Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery

• Multistage delivery systems for interstitial penetration and retention in tumors.
• Drug focusing to lymphatics and lymph nodes via interstitial and lymphatic flows.
• Lymph node drug targeting using nanoparticles or ‘albumin hitchhiking’.

Despite drug formulation improving circulation times and targeting, efficacy is stymied by inadequate penetration into and retention within target tissues. This review highlights the barriers restricting delivery to the connective tissue interstitium, lymphatics, and lymph nodes as well as advances in engineering drug carriers to overcome these delivery challenges. Three-dimensional tissue physiology is discussed in the context of providing material design principles for delivery to these tissues; in particular the influence of interstitial and lymphatic flows as well as differential permeabilities of the blood and lymphatic capillaries. Key examples of materials with different characteristics developed to overcome these transport barriers are discussed as well as potential areas for further development.

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