Lymphatic targeting by albumin-hitchhiking: Applications and optimisation

The lymphatic system plays an integral role in the development and progression of a range of disease conditions, which has impelled medical researchers and clinicians to design, develop and utilize advanced lymphatic drug delivery systems. Following interstitial administration, most therapeutics and molecules are cleared from tissues via the draining blood capillaries. Macromolecules and delivery systems >20 kDa in size or 10-100 nm in diameter are, however, transported from the interstitium via draining lymphatic vessels as they are too large to cross the blood capillary endothelium. Lymphatic uptake of small molecules can be promoted by two general approaches: administration in association with synthetic macromolecular constructs, or through hitchhiking on endogenous cells or macromolecular carriers that are transported from tissues via the lymphatics. In this paper we review the latter approach where molecules are targeted to lymph by hitchhiking on endogenous albumin transport pathways after subcutaneous, intramuscular or intradermal injection. We describe the properties of the lymphatic system and albumin that are relevant to lymphatic targeting, the characteristics of drugs and delivery systems designed to hitchhike on albumin trafficking pathways and how to further optimise these properties, and finally the current applications and potential future directions for albumin-hitchhiking approaches to target the lymphatics.