Fig. 3.

Distribution of drug based on oral (a) or subcutaneous (c) route of administration. A visual representation of the challenges faced in overcoming lymphatic drug insufficiency. Oral dosing (a) of anti-viral therapy has to overcome factors such as solubility of the drug, absorption of free drug through the GI, first-pass metabolism, and other elimination processes. After entering the systemic circulation (b), free drug can accumulate in peripheral tissues and only a small fraction of drug can enter the subcutaneous space (c). Free drug that does enter the lymphatic system can also be rapidly reabsorbed into the blood. Subcutaneous administration of drug can provide higher concentrations of drug in the lymph nodes; however, free drug rapidly transits to the blood with low residence time in the target tissues. Sustained release systems slow the release of free drug but do not alleviate rapid absorption into the blood. Anti-HIV lipid nanoparticles (LNP) accumulate in the lymph nodes and trap the drug at the target site allowing for increased concentration of drug as well as residence time in the lymph