the-mesenteric-lymph-duct-cannulated-rat-model-application-to

The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

The intestinal lymphatic system plays key roles in fluid transport, lipid absorption and immune function. Lymph flows directly from the small intestine ...

cervical-lymph-duct-cannulated-rat-model-for-assessing-lymphatic

Cervical Lymph Duct-Cannulated Rat Model for Assessing Lymphatic Transport from the Head and Brain

Lymph flows from the central nervous system (CNS) via a series of lymphatic vessels (LVs) and lymph nodes that converge at the cervical lymph ducts. In ...

Monash University (Parkville Campus)

China Pharmaceutical University

The purpose of this work was to investigate the potential of poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) (PCL-PEEP) micelles for brain-targeting drug delivery.

Poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) micelles for brain-targeting drug delivery: in vitro and in vivo valuation.

Micelle-based brain-targeted drug delivery enabled by a nicotine acetylcholine receptor ligand.

The successful treatment of central nervous system (CNS) disorders is hampered by inefficient drug delivery across the blood-brain barrier (BBB). Transferrin (Tf) could facilitate the transcytosis of coupled nanocarriers through Tf receptor (TfR) mediated pathway. In this study, Tf-modified paclitaxel-loaded polyphosphoester hybrid micells (TPM) was prepared and evaluated for its in vitro and in vivo brain-targeting efficiency. The polyphosphoester hybrid micelle formed a core-shell structure in aqueous solution, and demonstrated high drug entrapping efficiency (89.9±3.4%). In addition, the micelle showed negligible hemolysis even at 2.0 mg/mL. The TPM was 87.85±2.32 nm with ζ potentials -12.33±1.46 mV, and PTX showed sustained release from TPM. TPM demonstrated enhanced cellular uptake and brain accumulation, which were 2 and 1.8-fold of PM, respectively. TPM exhibited strongest anti-glioma activity, and the mean survival time of mice bearing intracranial U-87 MG glioma treated with TPM (39.5 days) was significantly longer than those treated with Taxol® (33.6 days). These results indicated that Tf conjugated micelle could be a promising carrier for brain-targeting drug delivery.

Transferrin-conjugated polyphosphoester hybrid micelle loading paclitaxel for brain-targeting delivery: synthesis, preparation and in vivo evaluation.

The effective chemotherapy for glioblastoma multiform (GBM) requires a nanomedicine that can both penetrate the blood-brain barrier (BBB) and target the glioma cells subsequently. In this study, Transferrin (Tf) modified cyclo-[Arg-Gly-Asp-d-Phe-Lys] (c[RGDfK])-paclitaxel conjugate (RP) loaded micelle (TRPM) was prepared and evaluated for its targeting efficiency, antiglioma activity, and toxicity in vitro and in vivo. Tf modification significantly enhanced the cellular uptake of TRPM by primary brain microvascular endothelial cells (BMEC) to 2.4-fold of RP loaded micelle (RPM) through Tf receptor mediated endocytosis, resulting in a high drug accumulation in the brain after intravenous injection.The c[RGDfK] modified paclitaxel (PTX) was released from micelle subsequently and targeted to integrin overexpressed glioma cells in vitro, and showed significantly prolonged retention in glioma tumor and peritumoral tissue. Most importantly, TRPM exhibited the strongest antiglioma activity, as the mean survival time of mice bearing intracranial U-87 MG glioma treated with TRPM (42.8 days) was significantly longer than those treated with Tf modified PTX loaded micelle (TPM) (39.5 days), PTX loaded micelle (PM) (34.8 days), Taxol (33.6 days), and saline (34.5 days). Noteworthy, TRPM did not lead to body weight loss compared with saline and was less toxic than TPM. These results indicated that TRPM could be a promising nanomedicine for glioma chemotherapy.

Transferrin-modified c[RGDfK]-paclitaxel loaded hybrid micelle for sequential blood-brain barrier penetration and glioma targeting therapy.

This work investigates the influence of drug absorption route (intestinal lymphatics vs. blood supply) on drug pharmacokinetics and tissue distribution. To achieve this aim, the pharmacokinetics and tissue distribution of model compounds [1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane, DDT; halofantrine] and lipids were assessed following intravenous delivery in lymph lipoproteins or plasma, and were found to differ significantly. For DDT, the clearance (CL) and volume of distribution (Vd ) were higher, whereas for halofantrine, CL and V(d) were lower, after entry in lymph versus plasma due, in particular, to differences in adipose tissue and liver uptake. In a recent study, halofantrine CL and V(d) were similar following entry in lymph or entry in plasma into the systemic circulation of animals predosed with lymph, whereas in the current study, predosing lymph did not influence DDT CL and V(d). For compounds such as DDT, changes to the route of absorption may thus directly impact on pharmacokinetics and tissue distribution, whereas for halofantrine factors that influence lymphatic transport may, by altering systemic lipoprotein concentrations, indirectly impact pharmacokinetics and tissue distribution. Ultimately, careful control of dosing conditions (formulation, prandial state), and thus the extent of lymphatic transport, may be important in assuring reproducible efficacy and toxicity for lymphatically transported drugs.

The impact of lymphatic transport on the systemic disposition of lipophilic drugs.

A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.

Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies.

Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs.

Profiling the Role of Deacylation-Reacylation in the Lymphatic Transport of a Triglyceride-Mimetic Prodrug.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.

Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions.

