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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. [ABSTRACT FROM AUTHOR]

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Finetuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)STG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bondbased linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect. [ABSTRACT FROM AUTHOR]

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration.Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport.Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively.Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

Many viruses, bacteria, and parasites rely on the lymphatic system for survival, replication, and dissemination. While conventional anti-infectives can combat infection-causing agents in the bloodstream, they do not reach the lymphatic system to eradicate the pathogens harboured there. This can result in ineffective drug exposure and reduce treatment effectiveness. By developing effective lymphatic delivery strategies for antiviral, antibacterial, and antiparasitic drugs, their systemic pharmacokinetics may be improved, as would their ability to reach their target pathogens within the lymphatics, thereby improving clinical outcomes in a variety of acute and chronic infections with lymphatic involvement (e.g., acquired immunodeficiency syndrome, tuberculosis, and filariasis). Here, we discuss approaches to targeting anti-infective drugs to the intestinal and dermal lymphatics, aiming to eliminate pathogen reservoirs and interfere with their survival and reproduction inside the lymphatic system. These include optimized lipophilic prodrugs and drug delivery systems that promote lymphatic transport after oral and dermal drug intake. For intestinal lymphatic delivery via the chylomicron pathway, molecules should have logP values >5 and long-chain triglyceride solubilities >50 mg/g, and for dermal lymphatic delivery via interstitial lymphatic drainage, nanoparticle formulations with particle size between 10 and 100 nm are generally preferred. Insight from this review may promote new and improved therapeutic solutions for pathogen eradication and combating infective diseases, as lymphatic system involvement in pathogen dissemination and drug resistance has been neglected compared to other pathways leading to treatment failure. [Display omitted] • A variety of viruses, bacteria, and parasites survive, replicate, and spread within the lymphatic system. • Lymphatics have been neglected compared to other pathways leading to treatment failure or re-infection. • Developing efficient lymphatic delivery strategies can enable effective targeting of pathogens within the lymphatic system. • A lymph-targeting strategy would improve systemic pharmacokinetics by bypassing liver first-pass metabolism. [ABSTRACT FROM AUTHOR]

[Display omitted] • ・SNEDDS A composed of castor oil significantly improved oral absorption of clofazimine. • ・SNEDDS A provided the fine droplets under acidic, neutral and basic conditions. • ・Over 90% of clofazimine systemically absorbed would be via lymphatic transport. Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular–luminal perfused small intestine–liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A. [ABSTRACT FROM AUTHOR]

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake. Targeting a remote nidus beyond the gut via oral administration is highly challenged by various biological barriers over and above the prevailing strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

Cytokine storm is a phenomenon whereby the overreaction of the human immune system leads to the release of inflammatory cytokines, which can lead to multiple organ dysfunction syndrome. At present, the existing drugs for the treatment of cytokine storm have limited efficacy and severe adverse effects. Here, we report a lymphatic targeting self-microemulsifying drug delivery system containing baicalein to effectively inhibit cytokine storm. Baicalein self-microemulsion with phospholipid complex as an intermediate carrier (BAPC-SME) prepared in this study could be spontaneously emulsified to form 12-nm oil-in-water nanoemulsion after administration. And then BAPC-SME underwent uptake by enterocyte through endocytosis mediated by lipid valve and clathrin, and had obvious characteristics of mesenteric lymph node targeting distribution. Oral administration of BAPC-SME could significantly inhibit the increase in plasma levels of 14 cytokines: TNF-α, IL-6, IFN-α, MCP-1, IL-17A, IL-27, IL-1α, GM-CSF, MIG, IFN-β, IL-12, MIP-3α, IL-23, and RANTES in mice experiencing systemic cytokine storm. BAPC-SME could also significantly improve the pathological injury and inflammatory cell infiltration of lung tissue in mice experiencing local cytokine storm. This study does not only provide a new lymphatic targeted drug delivery strategy for the treatment of cytokine storm but also has great practical significance for the clinical development of baicalein self-microemulsion therapies for cytokine storm. [ABSTRACT FROM AUTHOR]

