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

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.

Zheng B ，Pan F ，Shi M ，He C ，He B ，Wang R ，Ren G ，Yang S ，Zhang S ... -  《International Journal of Nanomedicine》

Bioactive-Chylomicrons for Oral Lymphatic Targeting of Berberine Chloride: Novel Flow-Blockage Assay in Tissue-Based and Caco-2 Cell Line Models.

Elsheikh MA ，Elnaggar YSR ，Otify DY ，Abdallah OY ... -  《-》

Fabrication of Luteolin Nanoemulsion by Box-Behnken Design to Enhance its Oral Absorption Via Lymphatic Transport.

Intestinal lymphatic transport offers an alternative and effective way to deliver drugs, such as avoiding first-pass metabolism, enhancing oral bioavailability, and facilitating the treatment of targeted lymphoid-related diseases. However, the clinical use of luteolin (LUT) is limited by its poor water solubility and low bioavailability, and enhancing lymphatic transport by nanoemulsion may be an efficient way to enhance its oral bioavailability. The objective of this work is to prepare the luteolin nanoemulsions (LUT NEs), optimized its preparation parameters by using Box-Behnken design optimization (BBD) and evaluated it in vitro and in vivo. An Caco-2 / Raji B cell co-incubation monolayer model was established to simulate the M-cell pathway, and the differences in the transmembrane transport of LUT and NEs were compared. Cycloheximide (CHX) was utilized to establish rat chylomicron (CM) blocking model, and for investigating the influence of pharmacokinetic parameters in rats thereafter. The results showed that LUT NEs have good stability, the particle sizes were about 23.87 ± 0.57 nm. Compared with LUT suspension, The Papp of LUT NEs was enhanced for 3.5-folds, the oral bioavailability was increased by about 2.97-folds. In addition, after binding with chylomicron, the oral bioavailability of LUT NEs was decreased for about 30% (AUC 0-∞ (μg/L*h): 5.356 ± 1.144 vs 3.753 ± 0.188). These results demonstrated that NEs could enhance the oral absorption of luteolin via lymphatic transport routes.

Tu L ，Wang J ，Sun Y ，Wan Y ... -  《AAPS PHARMSCITECH》

Regorafenib loaded self-assembled lipid-based nanocarrier for colorectal cancer treatment via lymphatic absorption.

Oral chemotherapy can improve the life quality of patients; however, the therapeutic effects are limited by low bioavailability and rapid in vivo elimination of anticancer drugs. Here, we developed a regorafenib (REG)-loaded self-assembled lipid-based nanocarrier (SALN) to improve oral absorption and anti-colorectal cancer efficacy of REG through lymphatic absorption. SALN was prepared with lipid-based excipients to utilize lipid transport in the enterocytes and enhance lymphatic absorption of the drug in the gastrointestinal tract. The particle size of SALN was 106 ± 10 nm. SALNs were internalized by the intestinal epithelium via the clathrin-mediated endocytosis, and then transported across the epithelium via the chylomicron secretion pathway, resulting in a 3.76-fold increase in drug epithelial permeability (Papp) compared to the solid dispersion (SD). After oral administration to rats, SALNs were transported by the endoplasmic reticulum, Golgi apparatus, and secretory vesicles of enterocytes and were found in the lamina propria of intestinal villi, abdominal mesenteric lymph, and plasma. The oral bioavailability of SALN was 65.9-fold and 1.70-fold greater than that of the coarse powder suspension and SD, respectively, and was highly dependent on the lymphatic route of absorption. Notably, SALN prolonged the elimination half-life of the drug (9.34 ± 2.51 h) compared to the solid dispersion (3.51 ± 0.46 h), increased the biodistribution of REG in the tumor and gastrointestinal (GI) tract, decreased biodistribution in the liver, and showed better therapeutic efficacy than the solid dispersion in colorectal tumor-bearing mice. These results demonstrated that SALN is promising for the treatment of colorectal cancer via lymphatic transport and has potential for clinical translation.

Xia D ，Hu C ，Hou Y 《-》

Chylomicron-pretended nano-bio self-assembling vehicle to promote lymphatic transport and GALTs target of oral drugs.

Lymphatic transport of oral drugs allows extraordinary gains in bioavailability and efficacy through avoidance of first-pass hepatic metabolism and preservation of drugs at lymphatic tissues against lymph-mediated diseases. Chylomicrons can transport dietary lipids absorbed from the intestine to the tissues through lymphatic circulation. Herein, we engineered for the first time a chylomicron-pretended mesoporous silica nanocarrier that utilizes the digestion, re-esterification, and lymphatic transport process of dietary triglyceride to promote lymphatic transport of oral drugs. Taking lopinavir (LNV) as a model antiretroviral drug with disadvantages such as poor solubility, high first-pass effect and off-target deposition, this vehicle exhibited several properties belonging to ideal nanocarriers, including high drug load, amorphous dispersion and controlled release in the gastrointestinal tract. Additionally, a nano-bio interaction was demonstrated between nanoparticles and a key protein involved in chylomicron assembly; this biochemical reaction in cellular was utilized for the first time to promote lymphatic transport of nanocarriers for oral delivery. As a result, the chylomicron-pretended nanocarrier afforded 10.6-fold higher oral bioavailability compared with free LNV and effectively delivered LNV to gut-associated lymphoid tissues, where HIV persists and actively evolves. This approach not only promises a potential application to HIV-infected individuals but also opens a new avenue to other lymph-mediated pathologies such as autoimmune diseases and lymphatic tumor metastasis.

Mao Y ，Feng S ，Li S ，Zhao Q ，Di D ，Liu Y ，Wang S ... -  《-》