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

项目摘要/摘要 据估计，每天有39亿人服用药物治疗急性或慢性病。然而， 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，这些因素阻止了它们的 更有效和更广泛的使用。理想情况下，药物会在作用部位达到理想的浓度 治疗所需的持续时间。在实践中，这是困难的，因为身体不断地新陈代谢 和排泄药物，这需要重新给药。取决于药物的治疗窗口和 生物半衰期，可能需要频繁给药，这会降低患者的依从性。这个问题是 慢性病的不依从率高达50%，导致发病率和 仅在美国，每年就有高达2900亿美元的医疗成本增加。这一领域 制药公司已经开发出减少给药频率的配方方法，包括注射 药物包埋在可生物降解材料中的控释系统。不幸的是，目前 临床批准的系统在它们可以传递的分子类型和药物方面都受到限制 他们能达到的释放动力学。该提案寻求开发非肠道给药策略，以 增强安全性和有效性，提高患者依从性，使生物药物能够持续释放。 我们假设，新兴的纳米制造方法(例如，多光子3D打印)可以用来控制 含有药物的表面侵蚀颗粒的结构--以及由此产生的行为。因为生物多样性的退化 这些疏水材料被限制在表面，药物均匀分布在其 体积将以与其侵蚀速度和裸露表面积成正比的速度释放。虽然这件事 概念可以应用于实现广泛的释放动力学，我们最感兴趣的是实现零- 顺序释放动力学，这对大多数疾病是可取的，以及顺序释放，这可能对 动态条件。此外，由于表面侵蚀材料不含水，其内部微环境 将保持干燥和中性，从而促进微囊化生物制剂在37℃下的稳定性。 能够从根本上改变药物的使用方式并改善所有患者的预后 医药。这一多样性补充资料将在先前为支持梅的工作而提出的工作的基础上扩展- McHugh实验室的西班牙裔女学生Li Laracuente说。美利将设计微粒子配方 三种不同的药物在肠外给药后实现长期零级释放动力学。在 最初的工作范围，这个项目的目的是利用这个平台给眼内注射甲氨蝶呤。在 根据这一补充奖励，扩大范围，美力将提供氟西汀、恩曲他滨和吗啡 该药物可将微粒保存长达60天，并建立其在体内的药代动力学曲线。然后她将应用这一点 将这项技术应用于疼痛模型，以确定通过这些微粒传递的吗啡的疗效。

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.