Intracellular Processing of Cell-penetrating Oligothioetheramides

细胞穿透性低聚硫醚酰胺的细胞内加工

• 批准号: 1917285
• 负责人: Christopher Alabi
• 金额: $ 37.15万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1917285&HistoricalAwards=false
• 关键词: Intracellular; Processing; Cell; penetrating; Oligothioetheramides

Bacteria can develop resistance to antibiotics at alarming rates. This poses a significant threat to public health and national security. This threat is even worse with the increasing number of pathogens that can enter and colonize cells. Polymers can be useful in helping antibiotics enter these cells and attack the pathogens. This project will explore the mechanisms and rates of such antibiotic delivery. New concepts and models pertaining to these systems will be developed. Undergraduate and graduate students will be engaged in executing this project. High school students engaged in a 4-H Focus for Teens workshop will be trained to present a polymer science experimental module to their local 4-H clubs. These activities will stimulate the development of a highly productive and inclusive STEM workforce. Cell penetrating oligothioetheramides are a new class of non-charged, cell-penetrating macromolecules that rapidly enter cells across different cell lines in a highly diffuse pattern. This project will expand the understanding of how these macromolecular agents are processed within the cell by developing a kinetic model that directly measures intracellular bond cleavage. The intracellular degradation rate constant will be specific for each antibiotic prodrug and cell line. This information will be used to investigate how linker composition and antibiotic type influence the kinetics of intracellular antibiotic release and thus antibacterial activity. The database of kinetic parameters obtained will inform the decision process leading up to the choice of a cleavable bond for a particular polymer-drug conjugate. Furthermore, the kinetic parameters will also be of significant value to the scientists and engineers working on compartmental and physiological models for a variety of applications.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.

细菌能够以惊人的速度对抗生素产生耐药性。这对公共健康和国家安全构成重大威胁。随着可以进入并定植细胞的病原体数量不断增加，这种威胁变得更加严重。聚合物可以帮助抗生素进入这些细胞并攻击病原体。该项目将探索此类抗生素输送的机制和速率。将开发与这些系统相关的新概念和模型。本科生和研究生将参与执行该项目。参加 4-H Focus for Teens 研讨会的高中生将接受培训，向当地的 4-H 俱乐部展示聚合物科学实验模块。这些活动将刺激高生产力和包容性 STEM 劳动力的发展。细胞渗透性寡硫醚酰胺是一类新型不带电、细胞渗透性大分子，能够以高度扩散的模式快速进入不同细胞系的细胞。该项目将通过开发直接测量细胞内键断裂的动力学模型来扩展对这些大分子药物在细胞内如何加工的理解。细胞内降解速率常数对于每种抗生素前药和细胞系来说是特定的。该信息将用于研究连接体组成和抗生素类型如何影响细胞内抗生素释放的动力学，从而影响抗菌活性。获得的动力学参数数据库将为决策过程提供信息，从而为特定的聚合物-药物缀合物选择可裂解键。此外，动力学参数对于致力于各种应用的隔室和生理模型的科学家和工程师也具有重要价值。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。