Leveraging Neutrophil-Particle Interactions to Develop Therapeutics for Acute Inflammatory Diseases

Abstract

Inflammatory diseases including acute respiratory distress syndrome (ARDS), sepsis, and deep vein thrombosis (DVT) are propagated by a systemic inflammatory response to the disease onset. Mortality rates of ARDS, sepsis, and DVT positively correlate with systemic inflammation, but there are no established curative protocols for systemic inflammation. In ARDS and sepsis, the inflammation in these diseases is propagated by neutrophils and neutrophil damage to tissues leading to organ failure. Neutrophils contribute to clot formation in DVT, high levels of neutrophil involvement can often lead to blood vessel blockage. Depletion of neutrophils can improve the outcome of inflammation in animal models but is not a practical solution for human patients. Particle-based therapeutics have been established as a method of redirecting neutrophils in inflammation, but little research has investigated effects of particle-based therapeutics on neutrophil physiology. Thus, the overarching goal of this research is to investigate anti-inflammatory properties of particle-based therapeutics both as neutrophil diversion tactics and as delivery vehicles for therapeutic agents.

Currently, the clinic utilizes IV-delivered particle-based therapeutics to treat cancer and as diagnostics. Side effects of these therapeutics include immunosuppression, implicating the immune system’s role in clearing intravenously delivered particles and the ability to modulate circulating immune cells through this tactic. Further, IV-delivered particles in the clinic have been limited to liposomal and protein-based formulations. These formulations are inherently less stable compared to polymeric materials. Polymeric materials are a novel solution to the particle-based therapeutic world due to ease of mass production, material consistency, and stability. My dissertation work has investigated a novel, degradable, polymeric particle system that targets circulating phagocytic immune cells and reprograms the cellular inflammation cascade. I first investigated the use of Poly-A particles as a therapeutic in acute localized inflammation in vivo. In this work, I found that Poly-A particles both modulate neutrophil accumulation and reprogram neutrophils to a quiescent state via inherent therapeutic properties. I next investigated the extent of neutrophil modulation via Poly-A particles in an in vitro model for NETosis, finding that Poly-A particles both reduce and slow the progression of NET formation.

After developing several in vitro models for studying particle interactions with neutrophils, I employed my expertise in evaluating a polymeric material already prevalent in the clinic, PLGA. Importantly, it is necessary to choose materials that have minimal inflammatory impact, and PLGA must be optimized to minimize inflammatory side effects. Finally, I investigated the safety of an in vivo infusion of polymeric particles and found that Poly-A particles did not induce infusion reactions. Overcoming this major hurdle of safely infusing poly-A particles shows the clinic translatability of Poly-A as a therapeutic for inflammatory diseases. My work fills the knowledge gap of neutrophil-particle interactions and allows for the development of an innovative and dependable treatment approach. The findings of my dissertation illuminate a new perspective on treating conditions characterized by immune dysfunction and inspire the application of particles elsewhere.