Autoimmune diseases, which include rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, gastritis and type I diabetes, occur when the immune system mistakenly attacks and destroys healthy tissue. Lymphocytes play a key role in initiation and progression of these diseases, and thus, immunosuppressants that reduce the activity and/or proliferation of lymphocytes are the main treatment option for most autoimmune diseases. However, a major drawback to the widespread application of immunosuppressants as mono-therapeutic agents is their limited distribution to the necessary sites of action, resulting in unwanted side-effects and ‘off-target’ toxicities. Targeting the delivery of immunosuppressive agents to lymphocytes in the lymphatic system therefore represents a potential strategy for improving their efficacy.
Lipophilic prodrugs have previously been used to target drugs to the lymphatic system1,2 but not to lymphocytes themselves. Furthermore, there are limited examples of optimising the most suitable type of prodrug construct for a given parent drug. Therefore, we have set out to develop synthetic methods for generating a range of lipid-soluble triglyceride and phospholipid prodrugs of mycophenolic acid, an immunosuppressant most commonly used for the prevention of organ transplant rejection. This presentation will outline the synthesis and biological evaluation of these initial targets and the design of modified prodrug scaffolds in an effort to improve their lymphotropic and pharmacokinetic properties.