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 patients’ adherence to their dosing regimens. 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. Using these methods, we can model and rationally design microparticle structures that release drug at predictable, geometrically-defined rates. 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. The features of surface-eroding microparticles run in stark contrast with existing FDA-approved microparticles composed of bulk-degrading polymers that absorb water and produce acidic degradation products, which makes it impossible to predict release kinetics a priori, contributes to the degradation of encapsulated biologics, and prevents sequential release. The strategies we propose are only now possible due to the convergence of advances in manufacturing and chemistry that allow us to exploit structure-function relationships at a scale small enough to retain microparticle injectability. If successful, this approach has the ability to fundamentally change how drugs are administered and improve patient outcomes across all of medicine.

NARRATIVE Pharmaceutical drugs have reduced mortality and morbidity across all areas of medicine; however, key challenges such as undesirable side effects, poor efficacy, and the need for frequent administration or complex administration routes limit their ability to have even more pronounced impact on patient welfare. The projects described within this proposal seek to overcome these challenges by developing injectable drug delivery platforms that can precisely control pharmacokinetics, reduce the frequency at which drug needs to be readministered, deliver biologics in their bioactive form, and enable multi-drug therapies that match dynamic patient needs. To achieve these goals, we will develop surface-eroding biomaterials that protect the encapsulated payload in combination with advanced fabrication methods that define microparticle geometry— and thus the release of drugs encapsulated in surface-eroding materials—to rationally design injectable particles that are compatible with a broad array of drug classes and exhibit predictable release kinetics.