The lymphatic system hosts a large number of therapeutic targets that can be used to modulate a wide range of diseases including cancers, autoimmune and inflammatory disorders, infectious diseases and metabolic syndrome; however, drug access to the lymphatic system is often challenging. Over the past decades significant efforts have been made to promote drug transport to the lymphatics through medicinal chemistry approaches, and a number of promising progresses are emerging. Nevertheless, so far it remains difficult to clearly delineate the mechanism of lymphatic drug transport and to map the design criteria for lymphotropic drug molecules, and the attempts to synthesize lymph-directing drug candidates or drug derivatives are largely in an experience-driven, trial and error basis. Furthermore, complex experimental procedures required for the study of lymphatic drug transport have limited data accumulation in the field, and this in turn hampers mechanistic studies and understanding of drug design criteria. Our current study aims to 1) review and summarize published work that assessed lymphatic drug transport by both direct measurement (e.g. determination of drug concentrations in lymph fluid) or indirect measurement (e.g. imaging methods or by comparing the changes of pharmacokinetics profile in the absence and presence of lymphatic transport blocker); 2) to analyze lymphatic drug transport data of 185 drugs according to experimental models and conditions, followed by dataset regrouping according to the extent of lymphatic transport; 3) to establish different Artificial Intelligence (AI) models including Graph Convolutional Network (GCN), Graph Attention Network (GAT) and Graph Transformer (GT) to predict the potential of drug transport via the lymphatics following oral administration, during which process data augmentation approaches were employed to compensate for the limited data. The results demonstrated that our model can enhance data and lymphatic drug transport prediction by correlating in vivo data with the chemical structure of drugs (represented by Simplified Molecular Input Line Entry System, SMILES). Additionally, we analyzed the relationship between the extent of lymphatic transport and a number of physicochemical parameters (including LogP, LogD and molecular weight) of drugs with reported lymphatic absorption data. The results demonstrate that the capability of lymphatic transport does not appear to be determined by any single parameter alone.

Predicting lymphatic transport potential using graph transformer based on limited historical data from in vivo studies.

Compared to classic intravenous (IV) administration, subcutaneous (SC) delivery of monoclonal antibodies (mAbs) offers new opportunities to improve patient compliance and healthcare efficiency. However, insufficient understanding of drug absorption process following SC administration, particularly the role of lymphatic transport, may hinder the development of SC formulations for mAbs. The current study aimed to examine the absorption route of widely used anti-PD-(L)1 mAbs following SC injection, and four marketed products (Pembrolizumab, Tislelizumab, Envafolimab, Sugemalimab) were selected as the model drugs. In the thoracic lymph duct-cannulated rat model, all mAbs were found to be primarily absorbed via the lymphatics following SC injection, with 63.1-72.0 % of the administered dose recovered in the thoracic lymph, contributing to >80 % of SC bioavailability. This absorption pattern also resulted in elevated exposure of mAbs in draining lymph nodes (an order of magnitude higher drug concentrations compared to the systemic drug exposure). In addition, markedly different lymphatic absorption profiles were observed following SC administration at different sites, reflecting specific draining routes associated with certain anatomical regions in the rat. Our data suggested that the food pad is likely the optimal SC injection site for quantitative studies of lymphatic transport, whereas injection to the lower hind leg (a common SC injection site in previous studies) appeared to underestimate the absolute extent of lymphatic drug transport in the thoracic lymph duct-cannulated rat model, as lymphatic drainage from this region partially bypasses the cannulation site, leading to incomplete collection of draining lymph.

Subcutaneously administered anti-PD-(L)1 antibodies are predominantly absorbed via the lymphatic system, resulting in high drug exposure to draining lymph nodes.

ArticleTotal : 2	Year
Publication title Cited by 48	2015
Publication title	2026

Article	Year
Poly(ε-caprolactone)-block-poly(ethyl ethylene phosphate) micelles for brain-targeting drug delivery: in vitro and in vivo valuation. Pharmaceutical research\| PubMed ID: 20848303	2010
Micelle-based brain-targeted drug delivery enabled by a nicotine acetylcholine receptor ligand. Angewandte Chemie (International ed. in English)\| PubMed ID: 21542074	2011
Transferrin-conjugated polyphosphoester hybrid micelle loading paclitaxel for brain-targeting delivery: synthesis, preparation and in vivo evaluation. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 22306333	2012
Transferrin-modified c[RGDfK]-paclitaxel loaded hybrid micelle for sequential blood-brain barrier penetration and glioma targeting therapy. Molecular pharmaceutics\| PubMed ID: 22497485	2012
The impact of lymphatic transport on the systemic disposition of lipophilic drugs. Journal of pharmaceutical sciences\| PubMed ID: 23696002	2013
Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 24398334	2014
Profiling the Role of Deacylation-Reacylation in the Lymphatic Transport of a Triglyceride-Mimetic Prodrug. Pharmaceutical research\| PubMed ID: 25446770	2014
Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions. Pharmacological reviews\| PubMed ID: 39179383	2024
Predicting lymphatic transport potential using graph transformer based on limited historical data from in vivo studies. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 40393527	2025
Subcutaneously administered anti-PD-(L)1 antibodies are predominantly absorbed via the lymphatic system, resulting in high drug exposure to draining lymph nodes. Journal of pharmaceutical sciences\| PubMed ID: 41093037	2026

Luojuan Hu

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