ERI: Degradation of Polyelectrolyte Complexes via Enzyme Addition

针对癌症、艾滋病毒和其他疾病的先进治疗已经开始结合多药物治疗，为患者提供更好的护理。当使用多种药物治疗时，在一个疗程中使用多种药物以达到充分的治疗效果是具有挑战性的，但也是必要的。解决这一挑战的办法是同时提供这两种药物。然而，一个缺点是，每种药物需要沉积或到达身体的不同部位，并具有不同类型的释放动力学。这个ERI项目的总体目标是研究带电聚合物复合物作为双重药物递送的新平台的使用，并能够独立地调节这些药物的释放概况。为了实现这一目标，首席研究员旨在研究两个途径：(1)固体聚合物配合物在酶引入后的降解；(2)液体聚合物配合物在添加适当的酶后的降解。这一项目的成功完成将为双重给药系统奠定基础，促进国民健康和福祉，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。虽然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要研究。ERI项目将通过将酶降解的羧甲基纤维素（CMC）聚合物与带相反电荷的聚电解质（如聚l -赖氨酸）络合来解决这一问题。这项研究是开发一个系统的第一步，在这个系统中，首席研究员可以利用多电解质复合物的静电性质，触发药物释放，并通过CMC的酶降解来分解这些复合物。PI试图使用液-液和固-液相分离作为评估聚合物络合物降解的起点。这个ERI项目的三个目标是：(1)研究带电荷的可降解聚合物与带相反电荷的肽或蛋白质配合的能力；(2)监测可降解聚合物在溶液中作为配合物和游离物的分解动力学；(3)通过结合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、明场显微镜和酶分析进行基础研究之后，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-通过静电变化和聚合物降解释放。该项目的成功完成具有变革性影响的潜力，通过产生具有可调，独立释放动力学的双重药物输送平台，同时进一步了解相分离和聚合物降解的基本知识。该奖项反映了美国国家科学基金会的法定使命，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.