[Display omitted] Cerasomes are a modified form of liposomes containing both inorganic and organic parts and due to their strong polyorganosiloxane surface have remarkably high morphological stability and provide easier functionalization compared with conventional liposomes. To investigate the potential of these nanocarriers for oral delivery, bile salt integrated cerasomes (named bilocerasomes) encapsulating idarubicin hydrochloride (IDA) were prepared and characterized. The optimum formulation showed excellent stability in the simulated gastrointestinal fluids as well as under storage conditions. The oral pharmacokinetics of the IDA solution, empty nanocarrier + drug solution, and IDA-loaded bilocerasome were evaluated. The nanoformulation significantly increased the area under the drug concentration–time curve and the mean residence time (∼14.3- and 9-fold, respectively). The results obtained from cell uptake and chylomicron flow blocking approach revealed that bilocerasomes are absorbed into the intestinal cells via a clathrin/caveolin-independent endocytosis pathway and transported to the systemic circulation extensively via the intestinal lymphatic vessels. Considering the high stability of the prepared bilocerasome, noticeable participation of lymphatic transport in its systemic absorption and marked enhancement in the oral absorption of IDA, bilocerasomes can be introduced as a capable carrier for improving the oral bioavailability of drugs, particularly those that hepatic first-pass metabolism seriously limits their oral absorption. [ABSTRACT FROM AUTHOR]

Buprenorphine (BUP) is a potent opioid analgesic that is widely used for severe pain management and opioid replacement therapy. The oral bioavailability of BUP, however, is significantly limited by first-pass metabolism. Previous studies have shown that triglyceride (TG) mimetic prodrugs of the steroid hormone testosterone circumvent first-pass metabolism by directing drug transport through the intestinal lymphatics, bypassing the liver. The current study expanded this prodrug strategy to BUP. Here different selfimmolative (SI) linkers were evaluated to conjugate BUP to the 2 position of the TG backbone via the phenol group on BUP. The SI linkers were designed to promote drug release in plasma. Lipolysis of the prodrug in the intestinal tract was examined via incubation with simulated intestinal fluid (SIF), and potential for parent drug liberation in the systemic circulation was evaluated via incubation in rat plasma. Lymphatic transport and bioavailability studies were subsequently conducted in mesenteric lymph duct or carotid artery-cannulated rats, respectively. TG prodrug derivatives were efficiently transported into the lymphatics (up to 45% of the dose in anaesthetised rats, vs. less than 0.1% for BUP). Incorporation of the SI linkers facilitated BUP release from the prodrugs in the plasma and in concert with high lymphatic transport led to a marked enhancement in oral bioavailability (up to 22-fold) compared to BUP alone. These data suggest the potential to develop an orally bioavailable BUP product which may have advantages with respect to patient preference when compared to current sublingual, transdermal patch or parenteral formulations. [ABSTRACT FROM AUTHOR]

The drainage of fluid and solutes along lymphatic pathways from the brain has been found to be impaired in mouse models of multiple sclerosis, Alzheimer's disease, and Parkinson's disease where neuroinflammation is present. We recently demonstrated that 3 H-albumin, a model therapeutic protein (∼65 kDa), undergoes preferential lymphatic transport from the brain using a cervical lymph cannulation model in healthy rats. We thus hypothesized that neuroinflammation would impede the lymphatic transport of 3 H-albumin from the brain. Our aim was to quantify the impact of acute neuroinflammation on drainage of the model therapeutic protein ( 3 H-albumin) from the rat brain into blood and deep cervical lymph. To establish the required neuroinflammation model, male Sprague-Dawley rats were administered an intraperitoneal (IP) dose of 0.5-2 mg/kg lipopolysaccharide (LPS, Escherichia coli ) or a saline control. After 12 or 24 h, brain samples were collected and analyzed for concentrations of interferon gamma (IFN-γ) using a commercial enzyme-linked immunosorbent assay (ELISA) kit. The impact of neuroinflammation on the drainage of 3 H-albumin from the brain was determined via IP administration of 2 mg/kg LPS or saline followed by cannulation of the carotid artery for blood collection 24 h later with/without cannulation or ligation at the efferent deep cervical lymph trunk. Rats were then administered 3 H-albumin via direct injection into the brain striatum or via intravenous (IV) injection (lymph-intact group only). Blood ± lymph samples were collected for up to 8 h following dosing. At the end of the study, brain and lymph node samples were harvested for biodistribution analysis, with samples analyzed for radioactivity levels via scintillation counting. Brain concentrations of the pro-inflammatory cytokine IFN-γ were only significantly elevated 24 h after IP administration of 2 mg/kg LPS compared to saline control. Therefore, this induction regimen was utilized for subsequent studies. The plasma concentrations of 3 H-albumin over time were elevated in LPS-induced rats compared to saline-injected rats in the lymph-intact and lymph-ligated groups but not in the lymph-cannulated group. In the deep cervical lymph-cannulated animals, the lymph transport of 3 H-albumin was not increased and appeared to be slower in the LPS-administered rats. Acute LPS-induced neuroinflammation therefore led to an enhanced overall transport of 3 H-albumin from the brain into the systemic circulation. This appeared to be primarily due to increased transport of 3 H-albumin from the brain directly into the blood circulation as 3 H-albumin transport from the brain via the lymphatics was not increased in the LPS-induced neuroinflammation model. Such changes in the clearance of therapeutic proteins from the brain in the setting of neuroinflammation may impact the therapeutic efficacy and safety.

