2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin

• Published in: International journal of nanomedicine Vol. 19; pp. 5273 - 5295
• Main Authors: Zheng, Bin, Pan, Fei, Shi, Minfei, He, Cuiping, He, Beibei, Wang, Rongrong, Ren, Guolian, Yang, Shuang, Zhang, Shuqiu
• Format: Journal Article
• Language: English
• Published: New Zealand Dove 01.01.2024; Dove Medical Press
• Subjects: Administration, Oral; Animals; Artemisinins - administration & dosage; Artemisinins - chemistry; Artemisinins - pharmacokinetics; Biological Availability; biomimetic liposomes; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacokinetics; Caco-2 Cells; dihydroartemisinin; first-pass hepatic metabolism; Humans; Intestinal Absorption - drug effects; intestinal lymphatic transport; Intestinal Mucosa - metabolism; Liposomes - chemistry; Liposomes - pharmacokinetics; Lymphatic System - drug effects; Lymphatic System - metabolism; Male; Mice; oral delivery; Original Research; Particle Size; Rats; Rats, Sprague-Dawley; Tissue Distribution; biomimetic liposomes; first-pass hepatic metabolism; dihydroartemisinin; intestinal lymphatic transport; oral delivery
• ISSN: 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S462374

Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.