Overcoming physiological barriers by nanoparticles for intravenous drug delivery to the lymph nodes

Abstract

The lymph nodes are major sites of cancer metastasis and immune activity, and thus represent important clinical targets. Although not as well-studied compared to subcutaneous administration, intravenous drug delivery is advantageous for lymph node delivery as it is commonly practiced in the clinic and has the potential to deliver therapeutics systemically to all lymph nodes. However, rapid clearance by the mononuclear phagocyte system, tight junctions of the blood vascular endothelium, and the collagenous matrix of the interstitium can limit the efficiency of lymph node drug delivery, which has prompted research into the design of nanoparticle-based drug delivery systems. In this mini review, we describe the physiological and biological barriers to lymph node targeting, how they inform nanoparticle design, and discuss the future outlook of lymph node targeting.

Keywords: Nanoparticles; barrier; drug delivery; hitchhiking; lymph node; targeting.

Figure 1.

Lymphatic vessels drain interstitial fluid secreted by blood vessels and tissues. Lymph flows unidirectionally toward the subclavian veins, where it mixes with venous blood and re-enters circulation. (A color version of this figure is available in the online journal.)

Figure 2.

Structure of the lymph node. Lymph enters via the afferent lymphatic vessels and exits via the efferent lymphatic vessels. Antigens from the lymph are sampled by node-resident immune cells such as lymphatic sinus associated dendritic cells (LS-DCs) and subcapsular sinus (SCS) macrophages and presented to B cells and T cells to generate an immune response. Antigen-naïve B cells and T cells enter the lymph node through specialized blood vessels called high endothelial venules (HEVs) and undergo expansion following antigen exposure in the B cell follicles and T cell zones, respectively. Reprinted with permission from Nakamura and Harashima. (A color version of this figure is available in the online journal.)

Figure 3.

To reach the lymph nodes, nanoparticles must avoid clearance from the blood stream by the mononuclear phagocyte system, extravasate out of the blood vessel endothelium, and diffuse past the extracellular matrix in the interstitium. Adapted with permission from Hong et al. (A color version of this figure is available in the online journal.)

Figure 4.

Junction proteins maintain tight cell–cell junctions between blood vessel endothelial cells. Adapted with permission from Cong and Kong. (A color version of this figure is available in the online journal.)

Figure 5.

Nanoparticles can extravasate out of the blood vessel endothelium into the ECM-containing insterstitium through cell–cell junctions (green arrow) or transcytosis (blue arrow). (A color version of this figure is available in the online journal.)

Figure 6.

The ECM in the interstitium forms a mesh with positively and negatively charged protein fibers. Reprinted with permission from Lieleg et al. (A color version of this figure is available in the online journal.)

Figure 7.

(a) Epirubicin-loaded micelles deliver drugs to metastatic lymph nodes. (b) Epirubicin micelle treatment inhibits the growth of lymph node metastases in a luciferase expressing murine breast cancer model. *P < 0.05, **P < 0.01. Adapted with permission from Chida et al.

Figure 8.

(a) T cell-targeted nanoparticles accumulate in the tumor-draining lymph nodes and (b) improve mouse survival (b). ***P < 0.001. Adapted with permission from Schmid et al. (A color version of this figure is available in the online journal.)