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

The formation of protein corona (PC) is important for promoting the in vivo delivery of nanoparticles (NPs). However, PC formed in the physiological environment of oral delivery is poorly understood. Here, we engineered seven types of trimethyl chitosan–cysteine (TC) NPs, with distinct molecular weights, quaternization degrees, and thiolation degrees, to deeply investigate the influence of various PC formed in the physiological environment of oral delivery on in vivo gene delivery of polymeric NPs, further constructing the relationship between the surface characteristics of NPs and the efficacy of oral gene delivery. Our findings reveal that TC7 NPs, with high molecular weight, moderate quaternization, and high sulfhydryl content, modulate PC formation in the gastrointestinal tract, thereby reducing particle size and promoting oral delivery of gene loaded TC7 NPs. Orally delivered TC7 NPs target macrophages by in situ adsorption of apolipoprotein (Apo) B48 in intestinal tissue, leading to the improved in vivo antihepatoma efficacy via the natural tumor homing ability of macrophages. Our results suggest that efficient oral delivery of genes can be achieved through an in situ customized ApoB48-enriched PC, offering a promising modality in treating macrophage-related diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

The oral delivery of doxorubicin (DOX), an anti-cancer drug, encounters multiple hurdles such as limited gastrointestinal permeability, P-glycoprotein-mediated efflux, brief intestinal residence, and rapid degradation. This study introduced a novel approach utilizing hyaluronic acid (HA)-grafted fatty acid monoglycerides (HGD) to encapsulate DOX, forming HGD-DOX nanoparticles, aimed at enhancing its oral bioavailability. Drug encapsulated by HGD provided several advantages, including extended drug retention in the gastrointestinal tract, controlled release kinetics, and promotion of lymphatic absorption in the intestine. Additionally, HGD-DOX nanoparticles could specifically target CD44 receptors, potentially increasing therapeutic efficacy. The uptake mechanism of HGD-DOX nanoparticles primarily involved clathrin-mediated, caveolin-mediated and macropinocytosis endocytosis. Pharmacokinetic analysis further revealed that HGD significantly prolonged the in vivo residence time of DOX. In vivo imaging and pharmacodynamic studies indicated that HGD possessed tumor-targeting capabilities and exhibited a significant inhibitory effect on tumor growth, while maintaining an acceptable safety profile. Collectively, these findings position HGD-DOX nanoparticles as a promising strategy to boost the oral bioavailability of DOX, offering a potential avenue for improved cancer treatment. [Display omitted] • The development of a series of hyaluronic acid derivatives characterized by high stability both in vitro and in vivo. • Identification and validation of an efficient oral transport mechanism via lymphatic pathways • Discovery of nanoparticles that demonstrates exceptional anticancer efficacy and safety through active CD44 engagement. [ABSTRACT FROM AUTHOR]

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake. [ABSTRACT FROM AUTHOR]

