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

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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.