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From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity

Key Points

  • The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune defence, and influences a diverse range of diseases, including infection, inflammatory and metabolic diseases, and cancer.

  • Targeted delivery to the lymphatics and lymphoid tissues has the potential to improve oral bioavailability, enhance vaccination and tolerance induction, target delivery to lymph-resident cancer metastasis and infection, and promote the utility of treatments for diseases ranging from infections such as HIV to cancer and inflammatory and metabolic disease.

  • Selective delivery to the lymph is largely dictated by size, as macromolecules or particulate carriers are excluded from access to blood capillaries, whereas interstitial fluid flow sweeps larger constructs into the more permeable lymphatics.

  • Lymphatic targeting may be achieved via the delivery of macromolecular therapeutics (for example, proteins and peptides), small-molecule therapeutics in association with macromolecular carriers (for example, nanoparticles, polymers, liposomes and dendrimers) or small-molecule therapeutics that associate, in situ, with endogenous macromolecular constructs (for example, lipoproteins and proteins) or cells that are transported from interstitial tissues via lymphatic rather than blood capillaries.

  • The design of lymphatic delivery systems ranges from simple systems that rely on passive lymphatic access to more complex structures that integrate into endogenous lymph transport processes. Recent studies have suggested the presence of active transport processes that facilitate entry across the lymphatic endothelium, and delivery systems that harness these processes are emerging.

  • In many cases, disease progression results in lymphatic remodelling. Next-generation lymphatic targeting approaches will probably seek to harness a better understanding of changes to lymphatic structure and function in disease to promote targeting to the lymphatics and enhance therapeutic utility.

  • Future efforts in lymphatic drug delivery might usefully address barriers to the clinical translation of lymphotropic delivery vehicles, such as the lack of well-validated models to predict lymphatic uptake in humans.

Abstract

The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.

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Figure 1: Access routes to the lymphatics after oral and parenteral delivery.
Figure 2: Lymphatic function in health and disease.
Figure 3: Mechanisms of access to the lymphatics from the interstitial space.
Figure 4: Lipid and lipophilic drug access to the intestinal lymphatics after oral administration.
Figure 5: Mechanisms of access to the intestinal lymphatics after oral administration.
Figure 6: Lipid conjugates for enhanced lymphatic delivery.
Figure 7: Lymph node entry and trafficking mechanisms.

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Acknowledgements

The title of this article was inspired by, and modified from, an excellent review of lymphatic lipid transport by J. B. Dixon (cited as reference 12 in this article). The authors gratefully acknowledge the reviewers of this article and the insightful comments provided by M. Swartz.

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Correspondence to Christopher J. H. Porter.

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C.J.H.P. and N.L.T. are named inventors on a patent application in the area of lymph-targeted prodrugs.

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Glossary

Lipoproteins

Biochemical complexes of lipids and soluble apolipoproteins that transport lipids in lymph fluid and blood to tissues throughout the body. The largest and least dense lipoproteins, chylomicrons, are assembled in the small intestine. Very low-density lipoproteins (VLDLs) and the smallest and most dense lipoproteins, high-density lipoproteins (HDLs), are assembled in both the liver and the intestine. Low-density lipoproteins (LDLs) are formed following removal of lipids from VLDL by tissues.

Initial lymphatic capillaries

Small blind-ended lymphatic vessels in the tissue periphery that have a discontinuous basement membrane, lack smooth muscle and are characterized by button-like interendothelial junctions and short anchoring filaments that are tethered to elastin fibres in the surrounding tissue. Initial lymphatics are adapted for the uptake of fluid and cells.

Collecting lymphatic vessels

These lymphatic vessels are characterized by a continuous smooth muscle cell layer and the presence of semilunar valves that facilitate the unidirectional transport of lymph and associated components. Afferent collecting lymphatics carry lymph into lymph nodes whereas efferent collecting lymphatics carry lymph from lymph nodes.

Thoracic lymph duct

The largest lymphatic vessel, sometimes called the left thoracic lymph duct, that collects most of the lymph in the body apart from the lymph draining the right thorax, arm, head and neck. The latter drain instead into the right lymphatic duct. Lymph empties from the thoracic lymph duct into the systemic circulation at the junction of the left subclavian and left internal jugular veins.

Antigen presenting cells

(APCs). A heterogeneous group of immune cells that initiate the cellular immune response by processing and presenting antigens for recognition by lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.

Tolerance

A state of immune unresponsiveness to an antigen that results from the suppression of immune responses to antigens that have been administered or encountered previously.

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatic vessels.

Glymphatic system

A recently identified paravascular pathway that enables the exchange of cerebrospinal fluid with interstitial fluid in the brain and provides a function similar to the lymphatic system elsewhere in the body. In this way, the glymphatics facilitate the clearance of solutes and waste products from the brain.

LogP

The logarithm of the ratio of the concentrations of un-ionized solute (drug) in two immiscible liquid phases (usually octanol and water) at equilibrium. LogP provides one measure of drug lipophilicity, with high logP values indicating higher lipophilicity.

Lipophilicity

The affinity of a molecule for a lipophilic environment (lipid or lipid-like). Lipophilic literally means 'fat loving'.

Rule of 5

Limits to a series of molecular properties of drugs (logP, molecular weight, hydrogen bond donors and acceptors), suggested by Lipinski to increase the likelihood of good oral absorption.

Mesenteric lymphatic vessels

The lymphatic vessels that collect lymph from the intestine. This includes the initial lymphatic capillaries ('lacteals'), pre-nodal (afferent) collecting lymphatic vessels and the post-nodal (efferent) mesenteric lymph duct. The mesenteric lymph duct collects almost all lymph from the small intestine.

High endothelial venules

(HEVs). Specialized post-capillary venules that are characterized by plump, as opposed to thin, endothelial cells. HEVs are found in lymph nodes and other lymphoid tissues and support high levels of lymphocyte extravasation from the blood into these tissues.

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Trevaskis, N., Kaminskas, L. & Porter, C. From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov 14, 781–803 (2015). https://doi.org/10.1038/nrd4608

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