ERI: Degradation of Polyelectrolyte Complexes via Enzyme Addition

ERI：通过添加酶降解聚电解质复合物

• 批准号: 2347080
• 负责人: Whitney Blocher McTigue
• 金额: $ 20万
• 依托单位: Lehigh University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2347080&HistoricalAwards=false
• 关键词: ERI; Degradation; Polyelectrolyte; Complexes; via

Advanced treatments for cancer, HIV, and other diseases have begun incorporating multi-drug therapeutics to provide better care for patients. When using multi-drug therapeutics, it is challenging, yet necessary, to administer multiple drugs during a session to achieve the full therapeutic effect. A solution to this challenge is to deliver both drugs at the same time. One downside, however, is the need for each drug to be deposited or reach a separate part of the body with different types of release kinetics. The overarching goal of this ERI project is to investigate the use of charged polymer complexes as a novel platform for dual drug delivery with the ability to regulate the release profiles of these drugs independently of each other. To advance this goal, the Principal Investigator aims to investigate two avenues: (1) the degradation of solid polymer complexes after enzyme introduction and (2) the degradation of liquid polymer complexes that break down after adding an appropriate enzyme. The successful completion of this project will benefit society by laying the groundwork for dual drug delivery systems and advancing national health and welfare. Graduate and undergraduate student education, mentoring, and training will further the societal benefits of this project. Although groups have investigated polyelectrolyte complexation and degradable polymers, there has not been significant investigation of integrating these two concepts together. This ERI project will address this gap by complexing an enzymatically degradable carboxymethyl cellulose (CMC) polymer with an oppositely charged polyelectrolyte, such as poly(L-lysine). This research is the first step toward developing a system where the Principal Investigator can utilize the electrostatic nature of polyelectrolyte complexes, trigger drug release, and dismantle these complexes through the enzymatic degradation of CMC. The PI seeks to use both liquid-liquid and solid-liquid phase separation as starting points for evaluating polymer complex degradation. The three objectives of this ERI project are: (1) investigating the ability to complex a charged degradable polymer with an oppositely charged peptide or protein; (2) monitoring the kinetics of how the degradable polymer breaks down both as part of the complex and free in solution; and (3) through the incorporation of a third charged species to act as a model drug and monitor the release kinetics of the drug. After conducting fundamental studies using absorbance studies, brightfield microscopy, and enzyme assays, future research can further design systems for dual drug delivery with two different release mechanisms - release via changes in electrostatics and polymer degradation. The successful completion of this project has the potential for transformative impact through the generation of a dual drug delivery platform with tunable, independent release kinetics while furthering a fundamental understanding of phase separation and polymer degradation.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.

癌症、艾滋病毒和其他疾病的先进治疗方法已经开始采用多种药物治疗，为患者提供更好的护理。当使用多药物治疗时，在一个疗程期间施用多种药物以实现完全的治疗效果是具有挑战性的，但也是必要的。解决这一挑战的一个办法是同时输送两种药物。然而，一个缺点是需要每种药物以不同类型的释放动力学沉积或到达身体的单独部分。ERI项目的首要目标是研究使用带电聚合物复合物作为双重药物递送的新型平台，能够独立地调节这些药物的释放曲线。为了推进这一目标，主要研究者旨在研究两种途径：（1）引入酶后固体聚合物复合物的降解和（2）添加适当酶后分解的液体聚合物复合物的降解。该项目的成功完成将为双重药物输送系统奠定基础，促进国家健康和福利，从而造福社会。研究生和本科生教育，指导和培训将进一步促进该项目的社会效益。虽然研究小组已经研究了生物络合和可降解聚合物，但还没有将这两个概念结合在一起的重要研究。该ERI项目将通过将可酶降解的羧甲基纤维素（CMC）聚合物与带相反电荷的聚赖氨酸（如聚L-赖氨酸）复合来解决这一差距。这项研究是开发一种系统的第一步，在该系统中，主要研究者可以利用CMC复合物的静电性质，触发药物释放，并通过CMC的酶促降解来拆除这些复合物。PI试图使用液-液和固-液相分离作为评价聚合物复合物降解的起点。该ERI项目的三个目标是：（1）研究将带电荷的可降解聚合物与带相反电荷的肽或蛋白质复合的能力;（2）监测可降解聚合物作为复合物的一部分和在溶液中游离时如何分解的动力学;以及（3）通过掺入第三种带电物质作为模型药物并监测药物的释放动力学。在使用吸光度研究，明场显微镜和酶测定进行基础研究后，未来的研究可以进一步设计具有两种不同释放机制的双重药物递送系统-通过静电和聚合物降解的变化释放。该项目的成功完成具有潜在的变革性影响，通过生成具有可调、独立释放动力学的双重药物递送平台，同时进一步加深对相分离和聚合物降解的基本理解。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响评审标准进行评估，被认为值得支持。