High Lipophilicity Research Articles

Design, Synthesis, and Anti-Mycobacterial Evaluation of Triclosan-Isoniazid Hybrids.

A series of Triclosan-based hybrids and their Schiff base derivatives with isoniazid were designed through in silico modelling and synthesized using copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were then evaluated against both Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mab). However, none of the synthesized hybrids exhibited significant growth inhibition, with minimum inhibitory concentration (MIC) values consistently exceeding 100 µg/mL. To further investigate these findings, we conducted mechanistic studies including thermogravimetric analysis (TGA) and UV-Vis stability tests. TGA demonstrated thermal stability of the Schiff bases up to 270 °C, while UV-Vis analysis confirmed their chemical resilience across a wide pH spectrum, showing resistance to hydrolysis under acidic and basic conditions. The lack of observed antimicrobial activity may be attributed to the high lipophilicity of these molecules, as indicated by LogP values exceeding 5, which could limit their bioavailability. These findings suggest that although combining triclosan and isoniazid holds potential, further optimization of this hybrid strategy is necessary to improve efficacy.

Adaptation mechanism of clam Ruditapes philippinarum under polycyclic aromatic hydrocarbon stresses: Accumulation and excretion

Persistent organic pollutants (POPs) are easily accumulated in organisms due to its high lipophilicity. Bivalves are still one of the marine invertebrates with high species diversity despite experiencing with environmental pollution. However, studies investigating the adaptation mechanisms of bivalves towards POPs have been lacking. In this study, we chose benzo[a]pyrene (B[a]P), a typical POPs, to investigate the accumulation and excretion mechanism of clam Ruditapes philippinarum towards B[a]P. Laser confocal microscopy images of ovaries and testes confirmed significant colocalization between lipid droplets and B[a]P. However, B[a]P in the testes might mainly excrete with the excretory fluid. Furthermore, lipidomics results indicated that the upregulated TGs were TGs with 48–58 total carbon atoms and 6–12 double bonds in acyl side chains in ovaries, while the upregulated TGs mainly distributed in 48–58 total carbon atoms and 4–14 double bonds in acyl side chains in testes. In ovaries, gene expression of lipid metabolism and phospholipid metabolism basically presented an upward trend at Pro and Mat stages, while entirely performed a downregulation trend at Gro stage. Testes had the opposite regulation with that. Additionally, B[a]P prompted the excretion ability of female clams, but exhibited a complex effect in the male. This study provides a scientific basis for bivalve toxicology and healthy aquaculture, which is of great significance for marine ecological environment protection and aquatic product safety of China.

Rapeseed oleosomes facilitate intestinal lymphatic delivery and oral bioavailability of cannabidiol.

Due to high lipophilicity and extensive first-pass metabolic loss, cannabidiol (CBD) has low oral bioavailability. Co-administration of CBD and long-chain lipids facilitates the intestinal lymphatic delivery, resulting in higher systemic bioavailability, as well as high levels of the drug within the intestinal lymphatic system. However, despite previous attempts with various lipid-based formulations, the oral bioavailability of CBD is still limited. In this work, we have developed a novel formulation of CBD based on natural rapeseed oleosomes. In vivo studies in rats demonstrated that oral administration of CBD-loaded rapeseed oleosomes leads to substantially higher oral bioavailability and intestinal lymphatic targeting of CBD in comparison with rapeseed oil or artificial emulsion made of rapeseed oil and lecithin. In vitro mechanistic assessments, including in vitro lipolysis and peroxide value determination suggest that the lower oxidative state of the oil in oleosomes in comparison to crude oil or artificial emulsion is likely to be the main factor responsible for the superior performance of the CBD-loaded rapeseed oleosomes in vivo. Although further investigation will be needed, the data suggest that natural seeds-derived oleosomes can be used as a promising lipid-based drug delivery platform promoting the bioavailability and lymphatic delivery of lipophilic drugs.

Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities

For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.

Defective porous urchin-like ZnO/NiO microspheres-coated solid-phase microextraction fiber for analysis of trace polychlorinated biphenyls in milk.

