Small-molecule drugs are pillars of modern medicine, used to prevent and treat a plethora of diseases. Their applications include modulating the immune response, where macrophages and other phagocytic innate immune cells are critical therapeutic targets. In comparison to biologics, small-molecule drugs benefit from relative ease of synthesis and structural modification, long shelf life, and low cost. However, these drugs often suffer from poor pharmacokinetics (i.e., rapid renal clearance, nonspecific tissue, and cell biodistribution) and off-target effects that limit their efficacy. We have, therefore, developed a macrophage-targeted nanoparticulate carrier (cyclodextrin nanoparticle [CDNP]) that can house a variety of hydrophobic small-molecule drugs for systemic delivery through the body. This system has further been manipulated to formulate an injectable polymer-nanoparticle (iPNP) hydrogel for local delivery, with the goal of concentrating drug effects at the target site while perpetuating sustained delivery and minimizing off-target effects. Herein, we describe the strategy for preparing these CDNPs and iPNP hydrogels for a wide range of therapeutic applications.
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