腺癌是美国女性中最常见的癌症，也是癌症死亡的第二大原因，许多人可以从效应纳米簇的发展中受益。这项工作验证了将细菌蛋白用于治疗应用的想法，并且该概念可以扩展到其他疾病的各种药物开发和递送需求。除了预期的科学成果之外，该项目还计划了各种活动，以教育非工程师以及在化学工程领域征聘和留住妇女。这项提案将支持一名少数族裔女性研究生。PI将积极指导该学生，鼓励她继续从事工程事业，并为下一代潜在的女工程师树立榜样。她还积极参与佐治亚理工学院（GT）的女性工程项目，并将参加“介绍女孩参加工程日”等推广项目。这些项目针对的是亚特兰大地区的初中和高中女生。目的是通过与女性工程师（如PI）的互动，让他们对化学工程师所从事的重要项目感到兴奋和兴趣。除了科学出版物和演讲外，这项提案的结果将通过归校癌症研究小组与GT校友分享，并在GT科学喜剧广播节目“黑盒子里面”中与所有亚特兰大人分享。

ID: MPS/DMR/BMAT(7623) 1105248 PI: Champion, Julie ORG: Georgia TechTitle: Engineering Effector Protein Nanoclusters for Breast Cancer TherapyINTELLECTUAL MERIT: A select group of bacterial pathogens secrete proteins called effectors during infection, which enable them to survive and grow in a hostile host. Some of these effectors have the capability to interfere with the same pathways that are altered in breast cancer. The goal of this proposal is to use these effector proteins as novel breast cancer therapies. In order for these proteins to be used as anticancer drugs, the normal bacterial delivery mechanisms must be replaced by a drug delivery system able to deliver biologically active protein to breast cancer cells. To achieve this, the effector proteins will be linked together into nano-sized clusters that can enter breast cancer cells and then fall apart to allow the individual proteins to act inside the cells. The proposed work will fabricate effector nanoclusters and assess their ability to restore normal behaviors in breast cancer cells, such as increased apoptotic cell death, decreased proliferation, decreased metastasis, or increased sensitivity to chemotherapeutics. Four technical objectives have been established to achieve this goal: (1) Identify candidate effector proteins with therapeutic potential. (2) Fabricate effector nanoclusters with controlled disassembly and effector protein release. (3) Assess nanocluster delivery efficiency and therapeutic effects on breast cancer cell lines. (4) Assess immunologic potential by measurement of nanocluster uptake and cytokine activation by macrophages. The results of these objectives will establish the feasibility of using bacterial proteins as breast cancer drugs and the capability to deliver these molecules to breast cancer cells with positive therapeutic outcomes. The nanoclusters described here are unique assemblies that protect proteins and increase delivery load over traditional polymer-drug nanoparticles. The result is a new type of protein therapeutic, mimicked from nature, which serves as both the bioactive agent and delivery vehicle, all in one, for the treatment of breast cancer.BROADER IMPACTS: Given that breast cancer is the most common cancer in U.S. women and the 2nd leading cause of cancer death, many people could benefit from the development of effector nanoclusters. This work validates the idea of using bacterial proteins for therapeutic applications and the concept can be expanded for a variety of drug development and delivery needs for other diseases. Beyond the anticipated scientific results, the PI has planned a variety of activities to educate non-engineers as well as to recruit and retain women in chemical engineering. This proposal will support one female under-represented minority graduate student. The PI will actively mentor this student to encourage her to continue her career in engineering and serve as a role model for the next generation of potential female engineers. The PI is also active in the Women in Engineering program at Georgia Tech (GT), and she will participate in outreach programs such as "Introduce a Girl to Engineering Day." These programs are aimed at Atlanta-area middle and high school girls. The objective is to get them excited and interested in the important projects that chemical engineers work on through interactions with women engineers such as the PI. In addition to scientific publications and presentations, results from this proposal will be shared with GT alumni through a homecoming cancer research panel and with all Atlantans on the GT science-comedy radio show "Inside the Black Box."