We previously developed a mechanism-based pharmacokinetic (MBPK) model to characterize the PK of a lymphocyte-targeted, long-acting 3 HIV drug-combination nanoparticle (DcNP) formulation of lopinavir, ritonavir, and tenofovir. MBPK describes time-courses of plasma drug concentration and has provided an initial hypothesis for the lymphatic PK of DcNP. Because anatomical and physiological interpretation of MBPK is limited, in this Part 2, we report the development of a Physiologically Based Pharmacokinetic (PBPK) model for a detailed evaluation of the systemic and lymphatic PK of drugs associated with DcNP. The DcNP model is linked to the PBPK model presented earlier in Part 1 to account for the disposition of released free drugs. A key feature of the DcNP model is the uptake of the injected dose from the subcutaneous site to the adjacent lymphoid depot, routing through the nodes within and throughout the lymphatic network, and its subsequent passage into the blood circulation. Furthermore, the model accounts for DcNP transport to the lymph by lymphatic recirculation and mononuclear cell migration. The present PBPK model can be extended to other nano-drug combinations that target or transit through the lymphatic system. The PBPK model may allow scaling and prediction of DcNP PK in humans. [ABSTRACT FROM AUTHOR]

Buprenorphine (BUP) is a potent opioid analgesic that is widely used for severe pain management and opioid replacement therapy. The oral bioavailability of BUP, however, is significantly limited by first-pass metabolism. Previous studies have shown that triglyceride (TG) mimetic prodrugs of the steroid hormone testosterone circumvent first-pass metabolism by directing drug transport through the intestinal lymphatics, bypassing the liver. The current study expanded this prodrug strategy to BUP. Here different self-immolative (SI) linkers were evaluated to conjugate BUP to the 2 position of the TG backbone via the phenol group on BUP. The SI linkers were designed to promote drug release in plasma. Lipolysis of the prodrug in the intestinal tract was examined via incubation with simulated intestinal fluid (SIF), and potential for parent drug liberation in the systemic circulation was evaluated via incubation in rat plasma. Lymphatic transport and bioavailability studies were subsequently conducted in mesenteric lymph duct or carotid artery-cannulated rats, respectively. TG prodrug derivatives were efficiently transported into the lymphatics (up to 45% of the dose in anaesthetised rats, vs. less than 0.1% for BUP). Incorporation of the SI linkers facilitated BUP release from the prodrugs in the plasma and in concert with high lymphatic transport led to a marked enhancement in oral bioavailability (up to 22-fold) compared to BUP alone. These data suggest the potential to develop an orally bioavailable BUP product which may have advantages with respect to patient preference when compared to current sublingual, transdermal patch or parenteral formulations.

Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK. Two species contribute simultaneously to the drug PK: drugs that dissociate from DcNP (Part 1) and drugs retained in DcNP (Part 2, presented separately). Here, we describe the PBPK modeling of the nanoparticle-free drugs. The free-drug model was built on subcutaneous injections of suspended lopinavir, ritonavir, and tenofovir in NHP, and validated by external experiments. A novelty was the design of a lymphatic network as part of a whole-body PBPK system which included major lymphatic regions: the cervical, axillary, hilar, mesenteric, and inguinal nodes. This detailed/regionalized description of the lymphatic system and mononuclear cells represents an unprecedented level of prediction that renders the free-drug model extendible to other small-drug molecules targeting the lymphatic system at both the regional and cellular levels. [ABSTRACT FROM AUTHOR]

Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated. [Display omitted] • Delivery to lymph is a valuable pathway to increase targeted delivery of therapeutics to their site of action. • The lipophilic prodrug technology is a viable strategy to increase lymphatic delivery. • Bioavailability and biodistribution can be modified after oral administration of lipophilic lymph-directed prodrugs. • Further research is warranted to define optimal medicinal chemistry parameters for the design of lymph-targeting prodrugs. [ABSTRACT FROM AUTHOR]

Heparins show great anticoagulant effect with few side effects, and are administered by subcutaneous or intravenous route in clinics. To improve patient compliance, oral administration is an alternative route. Nonetheless, oral administration of heparins still faces enormous challenges due to the multiple obstacles. This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins, to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism. Moreover, several approaches have been developed to overcome these obstacles, such as improving stability of heparins in the gastrointestinal tract, enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins. Overall, this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.

