Intracellular Processing of Cell-penetrating Oligothioetheramides

细菌会以惊人的速度对抗生素产生抗药性。这对公共卫生和国家安全构成了重大威胁。随着越来越多的病原体进入细胞并在细胞上定居，这种威胁更加严重。聚合物可以帮助抗生素进入这些细胞并攻击病原体。该项目将探索这种抗生素输送的机制和速率。将开发与这些系统有关的新概念和模型。本科生和研究生将参与执行这一项目。参加4-H Focus青少年工作坊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。这些活动将刺激发展一支生产力高、包容性强的STEM劳动力队伍。细胞穿透性低聚硫代乙酰胺是一类新型的不带电荷的穿透细胞的大分子，它们以高度扩散的模式快速穿过不同的细胞系进入细胞。这个项目将通过开发一个直接测量细胞内键断裂的动力学模型来扩大对这些大分子制剂在细胞内是如何处理的理解。每种抗生素前体药物和细胞系的细胞内降解速率常数都是特定的。这些信息将被用来研究连接子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-药物结合物选择可裂解键。此外，动力学参数也将对致力于各种应用的隔室和生理模型的科学家和工程师具有重要价值。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.