Owing to the high lipophilicity of polychlorinated biphenyls (PCB), they easily accumulate in dairy products. Although usually present at very low levels, they pose a serious threat to human health. Therefore, developing a sensitive and reliable method for detecting PCB in dairy products is crucial. Herein, Herein, a metal-organic framework (MOF) material named with bimetallic nodes and double ligands was prepared as a precursor using a one-pot hydrothermal method. Defective porous urchin-like ZnO/NiO, derived from these MOF-based precursors (ZnNi-MOF-NH2) as a sacrificial template, was synthesized via pyrolysis to remove heat-sensitive ligands. To the best of our knowledge, this urchin-like nanostructured ZnO/NiO hybrid was utilized as a solid-phase microextraction (SPME) coating for the first time. Headspace SPME (HS-SPME) was developed for non-contact extraction of PCB in milk prior to gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis. Under optimal conditions, the HS-SPME-GC-MS/MS method exhibited a wide linear range (0.01-1000ng·L-1), low limits of detection (0.003-0.025ng·L-1), and high enrichment factors (5714-9906). Additionally, the performance of the ZnO/NiO SPME fiber coating showed no noticeable decrease after 175 uses. The method was applied to trace PCB analysis in milk samples, yielding recoveries of 70.3-114.1%. The ZnO/NiO derived from MOF-based material provides a promising candidate for SPME coatings to extract PCB and other analogs.

Comparison of triclosan and triclocarban in triggering immunotoxicity in larval zebrafish

As two efficient broad-spectrum sterilizing agents, triclosan (TCS) and triclocarban (TCC) are widely used, especially during the COVID-19 pandemic. The health risks caused by secondary pollution of TCS and TCC have aroused wide concern. Because of the similar mother nucleus structure and high lipophilicity, it remains unknown about the differences in the effect and mechanism of the toxicity (especially immunotoxicity) between TCS and TCC in organisms in the environment. In this study, we used zebrafish as a model to compare the immunotoxicity and mechanisms between the two pollutants at the same exposure concentration (0.6 µmol/L). The results showed that both TCS and TCC led to a hatching rate below 60% at the time point of 72 hours post fertilization (hpf) and the mortality rates of 40% and 50% at 120 hpf in larval zebrafish, respectively. The zebrafish exposed to TCS and TCC displayed malformations, such as shortened body, swimming sac closure, pericardial edema, yolk cyst deposition, and absorption disorder. Moreover, the developmental abnormalities caused by TCC were significantly severer than those caused by TCS. TCS exposure increased the proliferation rate of innate immune cells to 20% and decreased the number of mature T cells by 35%, while TCC exposure inhibited the differentiation of both innate immune cells and T cells, with the inhibition rates of 25% and 60%, respectively. The results of real-time quantitative PCR (RT-qPCR) and ELISA showed that TCS and TCC exposure up-regulated the expression levels of il-1β, il-6, and tnf-α, while il-10 and IgM exhibited opposite expression patterns. Additionally, both compounds slightly decreased C3 expression. The Pearson correlation analysis showed that the developmental toxicity induced by TCS and TCC had positive and negative correlations with the differentiation of immune cells, respectively. However, the toxicity induced by either TCS or TCC was positively correlated with the expression of pro-inflammatory cytokines. GO function and KEGG pathway enrichment analyses demonstrated that the target molecules of TCS and TCC were enriched in different signaling pathways, and the key network hub genes and the enriched regulatory pathways differed between TCS and TCC. The findings provide compelling evidence that TCS and TCC adopt different mechanisms in triggering immunotoxicity and offer a theoretical reference for the recognition, warning, and management of TCS and TCC-induced health risks.

Divergent Synthesis of Trifluoromethyl Ketones via Photoredox Activation of Halotrifluoroacetones

AbstractFluorine's high electronegativity, lipophilicity, and metabolic stability make it a valuable element for drug design and development. Consequently, significant synthetic efforts have focused on introducing fluorine and fluorinated motifs into organic molecules, with the synthesis of trifluoromethyl ketones (TFMKs) recently attracting considerable attention. Building on our ongoing research on radical organofluorine chemistry, we present herein the divergent synthesis of trifluoromethyl ketones directly from olefins using readily available chloro‐ and bromotrifluoroacetone as synthetic precursors of the trifluoroacetonyl radical under photoredox catalysis. Mechanistic studies revealed that the divergence is attained through radical polar crossover (RPC) and hydrogen atom transfer (HAT) mechanisms.