The aim of the present investigation was to fabricate and evaluate solid lipid nanoparticles (SLNs) of asenapine maleate (AM) to improve its oral bioavailability (BA). AM-SLNs were prepared by high speed homogenization followed by ultrasonication technique. The resultant SLNs exhibited particle size, zeta potential and entrapment efficiency of 114.3 ± 3.5 nm, −12.9 ± 3.8 mV, and 84.10% ± 2.90% respectively. In vitro release study of AM-SLNs showed 9.23% ± 2.72% and 92.09% ± 3.40% release of AM in pH 1.2 medium and phosphate buffer pH 6.8, respectively, indicating higher potential of lymphatic uptake. Cell viability study using Caco-2 cell line indicated non-toxicity of the carriers and drug. The uptake of AM-SLNs across Caco-2 cell line was time and energy dependent exhibiting clathrin-claveole mediated endocytosis transport. Cellular uptake of Coumarin loaded SLNs was effectively increased as compared to the dye solution. The pharmacokinetic results in rats showed 50.19-fold improvement in BA of AM after fabrication of SLNs. Collectively, all these findings demonstrated effectiveness of SLNs to improve therapeutic efficacy of AM in the treatment of schizophrenia.

The transport of lymph through the lymphatic vasculature is the mechanism for returning excess interstitial fluid to the circulatory system, and it is essential for fluid homeostasis. Collecting lymphatic vessels comprise a significant portion of the lymphatic vasculature and are divided by valves into contractile segments known as lymphangions. Despite its importance, lymphatic transport in collecting vessels is not well understood. We present a computational model to study lymph flow through chains of valved, contracting lymphangions. We used the Navier–Stokes equations to model the fluid flow and the immersed boundary method to handle the two-way, fluid–structure interaction in 2D, non-axisymmetric simulations. We used our model to evaluate the effects of chain length, contraction style, and adverse axial pressure difference (AAPD) on cycle-mean flow rates (CMFRs). In the model, longer lymphangion chains generally yield larger CMFRs, and they fail to generate positive CMFRs at higher AAPDs than shorter chains. Simultaneously contracting pumps generate the largest CMFRs at nearly every AAPD and for every chain length. Due to the contraction timing and valve dynamics, non-simultaneous pumps generate lower CMFRs than the simultaneous pumps; the discrepancy diminishes as the AAPD increases. Valve dynamics vary with the contraction style and exhibit hysteretic opening and closing behaviors. Our model provides insight into how contraction propagation affects flow rates and transport through a lymphangion chain. [ABSTRACT FROM AUTHOR]

Andrographolide (AG) is an antitumor phytochemical that acts against non-Hodgkin’s lymphoma. However, AG shows low oral bioavailability due to extensive first-pass metabolism and P-glycoprotein efflux. Novel biocompatible lipoprotein-simulating nanosystems, emulsomes (EMLs), have gained significant attention due to their composition of natural components, in addition to being lymphotropic. Loading AG on EMLs is believed to mitigate the disadvantage of AG and enhance its lymphatic transport. This study developed a chylomicron-simulating system (EMLs) as a novel tool to overcome the AG oral delivery obstacles. Optimized EML-AG had a promising vesicular size of 281.62 ± 1.73 nm, a zeta potential of − 22.73 ± 0.06 mV, and a high entrapment efficiency of 96.55% ± 0.25%, which favors lymphatic targeting. In vivo pharmacokinetic studies of EML-AG showed significant enhancement (> sixfold increase) in the rate and extent of AG absorption compared with free AG. However, intraperitoneal injection of a cycloheximide inhibitor caused a significant decrease in AG absorption (~ 52%), confirming the lymphatic targeting potential of EMLs. Therefore, EMLs can be a promising novel nanoplatform for circumventing AG oral delivery obstacles and provide targeted delivery to the lymphatic system at a lower dose with fewer side effects. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to elaborate on 'bioemulsomes,' novel biocompatible lipoprotein analogs for effective lymphatic transport of baicalin (BCL). Methods: BCL bioemulsomes were developed and optimized and in vitro physicochemical characterization performed. The bioavailability of BCL bioemulsomes compared with free BCL was investigated using in vivo pharmacokinetics studies. Finally, BCL lymphatic transport was assessed via cycloheximide blockade assay. Results: Optimized BCL-loaded nanoemulsomes showed promising in vitro characteristics that favor lymphatic targeting. In vivo pharmacokinetics showed a significant improvement in bioavailability over free BCL. A significant decrease in BCL emulsome absorption (33%) was exhibited after chemical blockage of the lymphatic pathway, confirming the lymphatic transport potential. Conclusion: Bioemulsomes could be a promising tool for bypassing BCL oral delivery hurdles as well as lymphatic transport, paving the way for potential treatment of lymphoma. [ABSTRACT FROM AUTHOR]

