Analysis of Nanomaterial Physiochemical Property Influences on Lymph Node Accumulation and Leukocyte Association

Lymph nodes house high concentrations of immune cells, and are critical tissues for regulating and priming the adaptive immune response. Thus, these tissues are an important therapeutic target for treatments that modulate immune activity, including but not limited to vaccination, induction of tolerance, and cancer immunotherapy. However, lymph nodes are also highly structured with physical and cellular barriers that can limit therapeutic access to important immune cell targets housed within them. Nanomaterial delivery approaches have been established to increase accumulation within the lymph node via locoregional methods of administration, but nanomaterials that highly efficiently accumulate within lymphatics are also restricted from entering the lymph node’s deeper regions in a size-dependent manner, limiting their delivery to lymphocytes. This motivates the need for better understanding and control over therapeutic access to cells within the lymph node, which is the overall objective of this thesis work. As such, work in the first part of this thesis quantifies the influences of lymphatic transport barriers on access of locoregionally administered nanomaterials to immune cell subsets within the tissue, and describes engineered biomaterial approaches to mitigate these barrier influences. Delivery to the lymph node from the blood supply via intravenous administration is next explored as a means to alter route of entrance to the lymph node and therefore distribution of cells accessed. Intravenous delivery is also standard practice for many cancer immunotherapies in the clinical setting, but delivery to the lymph node from this administration method is not well characterized, so nanomaterial properties favorable for intravenous delivery to immune cells within the lymph node are thoroughly studied. Finally, a cell-targeted antibody nanoparticle conjugate approach is employed to enhance delivery to T cells subsets specifically relevant in cancer immunotherapy. As a whole, this work provides new insights into therapeutic considerations for delivery to specific immune cell subsets within the lymph node and informs biomaterial design approaches to improve therapeutic outcomes.Ph.D