Engineered biomaterial drug delivery systems for enhanced delivery to lymph nodes
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State-of-the-art drug delivery currently focuses on delivery vehicle size, surface chemistry, and/or receptor interactions, all with the hope of improving drug accumulation within the tissue target. This work seeks to alter this paradigm by recognizing that tissue targets are not black boxes to which simply achieving accumulation is sufficient, but instead, complex microenvironments that house the cells that actually produce the function of the tissue and are the real targets of drug delivery. For example, while tissues critically involved in the regulation of immune processes, such as the lymphatics and lymph nodes, possess delivery barriers to getting drugs to their anatomical location, due to the complex spatial and temporal regulations of adaptive immune responses, these tissues, more importantly, possess delivery barriers to specific cells within them that must be overcome to achieve the desired immune response. The main innovation of this work, therefore, is that it addresses all drug delivery barriers, from site of injection to site of action, for the lymphatics and lymph nodes. This work has produced two novel nanoparticle-based delivery systems: one which proposes nitric oxide as a therapeutic for lymphatic-related therapies including direct delivery of nitric oxide to the lymphatics to regulate pumping function, and delivery of nitric oxide to lymph node-resident antigen presenting cells to increasing nanoparticle uptake as well as possibly promote tolerance; and the second which proposes a novel mechanism for the delivery of small molecules to deep lymph node cells for enhanced immune responses. Both of these systems while being nanoparticle-based, however, have engineered through either endogenous or synthetic chemistry the ability to release their small molecule payload, and thus are the first multi-stage lymphatic and lymph node drug delivery systems.