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 ... -  《-》

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》

Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir.

The present studies entail the development of the systematically optimized solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the systemic bioavailability of lopinavir and targeting the same to the sanctuary site, i.e., lymphatic system for complete HIV inhibition. The patient-centric quality target product profile (QTPP) was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through failure mode and effect critically analysis (FMECA), helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. As per the preliminary studies, viz solubility and phase titration studies, and factor screening studies, Maisine (i.e., lipid), Tween 80 (emulgent), Transcutol HP (i.e., cosolvent) were selected as the critical material attributes (CMAs) of the liquid SNEOFs (L-SNEOFs). D-optimal mixture design was employed for the optimization of aforesaid CMAs and evaluated for in vitro dissolution, globule size, ex vivo permeation studies as the critical quality attributes (CQAs). Optimal composition of CMAs, was embarked through numerical optimization and desirability function, exhibited excellent permeation and drug release characteristics besides possessing globule size in nano range, i.e., 53.16 nm. Further to increase the stability and drug loading, the OPT-L-SNEOFs were then adsorbed onto the porous carrier, i.e., Aeroperl, to prepare the OPT-SNEOF tablets which were finally compressed into the tablet employing MCC as the filler. The performance evaluation through in situ SPIP studies ascribed the significant enhancement in absorptivity parameters of both the SNEOFs vis-à-vis the pure drug. Also, chylomicron flow block SPIP studies revealed lymphatic uptake of lopinavir from the SNEOFs. Overall, in vivo pharmacokinetic studies in rats revealed significant improvement in the rate and extent of oral bioavailability of the SNEOFs compared to the pure drug. These studies further substantiate the intestinal lymphatic transport of lopinavir for the management of the sanctuary site HIV. In a nutshell, the SNEOFs offer a complete and holistic solution for the management of the viral loads in the lymph and blood.

Garg B ，Katare OP ，Beg S ，Lohan S ，Singh B ... -  《-》

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 ... -  《-》

Solid lipid nanoparticles (SLN) of Efavirenz as lymph targeting drug delivery system: Elucidation of mechanism of uptake using chylomicron flow blocking approach.

The aim of the present work was to develop a lymph targeted SLN formulation of antiretroviral (ARV) drug and to have an understanding of its underlying mechanism of uptake by the lymphatics. The lymphatics are the inaccessible reservoirs of HIV in human body. Efavirenz (EFV) is a BCS class II, ARV drug that undergoes extensive first pass metabolism. The EFV SLN formulation was prepared using Gelucire 44/14, Compritol 888 ATO, Lipoid S 75 and Poloxamer 188 by hot homogenization technique followed by ultrasonication method, with mean particle size of 168 nm, polydispersity index (PDI) <0.220, and mean zeta potential of -35.55 mV. DSC and XRPD studies revealed change in crystallinity index of drug when incorporated into SLN. In vitro drug release was found to be prolonged and biphasic in PBS pH 6.8. There was no significant change in the mean particle size, PDI, zeta potential and entrapment efficiency of EFV SLN after storage at 30 ± 2°C/60 ± 5%RH for two months. The results from lymphatic transport and tissue distribution study indicate that a significant part of the EFV had by-passed portal system and was recovered in the lymph via chylomicron uptake mechanism. Reduction in the amount (44.70%) of the EFV reaching to liver indicates that major amount of EFV bypasses the liver and thereby, enhances the oral bioavailability of the EFV. A significant amount of EFV was found in spleen, a major lymphatic organ. EFV SLN seems to have potential to target the ARV to lymphatics for the better management of HIV.

Makwana V ，Jain R ，Patel K ，Nivsarkar M ，Joshi A ... -  《-》