Cyclodextrin effects on the distribution, solubility and transport properties of umifenovir

The present study was initiated by an ambiguous opinion on the therapeutic efficacy of antiviral and potential anti-SARS-CoV-2 drug umifenovir (UMF). With a high degree of probability, low efficacy of UMF can be due to its poor solubility and, as follows, inefficient bioavailability after oral administration. In our investigation we aimed at improving the UMF solubility with cyclodextrins and its correlation to distribution (1-octanol/buffer and n-hexane/buffer systems) and permeability (biomimetic PermeaPad barrier). The experiments demonstrated a strong dependence of the UMF solubility and distribution parameters on the pH of the aqueous medium. The solubility of UMF was maximally increased up to 11.2-fold and 29.5-fold in HP-β-CD and SBE-β-CD solutions, respectively, with buffer pH 7.4. The distribution tests with the additions of several CDs concentrations to the buffer phase allowed to determine the intrinsic value of the distribution coefficient - the parameter important for the evaluation of the compound lipophilicity. The permeability-distribution interplay demonstrated the permeability to be mainly governed by the high lipophilicity of UMF.

Mono-palmitoyl-N-alkylurea ligands as specific activators of human Toll-like receptor 2/6 heterodimer.

Ligands for Toll-like-receptor 2 (TLR2) have demonstrated significant potential as immune-stimulating components in synthetic vaccines. Activation of TLR2 relies on the formation of dimeric complexes with either TLR1 or TLR6 and the nature of these dimers can impact therapeutic outcomes. The lipopeptide-based TLR2 ligands Pam3CysSK4 and Pam2CysSK4 have been extensively studied, and their recognition by different TLR-receptor heterodimers, TLR2/TLR1 and TLR2/TLR6, respectively, has been established. However, the high lipophilicity of these ligands, containing multiple palmitoyl residues, can result in solubility issues when used as vaccine adjuvants. To address this, we previously synthesized a less lipophilic ligand containing a single palmitoyl chain called mini-UPam, which effectively stimulates human moDC maturation. We here probe the receptor-dimer specificity of several mini-Upam derivatives and reveal that these mini-UPam are hTLR2/TLR6 selective ligands and that the introduction of longer urea alkyl chains does not shift the binding specificity to hTLR2/TLR1 heterodimers, in contrast to their Pam2CysSK4 and Pam3CysSK4 counterparts, pointing to a different binding mode of the UPam ligands.

Iridium-Catalyzed Enantioselective Propargylic C-H Trifluoromethylthiolation and Related Processes.

The trifluoromethylthio group (SCF3) has gained increasing prominence in the field of drug design and development due to its unique electronic properties, remarkable stability, and high lipophilicity, but its derivatives remain challenging to access, especially in an enantioselective manner. In this Communication, we present an enantioselective iridium-catalyzed trifluoromethylthiolation of the propargylic C(sp3)-H bonds of alkynes. This protocol demonstrates its efficacy across a diverse array of alkyne substrates, including B- and Si-protected terminal alkynes as well as those derived from natural products and pharmaceuticals, to give trifluoromethyl thioethers with good to excellent yield and stereoselectivity. Moreover, this protocol could be modified to access enantioenriched difluoromethyl and chlorodifluoromethyl thioethers (SCF2H and SCF2Cl derivatives), significantly expanding the space of synthetically accessible enantioenriched fluoroorganic compounds.

Advances in Research on Semi-Synthesis, Biotransformation and Biological Activities of Novel Derivatives from Maslinic Acid

Since ancient times, humans have turned to medicinal plants for treating various ailments and curing specific diseases, as these natural plants serve as the primary source of a range of phytochemicals, including triterpenes. Maslinic acid (MA), also known as (2α,3β)-2,3-dihydroxyolean-12-en-28-oic acid, is a pentacyclic triterpene acid present in numerous plants including olive, known for its high safety profile in humans. Recent experimental data increasingly suggests that MA exhibits diverse biological properties and therapeutic effects on various organ diseases, highlighting its significant potential for clinical applications due to its diverse potential pharmacological activities that promote health and resist various diseases, such as hypoglycemic, neuroprotective, anti-tumor, anti-inflammatory, antioxidant and multiple other biological activities. However, the undesirable pharmacokinetic properties of MA, such as high lipophilicity, pose a limitation to its application and development, impacting its bioavailability. Consequently, extensive research spanning decades has focused on structurally modifying MA to overcome these limitations and enhance its pharmacokinetic and therapeutic characteristics, leading to the identification of several potential lead compounds. In this review, we focus on the progress of research in recent years on MA with interest to its chemical and enzymatic modifications as well as the relationships between the modified structures or derivatives and their biological activities.

