**6. Lymphatic transport of lipid carriers**

There are two pathways for entry to the lymphatic system: M-cell uptake of particles and absorption of lipidic molecules through lymph vessels. The vascular region throughout the body is surrounded by specialized lymphatic vessels that absorb the molecules giving entry to a complex network of lymphatic systems [69, 70]. The pore size of blood vessels is not enough for the uptake of large molecules of triglycerides and phospholipids. However, the lymphatic capillaries are single-layer, thin-walled and non-fenestrated due to which it is easily able to permit these large molecules [71]. Upon absorption through lymph vessels, the lymph fluid containing absorbed molecules enters the thoracic duct followed by subclavian vein and finally is drained into the circulatory system. This pathway bypasses the liver before entering the blood circulatory system thus avoiding first-pass hepatic metabolism [72]. When drug reaches the circulatory system, it is in form of micelles or mixed micelles which dissociate into monomers because of dilution with the large volume of lymph/blood (the surfactant concentration decreases due to dilution and results in a concentration below its CMC value) [73]. In other cases where the drug is carried in lipid vesicle form, the release of drug becomes prolonged. It has been reported in literature that the presence of triglyceride-rich lipoproteins diverts the absorption of drug exclusively through

lymphatic route. Moreover, it has been also reported that greater lipoprotein synthesis particularly after postprandial administration diverts absorption of drugs dominantly through lymphatic system [67, 74]. This indicates that lipid derived either from diet or formulation determines the transport of drug either through lymphatic system or portal blood circulation [75]. This further relates to the new era for formulation development ruling out the necessity of traditional pathways like increasing solubilization capacity. It also brings new opportunities for various excipients that are emerging as bioactive recently in the last decade [76]. Further, excipients such as Cremophor EL and pluronic polymers have been shown to decrease chylomicron production and reduce the P-gp efflux transport of drug molecules [77, 78]. One of the versatile excipients in this category is tween 80 which has been found as excellent solubilizer, inhibitor of P-gp efflux and increase chylomicron production [76, 79]. Another pathway for lymphatic absorption through M cells has also been explored in the last two decades. These cells are able to recognize pathogens due to the presence of specific ligands on their surface. The particles of formulation have thus been engineered to mimic these ligands that are recognized by M-cells. Such ligands include peptides like Arg-Gly-Asp, glucans, proteins like lectins etc. [80–82]. Another peptide ligand investigated for M-cell uptake is RGD which recognizes a5b1 integrin on M-cells. However, due to its instability in gastrointestinal tract media, its analogue RGD peptidomimetic has been developed. This new moiety has been grafted on the surface of poly(lactic-*co*-glycolic acid) nanoparticles and tested for M-cell uptake. It was found that the efficacy of this new molecule remained the same as compared to its parent moiety (RGD) but the stability in GI media was improved [83, 84].
