Research Supplement to Promote Diversity: Mei-Li Laracuente (1R35GM143101 Parent Award)

项目总结/摘要 据估计，每天有39亿人服用药物治疗急性或慢性疾病。然而，在这方面， 尽管目前的药物具有巨大的效用，但它们受到几个因素的限制，这些因素阻碍了它们的应用。 更有效和更广泛的使用。理想情况下，药物将在作用部位达到所需浓度， 治疗所需的持续时间。在实践中，这是困难的，因为身体不断代谢 和排泄药物，这需要重新给药。取决于药物的治疗窗口， 生物半衰期，可能需要频繁给药，这降低了患者的依从性。这个问题 慢性病的不依从率高达50%，导致发病率增加， 仅在美国，每年就增加了高达2900亿美元的医疗费用。领域 制药公司已经开发了减少给药频率的制剂方法，包括注射给药。 由包埋在可生物降解材料中的药物组成的控释系统。不幸的是，目前 临床批准的系统在它们可以递送的分子类型和药物 释放动力学可以实现。该提案寻求开发肠胃外药物递送策略， 增强安全性和有效性，提高患者依从性，并使生物药物能够持续释放。 我们假设新兴的纳米纤维方法（例如，多光子3D打印）可以用于控制 含有药物的表面侵蚀颗粒的结构和行为。因为， 这些疏水材料被限制在表面，药物均匀地分布在它们的整个表面上。 体积将以与其侵蚀速率和暴露表面积成比例的速率释放。虽然这 概念可用于实现广泛的释放动力学，我们最感兴趣的是实现零释放 顺序释放动力学，这是大多数疾病所需要的，和顺序释放，这可能是有用的， 动态条件此外，由于表面侵蚀材料排斥水， 将保持干燥和中性，从而促进包封生物制剂在37°C下的稳定性。这种方法有 能够从根本上改变药物的给药方式，并改善所有患者的治疗结果， 药这一多样性补充将扩大以前提出的工作，以支持梅的工作- 麦克休实验室的一名西班牙裔女学生Li Laracuente。Mei-Li将设计微粒配方， 三种不同的药物在肠胃外给药后实现长期零级释放动力学。在 最初的工作范围，该项目旨在使用该平台输送眼内甲氨蝶呤。在 根据该补充合同，Mei-Li将提供氟西汀，恩曲他滨和吗啡， 将它们在微粒中孵育长达60天，并在体内建立它们的药代动力学曲线。然后她会把这个 将该技术应用于疼痛模型，以建立由这些微粒递送的吗啡的功效。

PROJECT SUMMARY/ABSTRACT Every day, an estimated 3.9 billion people take medication to treat acute or chronic conditions. However, despite the enormous utility of current pharmaceuticals, they are limited by several factors that prevent their more effective and expanded use. Ideally, drugs would reach the desired concentration at the site of action for the duration that the therapy is required. In practice, this is difficult because the body is constantly metabolizing and excreting drugs, which necessitates re-administration. Depending on a drug’s therapeutic window and biological half-life, frequent administration may be required, which lowers patient adherence. This issue is pervasive with non-adherence rates as high as 50% for chronic diseases, leading to increased morbidity and mortality and as much as $290 billion in added healthcare costs each year in the U.S. alone. The field of pharmaceutics has developed formulation methods that reduce administration frequency, including injectable controlled-release systems composed of drug embedded in biodegradable materials. Unfortunately, current clinically-approved systems are limited in both the types of molecules that they can deliver and the drug release kinetics they can achieve. This proposal seeks to develop parenteral drug delivery strategies that enhance safety and efficacy, improve patient adherence, and enable the sustained release of biological drugs. We hypothesize that emerging nanofabrication methods (e.g., multi-photon 3D printing) can be used to control the structure—and thus behavior—of surface-eroding particles containing drug. Because the degradation of these hydrophobic materials is confined to the surface, drug distributed homogeneously throughout their volume will be released at a rate proportional to their erosion rate and exposed surface area. Although this concept could be applied to achieve a wide array of release kinetics, we are most interested in attaining zero- order release kinetics, which are desirable for most diseases, and sequential release, which may be useful for dynamic conditions. Further, because surface eroding materials exclude water, their interior microenvironment will remain dry and neutral, thus promoting the stability of encapsulated biologics at 37°C. This approach has the ability to fundamentally change how drugs are administered and improve patient outcomes across all of medicine. This diversity supplement will expand upon the work previously proposed to support the work of Mei- Li Laracuente, a Hispanic female student in the McHugh Lab. Mei-Li will engineer microparticle formulations for three different drugs that achieve long-term, zero-order release kinetics after parenteral administration. In the original scope of work, this project aimed to deliver intraocular methotrexate using this platform. In the expanded scope under this supplemental award, Mei-Li will deliver fluoxetine, emtricitabine, and morphine with microparticles for up to 60 days and establish their pharmacokinetic profiles in vivo. She will then apply this technology to a pain model to establish the efficacy of morphine delivered by these microparticles.