Development and Evaluation of a Cost-Effective, Carbon-Based, Extended-Release Febuxostat Tablet.

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with varying FEB-to-charcoal ratios using FTIR and DSC for physical interactions and followed USP standards for overall assessment. The optimal 1:0.25 FEB-to-charcoal ratio demonstrated a consistent 12 h zero-order release pattern. In vivo studies indicated a significantly extended plasma profile compared to immediate-release tablets. The optimal tablets demonstrated acceptable hardness and disintegration times. This innovative approach enhances patient compliance, improves bioavailability, and reduces production costs, offering a promising solution for controlled FEB delivery.

Effect of molecular structure on membrane diffusion: Triphenylmethanes across Escherichia coli studied by second harmonic light scattering

Understanding how the structure of molecules affects their permeability across cell membranes is crucial for many topics in biomedical research, including the development of drugs. In this work, we examine the transport rates of structurally similar triphenylmethane dyes, malachite green (MG) and brilliant green (BG), across the membranes of living Escherichia coli (E. coli) cells and biomimetic liposomes. Using the time-resolved second harmonic light scattering technique, we found that BG passively diffuses across the E. coli cytoplasmic membrane (CM) 3.8 times faster than MG. In addition, BG exhibits a diffusion rate 3.1 times higher than MG across the membranes of liposomes made from E. coli polar lipid extracts. Measurements on these two molecules, alongside previously studied crystal violet (CV), another triphenylmethane molecule, are compared against the set of propensity rules developed by Lipinski and co-workers for assessing the permeability of hydrophobic ion-like drug molecules through biomembranes. It indicates that BG’s increased diffusion rate is due to its higher lipophilicity, with a distribution coefficient 25 times greater than MG. In contrast, CV, despite having similar lipophilicity to MG, shows negligible permeation through the E. coli CM on the observation scale, attributed to its more hydrogen bonding sites and larger polar surface area. Importantly, cell viability tests revealed that BG’s antimicrobial efficacy is ∼2.4 times greater than that of MG, which aligns well with its enhanced diffusion into the E. coli cytosol. These findings offer valuable insights for drug design and development, especially for improving the permeability of poorly permeable drug molecules.

Evaluating the efficacy of Rose Bengal-PVA combinations within PCL/PLA implants for sustained cancer treatment.

The current investigation aims to address the limitations of conventional cancer therapy by developing an advanced, long-term drug delivery system using biocompatible Rose Bengal (RB)-loaded polyvinyl alcohol (PVA) matrices incorporated into 3D printed polycaprolactone (PCL) and polylactic acid (PLA) implants. The anticancer drug RB's high solubility and low lipophilicity require frequent and painful administration to the tumour site, limiting its clinical application. In this study, RB was encapsulated in a PVA (RB@PVA) matrix to overcome these challenges and achieve a localised and sustained drug release system within a biodegradable implant designed to be implanted near the tumour site. The RB@PVA matrix demonstrated an RB loading efficiency of 77.34 ± 1.53%, with complete RB release within 30min. However, when integrated into implants, the system provided a sustained RB release of 75.84 ± 8.75% over 90 days. Cytotoxicity assays on PC-3 prostate cancer cells indicated an IC50 value of 1.19 µM for RB@PVA compared to 2.49 µM for free RB, effectively inhibiting cancer cell proliferation. This innovative drug delivery system, which incorporates a polymer matrix within an implantable device, represents a significant advancement in the sustained release of hydrosoluble drugs. It holds promise for reducing the frequency of drug administration, thereby improving patient compliance and translating experimental research into practical therapeutic applications.

Synthesis and characterization of rhenium and Technetium-99 m tricarbonyl and dicarbonyl complexes with quinaldic acid and Arsenic/Phosphorus derivatives

