Lymphedema therapy via lymphatic targeted drug delivery

PROJECT SUMMARY Lymphedema, which results from the failure of the lymphatic system to properly drain fluid, proteins, lipids, and immune cells from the interstitium of the skin, leads to irreversible tissue remodeling including fibrosis, swelling, and lipid accumulation. It occurs most commonly in the US as a result of cancer treatment. In breast cancer almost 1 in 3 survivors develop lymphedema and the presence has persisted in spite of reductions to the aggressiveness of cancer therapy achieved through sentinel lymph node biopsy. Being diagnosed with lymphedema remains a life sentence as there is no cure. In this project, a new therapeutic paradigm for treating lymphedema will be explored using pre-clinical models of surgically induced disease. The objective of this program is to further develop and optimize a lymphatic-targeting sustained drug delivery system for lymphedema therapy. Different types of lymphatic pump function modulators [L-type calcium channel activator and potassium channel blocker] and two classes of immunomodulators that ameliorate lymphedema- induced inflammation [inhibitors of calcineurin and transforming growth factor beta], and synergies in improving the benefits of vascularized lymph node transfer will be tested. The single vessel ligation mouse model of lymphedema will be used as, in contrast to genetic models, it is not plagued by transgene-associated immune deficiencies and closely resembles the pathophysiology of human disease. Utilizing unique dual-wavelength near infrared imaging capabilities, lymphatic function and drug biodistribution over disease progression and therapy will be tracked. This will be achieved through three specific aims: Aim 1 will focus on lymphatic delivery and effects of drugs restoring lymphatic pump function. Aim 2 will harness methods of sustained delivery into locoregional tissues as well as lymphatic delivery to lymph nodes to determine the effects of immune modulatory cargos on the immune cell populations within the draining lymph node, the resulting pathology in the lymphedematous tissue, and the consequences to lymphatic function. Aim 3 will investigate the combined delivery of lymphatic function bolstering or immune modulatory agents in a model of chronic lymphedema and synergies in combination with vascular lymph node transplant, the only existing investigational surgical intervention for lymphedema. The expected outcome of this project is a therapeutic regime for improving lymphatic function in the treatment of lymphedema, replacing watch-and-wait philosophy with low-dose (but focused) drugs that support lymphatic transport functions.