ERI: Degradation of Polyelectrolyte Complexes via Enzyme Addition

癌症、艾滋病毒和其他疾病的高级治疗已经开始融合多种药物疗法，为患者提供更好的护理。当使用多种药物治疗时，在一次治疗中使用多种药物以达到完全的治疗效果是具有挑战性的，但也是必要的。应对这一挑战的一个解决方案是同时提供这两种药物。然而，一个缺点是，每种药物都需要以不同类型的释放动力学储存或到达身体的不同部位。这一ERI项目的主要目标是研究将带电聚合物复合体用作双重给药的新平台，并能够独立地调节这些药物的释放情况。为了推进这一目标，首席研究员致力于研究两个途径：(1)引入酶后固体聚合物复合体的降解；(2)添加适当酶后分解的液体聚合物复合体的降解。该项目的成功完成将为双重给药系统奠定基础，促进国民健康和福利，从而造福社会。研究生和本科生的教育、指导和培训将进一步促进该项目的社会效益。尽管研究小组已经研究了聚电解质络合和可降解聚合物，但还没有将这两个概念整合在一起的重大调查。这个ERI项目将通过将可酶降解的羧甲基纤维素聚合物与相反电荷的聚电解质(如聚L-赖氨酸)络合来解决这一缺口。这项研究是开发一种系统的第一步，在该系统中，首席调查员可以利用聚电解质络合物的静电性质，触发药物释放，并通过CMC的酶降解来分解这些络合物。PI试图使用液-液和固-液相分离作为评价聚合物络合物降解的起点。这一ERI项目的三个目标是：(1)研究荷电可降解聚合物与相反电荷的肽或蛋白质络合的能力；(2)监测可降解聚合物作为络合物的一部分如何在溶液中自由分解的动力学；以及(3)通过加入第三个荷电物种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、明场显微镜和酶分析进行基础研究后，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传递系统-通过改变静电和聚合物降解来释放。该项目的成功完成有可能产生变革性的影响，通过生成具有可调的、独立的释放动力学的双药物输送平台，同时加深对相分离和聚合物降解的基本了解。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。

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.