Journal Article

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

Yang, Shuang, He, Cuiping, Zheng, Bin, Pan, Fei, He, Beibei, Ren, Guolian, Zhang, Shuqiu, Wang, Rongrong, Shi, Minfei

2024

Overview

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.

• Publisher: Taylor & Francis Ltd,Dove Press,Dove,Dove Medical Press
• Subject: Administration, Oral / Animals / Artemisinins - administration & dosage / Artemisinins - chemistry / Artemisinins - pharmacokinetics / Bioavailability / Biological Availability / biomimetic liposomes / Biomimetic Materials - chemistry / Biomimetic Materials - pharmacokinetics / Caco-2 Cells / Cholesterol / dihydroartemisinin / Drug delivery systems / Drugs / Enzymes / Ethanol / Fatty acids / first-pass hepatic metabolism / Humans / Intestinal Absorption - drug effects / intestinal lymphatic transport / Intestinal Mucosa - metabolism / Laboratory animals / Lipids / Liposomes - chemistry / Liposomes - pharmacokinetics / Lymphatic system / Lymphatic System - drug effects / Lymphatic System - metabolism / Male / Medical research / Metabolism / Mice / Oral administration / oral delivery / Original Research / Particle Size / Penicillin / Rats / Rats, Sprague-Dawley / Tissue Distribution