Engineering and intracellular delivery of recombinant antibodies

AbstractsNontechnical Abstract：抗体被用作进行生物学研究的关键工具，并被用作癌症、关节炎和其他疾病的治疗剂。虽然抗体可以被设计成精确地靶向几乎任何生物过程，但它们不能进入细胞内部，这限制了它们的应用。将抗体引入细胞的一般策略将使许多关于细胞功能的新研究成为可能，也将使新疗法得以开发。该提案将研究关键因素，这些因素将使抗体能够使用基于称为纳米颗粒的非常小的颗粒的药物递送策略引入细胞。由于抗体具有大量的共同特征，该项目的具体工作预计将直接导致非常广泛的应用，以了解细胞如何工作，以及从长远来看，如何靶向导致疾病发生和进展的过程。该项目将支持塔夫茨大学研究生和本科生的严格研究培训。此外，一个扩大的夏季研究计划将提供机会，介绍地区高中生在现代生物技术产业的关键概念，当地经济的快速增长的一部分。技术摘要：抗体是生物研究中使用的关键工具，可以被设计成精确地干扰个别信号事件，但由于持续的交付挑战，抗体的细胞内应用仍然有限。该项目将建立一种细胞内递送抗体的总体策略，最终目标是癌症和其他疾病的靶向治疗。为了实现这种方法，在该提案中进行的具体工作将能够阐明决定有效抗体纳米颗粒制剂、细胞内递送和干扰细胞信号传导的分子特征。由于抗体可以被工程化以破坏几乎任何感兴趣的过程，因此该项目将促进建立用于干扰细胞内过程的一般策略，而不需要对靶细胞进行遗传修饰。用于细胞内抗体递送的稳健策略具有使得能够快速探索多种疾病中的治疗靶标的潜力，包括传统上被视为“不可用药”的那些靶标。 拟议的工作将培养本科生和研究生在蛋白质工程和纳米生物技术领域进行严格的科学研究。此外，本发明还提供了一种方法，扩大现有的夏季研究计划，包括为期三周的塔夫茨蛋白质工程和纳米医学夏令营（TUSC-PEN）该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响进行评估来支持审查标准。

AbstractsNontechnical Abstract:Antibodies are used as key tools for conducting biological research and are used as therapeutics for cancer, arthritis, and other conditions. While antibodies can be engineered to precisely target nearly any biological process, they cannot access the insides of cells, limiting their applications. A general strategy for introducing antibodies into cells would enable many new studies of how cells function and would also enable new therapies to be developed. This proposal will examine the key factors that will enable the introduction of antibodies into cells using a drug delivery strategy based on very small particles called nanoparticles. Because antibodies share a large number of common features, the specific work of this project is anticipated to lead directly to very broad applications in understanding how cells work and, in the long term, how to target processes that lead to disease initiation and progression. This project will support rigorous research training for graduate and undergraduate students at Tufts University. In addition, an expanded summer research program will provide opportunities for introducing area high school students to key concepts in the modern biotechnology industry, a rapidly growing portion of the local economy.Technical Abstract:Antibodies are key tools used in biological research that can be engineered to precisely interfere with individual signaling events, but intracellular applications of antibodies remain limited because of ongoing delivery challenges. This project will establish a general strategy for delivering antibodies intracellularly with the ultimate goal of targeted therapies for cancer and other diseases. To realize this approach, specific work to be conducted in this proposal will enable the elucidation of the molecular features that dictate effective antibody nanoparticle formulation, intracellular delivery, and interference with cell signaling. Because antibodies can be engineered to disrupt virtually any process of interest, this project will facilitate the establishment of general strategies for interfering with intracellular processes without the need for genetically modifying target cells. Robust strategies for intracellular antibody delivery have the potential to enable rapid exploration of therapeutic targets in a variety of diseases, including those targets traditionally viewed as "undruggable". The proposed work will train undergraduate, and graduate students in conducting rigorous scientific research in the areas of protein engineering and nanobiotechnology. In addition, expanding an existing summer research program to include a three-week Tufts Summer Camp for Protein Engineering and Nanomedicine (TUSC-PEN) will provide opportunities for introducing area high school students to key concepts in crucially important areas of the modern biotechnology industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.