The synthesis and characterization of neutral tricarbonyl fac-[Re/99mTc(quin)(X)(CO)3] and dicarbonyl cis–trans-[Re/99mTc(quin)(X)2(CO)2] mixed ligand complexes with quinaldic acid (quin) as the bidentate ligand and trimethoxyphosphine [P(OCH3)3], tris(hydroxymethyl)-phosphine [P(CH2OH)3], triphenylphosphine (PPh3), and triphenylarsine (AsPh3) as the monodentate ligands (X) is described. The synthesis of the [2 + 1] tricarbonyl complexes proceeds by displacement of the water molecule of the fac-[Re/99mTc(quin)(H2O)(CO)3] by the monodentate ligand. Interestingly, the synthesis of the [2 + 1 + 1] dicarbonyl complexes was achieved only for PPh3 after replacing the CO group trans to PPh3 with a second PPh3 molecule. The latter complex was also obtained by refluxing quinaldic acid with the trans-mer-[Re(PPh3)2(Cl)(CO)3] precursor in toluene. Rhenium complexes were prepared in satisfactory yields and fully characterized. At the technetium-99 m level, complexes were produced in high radiochemical yields and characterized by comparative chromatographic analysis using the analogous rhenium complexes. Complexes have shown varying stability against transchelation by cysteine and histidine in agreement with the decreasing σ-donating capacity of the monodentate ligand (P(OCH3)3 > P(CH2OH)3 > PPh3 > AsPh3. The stable complexes with PPh3 showed high lipophilicity (LogP 2.90 and 3.10, respectively) due to the lipophilic nature of the monodentate ligands. The σ-donor and π-acceptor capacity of the monodentate ligand strongly influences the formation and stability of the complexes, and these characteristics should be considered before choosing the appropriate ligand for radiopharmaceuticals design.

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Between Theory and Practice: Computational/Experimental Integrated Approaches to Understand the Solubility and Lipophilicity of PROTACs.

Emerging drug candidates more often fall in the beyond-rule-of-five chemical space. Among them, proteolysis targeting chimeras (PROTACs) have gained great attention in the past decade. Although physicochemical properties of small molecules accomplishing Lipinski's rule-of-five can now be easily predicted through models generated by large data collections, for PROTACs the knowledge is still limited and heterogeneous, hampering their prediction. Here, the kinetic solubility and the coefficient of distribution at pH 7.4 (LogD7.4) of 44 PROTACs, designed and synthesized to cover a wide chemical space, were measured. Their generally low solubility and high lipophilicity required an optimization of the experimental methods. Concerning the LogD7.4, several in silico prediction tools were tested, which were quite accurate for classical small molecules but provided dissimilar outcomes for PROTACs. Finally, in silico models for the prediction of PROTACs' kinetic solubility and LogD7.4 were proposed by combining in-house generated experimental data with 3D description of PROTACs' structures.

Phyto-Active Components Delivered through Lipid Nanodrug Carriers as a Promising Avenue for the Treatment of Alzheimer’s Disease: Their Present Status and Industrial Viability

Introduction: Present years have witnessed an unprecedented growth of Alzheimer’s disease (AD) with limited scope for conventional therapeutics. Plant-derived active components (PACs) are being widely utilized as alternate, compatible, efficacious, eco-friendly strategies to ameliorate therapeutic benefits in AD while minimizing toxic effects. However, delivery of PACs in the regular dosage form often faces challenges due to low stability and bioavailability, brainspecific delivery, dose-related toxic effects, etc., which can be subsided by experimentally fabricated Lipid Nano Drug Carriers (LNCs). The objective of this study is to provide a comprehensive, evidence-based review on recent progress in the PACs-loaded lipid nanocarriers (PLNs)-based therapeutic strategies for AD. Methods: For the study implementation, a systematic literature review was carried out from various scientific potential databases like Scopus, Pubmed, Web of Science, etc., and relevant evidence- based pre-clinical research data was pooled to draw conclusive outcomes. Results: LNCs are treated as promising avenues to effectively deliver various PACs into the brain due to their high lipophilicity with ultra-micron size and tunable surface features, which make them eligible to pass through the blood-brain barrier. Both passive and active targeting of PLNs has been explored to target AD by overcoming the off-target bio delivery problems. Conclusion: The review provided updated preclinical study-based data on the potentialities of PLNs in overcoming AD. Simultaneously, equal weightage was devoted to the issues faced beyond the laboratory in their successful technology transfer. The study would be beneficial in unveiling important insights into the implications of PLNs for their futuristic clinical applicability.

Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold

The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC50: 4.9 μM) and the nuclear translocation of NFAT at 30 and 10 μM, respectively, without affecting the electrophysiological function of TRPM4 and TRPM7 channels. Computational modeling appears to support its direction binding to Orai proteins that form the transmembrane CRACchannel.

Intestinal Lymphatic Biology, Drug Delivery and Therapeutics: Current status and Future directions.

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 focussed primarily on the drug 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' on lymphatic transport pathways. With the increasing development of novel biological therapeutics there has been interest in whether these novel 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 summarise 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 into the future. Significance Statement This comprehensive review details 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.