Lymphatic absorption and targeted delivery to the lymphatic system

Comprising a network of vessels, nodes and tissues throughout the vascular regions of the body, the lymphatic system plays a critical role in immune response, infection, fat metabolism, protein transport and cancer metastasis. Recent interest in the involvement of the lymphatic system in a wide range of diseases has focused attention on designing drug delivery systems to target the lymphatics and lymphoid tissues.

Lymphatic drug transport is an area of particular interest and expertise at MIPS, and one in which our scientists are leading efforts worldwide. D4's focus here is on three programs:

Drug transport into the lymphatic vessels of the small intestine

The intestinal lymphatics—not the blood capillaries—are responsible for the transport of dietary lipids from the intestine back to the general (systemic) circulation. Drugs that are intrinsically lipophilic, or prodrugs that can be modified to be transiently lipophilic, are able to piggyback on this lipid absorption pathway, effectively achieving drug concentrations in the intestinal lymph 10 to 100 times higher than in the blood.

This unique drug absorption pathway has a number of highly significant benefits. Drug transport via the intestinal lymph circumvents first-pass metabolism in the liver, enhancing the oral bioavailability of drugs with high first-pass metabolism. The intestinal lymphatics channel drug absorption through the largest lymph node in the body, the mesenteric lymph node—a critical 'sensor' in determining whether the body launches an immune response. Drug delivery via the intestinal lymphatics has significant potential for the delivery of drugs, antigens and adjuvants that enhance or suppress immunity or tolerance.

Drug targeting of lymphatics after injection

After subcutaneous or intramuscular injection of high molecular weight materials—such as proteins or nanoparticles—absorption usually occurs preferentially via the lymphatic vessels that drain the injection site, rather than the blood vessels. Deliberate design of nano-sized drug delivery systems, or macromolecular therapeutics, provides an opportunity to specifically target the lymphatics after injection. Considerable potential exists, not only in the development of vaccines, but also in the treatment of cancer metastases, which often lodge in lymph nodes.

Potential interventions in metabolic disease via a lymph-targeted drug delivery strategy

Emerging evidence suggests a strong link between the lymphatics, lipid absorption, the development of fat (adipose) deposits around the body, and metabolic disease. It has long been suggested that high fat diets may promote obesity and related diseases, such as metabolic syndrome and insulin resistance. However, it has only recently become evident that adipose deposits may act as sensing and secretory organs—reacting to changes in lipid levels and promoting lipid storage and utilisation. Importantly, direct access of lymph to adipose appears to occur, paving the way for potential interventions.

Research laboratories