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

Abstract

Bin Zheng,1– 3,* Fei Pan,1– 3,* Minfei Shi,1– 3 Cuiping He,1– 3 Beibei He,1– 3 Rongrong Wang,1– 3 Guolian Ren,1– 3 Shuang Yang,4 Shuqiu Zhang1– 3 1School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 3Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 4School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Yang, School of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, 030001, People’s Republic of China, Email [email protected] Shuqiu Zhang, School of Pharmacy, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, 030001, People’s Republic of China, Email [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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. Keywords: intestinal lymphatic transport, biomimetic liposomes, first-pass hepatic metabolism, oral delivery, dihydroartemisinin

Keywords

• intestinal lymphatic transport
• biomimetic liposomes
• first-pass hepatic metabolism
• oral delivery
• dihydroartemisinin