Examining and exploiting lymphatic vessels for drug delivery at mucosal surfaces

K. Maisel
University of Maryland,
United States

Keywords: nanoparticles, immune modulation, respiratory tract, gastrointestinal tract

Summary:

Mucosal surfaces, including lungs and gastrointestinal tract, are the first to be exposed to external pathogens and are essential for maintaining homeostasis in the body. Chronic mucosal diseases, such as inflammatory bowel disease, allergies, and asthma affect an ever increasing number of people in the United States. Stromal cells, connective tissues cells that include epithelial and endothelial cells, make up a large fraction of cells in mucosal tissues and are often the first to encounter molecules, pathogens, drugs, or nanocarriers arriving at these sites. Furthermore, a growing body of work is revealing the multitude of ways in which that stromal cells can modulate disease pathology, including fluid, cell, and particulate transport, extracellular matrix remodeling, and, most recently, immune modulation. My lab’s interest centers around lymphatic vessels, both in understanding their contribution to disease pathology and targeting them for immunotherapeutic applications. Lymphatics are the natural conduit between peripheral tissues and the lymph nodes, where the adaptive immune response is shaped. Lymph node targeted drug delivery has emerged as a promising method to enhance efficacy of immunotherapeutic treatments and vaccination. Reaching the lymphocytes in the lymph nodes is key to immunotherapeutic efficacy and has been shown to reduce dosage amounts and number of required treatment administrations. Drug delivery to the lymph nodes can be achieved by harnessing lymphatic transport. Small nanoparticles particularly have been identified to target lymphatics and subsequently enhance immunotherapeutic and vaccine efficacies. In our research, we ask how surface chemistry of these nanocarriers affects their transport across lymphatic vessels. We have established nanoparticle functionalization strategies to specifically promote lymphatic entry. Furthermore, we have determined the underlying cellular mechanisms governing nanoparticle transport and uptake by lymphatic endothelial cells. Additionally, since lymphatics are also mainly responsible for maintaining tissue homeostasis and fluid balance between tissues and systemic circulation, we are interested in the regulation of lymphatic transport as it relates to fluid balance during health and disease. Here, we ask if other stromal cells can regulate lymphatic transport, and if this indirect modulation can be harnessed for drug delivery and is modulated by disease states. We have developed mucosal in vitro systems to study transport across mucosal epithelial surfaces and into lymphatics. These models provide platforms to identify new regulatory mechanisms of lymphatic transport that could serve as therapeutic targets. In summary, our findings provide design criteria for lymph node targeting drug delivery, as well as platforms to probe lymphatic transport physiology in vivo. Furthermore, our in vitro models and nanoparticle-based methods allow us to identify regulatory pathways of lymphatic transport, which can be taken advantage of as therapeutic targets to enhance lymphatic transport for local immunomodulatory and systemic drug delivery. Finally, our work has provided novel insights modeling and understanding the complex workings of lymphatic transport mechanisms, particularly at mucosal surfaces.