Polymeric Prodrugs for Infectious Disease and Immune Therapies

Abstract

Small molecule drugs are a mainstay of modern medicine, however their suboptimal delivery to a therapeutic target can undermine their value and utility. In this body of work, we explore the adoption of polymer prodrugs (“drugamers”) to facilitate the delivery and controlled release of small molecule drugs to multiple important therapeutic settings. First, we explain why drugamers synthesized by Reversible Addition Fragmentation-chain Transfer (RAFT) are ideal small molecule drug delivery vehicles (Chapter 1). We then show that antibiotic drugamers, originally designed to treat intracellular pulmonary infections, significantly improve survival against extracellular Klebsiella pneumoniae infections due to enhanced targeting to local alveolar macrophage reservoirs (Chapter 2). A major innovation of the work described herein is the demonstration that drugamers can be combined with and can enhance protein and cellular immune therapeutics. A radiant star drugamer adjuvant was designed for effective loading within self-assembling protein nanoparticles as an alternative approach to vaccination (Chapter 3). Sustained release of the TLR7/8 agonist from the encapsulated drugamer facilitated potent immunization in vivo while mitigating toxicity associated with parent adjuvant. In Chapter 4, we demonstrate arming of immune cell therapeutics with drugamers. Fluorescein-tagged drugamers containing phosphoinositide-3-kinase (PI3K) inhibitors direct stable noncovalent binding to Genetically Engineered Macrophages (GEMs) via a bioorthogonal anti-fluorescein surface receptor. We conclude with an outlook of future directions to build upon drugamer therapeutics, specifically highlighting the potential for combination with biologic-secreting GEMs (Chapter 5).