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications. Orally administered molecular drugs and particulates could be absorbed alternatively via lymphatic transport. There are two main pathways—the chylomicron and M cell pathway—for efficient lymphatic transport. [Display omitted] [ABSTRACT FROM AUTHOR]

Hengfeng Liao1,2, Yue Gao1,2, Chunfang Lian1,2, Yun Zhang1,2, Bangyuan Wang1,2, Yanfang Yang1,2, Jun Ye1,2, Yu Feng1,2, Yuling Liu1,2 1State Key Laboratory of Bioactive substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, People’s Republic of China; 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of ChinaCorrespondence: Yuling LiuState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050, People’s Republic of ChinaTel +86 108 928 5188Fax +86 108 928 5190Email ylliu@imm.ac.cnPurpose: The aims of this study were to prepare a baicalein self-microemulsion with baicalein-phospholipid complex as the intermediate (BAPC-SMEDDS) and to compare its effects with those of conventional baicalein self-microemulsion (CBA-SMEDDS) on baicalein oral absorption and lymphatic transport.Methods: Two SMEDDS were characterized by emulsifying efficiency, droplet size, zeta potential, cloud point, dilution stability, physical stability, and in vitro release and lipolysis. Different formulations of 40 mg/kg baicalein were orally administered to Sprague-Dawley rats to investigate their respective bioavailabilities. The chylomicron flow blocking rat model was used to evaluate their lymphatic transport.Results: The droplet sizes of BAPC-SMEDDS and CBA-SMEDDS after 100x dilution were 9.6±0.2 nm and 11.3±0.4 nm, respectively. In vivo experiments indicated that the relative bioavailability of CBA-SMEDDS and BAPC-SMEDDS was 342.5% and 448.7% compared to that of free baicalein (BA). The AUC0–t and Cmax of BAPC-SMEDDS were 1.31 and 1.87 times higher than those of CBA-SMEDDS, respectively. The lymphatic transport study revealed that 81.2% of orally absorbed BA entered the circulation directly through the portal vein, whereas approximately 18.8% was transported into the blood via lymphatic transport. CBA-SMEDDS and BAPC-SMEDDS increased the lymphatic transport ratio of BA from 18.8% to 56.2% and 70.2%, respectively. Therefore, self-microemulsion not only significantly improves oral bioavailability of baicalein, but also increases the proportion lymphatically transported. This is beneficial to the direct interaction of baicalein with relevant immune cells in the lymphatic system and for proper display of its effects.Conclusion: This study demonstrates the oral absorption and lymphatic transport characteristics of free baicalein and baicalein SMEDDS with different compositions. This is of great significance to studies on lymphatic targeted delivery of natural immunomodulatory compounds.Keywords: SMEDDS, phospholipid complex, baicalein, oral bioavailability, lymphatic transport

In the present study, a water insoluble drug named silybin was encapsulated into self-nanoemulsifying drug delivery system (SNEDDS) following the preparation of silybin–phospholipid complex (SB–PC), then several methods were carried out to characterize SB–PC–SNEDDS and elucidate its mechanisms to improve the oral absorption of SB. Using a dynamic in vitro digestion model, the lipolysis of SB–PC–SNEDDS was proved to be mainly related with the property of its lipid excipients. SB–PC–SNEDDS could significantly enhance the transport of SB across Caco-2 cells, which may partly attribute to the increased cell membrane fluidity and the loss of tight junction according to the analysis results of fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and tight junction protein (ZO-1). The result of in situ perfusion showed the intestinal absorption of SB from high to low was SB–PC–SNEDDS, SB–PC, and SB. The extent of lymphatic transport of SB–PC and SB–PC–SNEDDS via the mesenteric duct was 12.2 and 22.7 folds of that of SB, respectively. In the lymph duct cannulated rats, the relative bioavailability (Fr) of SB–PC and SB–PC–SEDDS compared to SB was 1265.9% and 1802.5%, respectively. All the above results provided mechanistic support for oral absorption improvement of water insoluble drugs by the combination of PC and SNEDDS.

Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (f a) via the lymph in the fed state was 0.26, representing 62% of the increase in f a in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles (SLNs) considered as an alternative vehicle for the enhanced oral absorption of drugs, and also to enhance therapeutic effectiveness after oral administration. Pharmacodynamic activity of drug is mainly describes the pharmacological and therapeutic activity of drug to the biological system. Lipid nanoparticles especially SLNs made of physiological inert lipid molecules and helps the lymphatic transport. Numerous literatures is available on the effect of SLNs and other colloidal carrier systems on the pharmacokinetic activity of poorly bioavailable drugs, to improve their oral absorption and also respective mechanisms for the improved oral bioavailability. However, very few literatures is reported on the pharmacodynamic activity and the effect of dose on the pharmacodynamic activity. Therefore, the current review is mainly dealing with the effect of SLNs on the pharmacodynamic activity discussed. [ABSTRACT FROM AUTHOR]

Drug delivery to the lymphatic system is gaining increasing attention, particularly in fields such as immunotherapy where drug access to lymphocytes is central to activity. We have previously described a prodrug strategy that facilitates the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA) via incorporation into intestinal triglyceride transport pathways. The current study explored a series of structurally related glyceride and phospholipid mimetic prodrugs of MPA in an attempt to enhance lymph targeting and to better elucidate the design criteria for lipid mimetic prodrugs. MPA was conjugated to a glyceride or phospholipid backbone at various positions using different spacers employing ester, ether, carbonate and amide bonds. Patterns of prodrug hydrolysis were evaluated in rat digestive fluid, and lymphatic transport and plasma pharmacokinetics were assessed in lymph duct cannulated rats. Prodrugs with different spacers between MPA and the glyceride backbone resulted in up to 70-fold differences in gastrointestinal stability. MPA conjugation at the 2 position of the glyceride backbone and via an ester bond were most effective in promoting lymphatic transport. Phospholipid prodrug derivatives, or glyceride derivatives with MPA attached at the 1 position or when linked via ether, carbonate or amide bonds were poorly incorporated into lymphatic transport pathways. [ABSTRACT FROM AUTHOR]

In recent years, the drainage of fluids, immune cells, antigens, fluorescent tracers, and other solutes from the brain has been demonstrated to occur along lymphatic outflow pathways to the deep cervical lymph nodes in the neck. To the best of our knowledge, no studies have evaluated the lymphatic transport of therapeutics from the brain. The objective of this study was to determine the lymphatic transport of model therapeutics of different molecular weights and lipophilicity from the brain using cervical lymph cannulation and ligation models in rats. To do this, anesthetized Sprague-Dawley rats were cannulated at the carotid artery and cannulated, ligated, or left intact at the cervical lymph duct. Rats were administered 14 C-ibuprofen (206.29 g/mol, logP 3.84), 3 H-halofantrine HCl (536.89 g/mol, logP 8.06), or 3 H-albumin (∼65,000 g/mol) via direct injection into the brain striatum at a rate of 0.5 μL/min over 16 min. Plasma or cervical lymph samples were collected for up to 6-8 h following dosing, and brain and lymph nodes were collected at 6 or 8 h. Samples were subsequently analyzed for radioactivity levels via scintillation counting. For 14 C-ibuprofen, plasma concentrations over time (plasma AUC 0-6h ) were >2 fold higher in lymph-ligated rats than in lymph-intact rats, suggesting that ibuprofen is cleared from the brain primarily via nonlymphatic routes (e.g., across the blood-brain barrier) but that this clearance is influenced by changes in lymphatic flow. For 3 H-halofantrine, >73% of the dose was retained at the brain dosing site in lymph-intact and lymph-ligated groups, and plasma AUC 0-8h values were low in both groups (<0.3% dose.h/mL), consistent with the high retention in the brain. It was therefore not possible to determine whether halofantrine undergoes lymphatic transport from the brain within the duration of the study. For 3 H-albumin, plasma AUC 0-8h values were not significantly different between lymph-intact, lymph-ligated, and lymph-cannulated rats. However, >4% of the dose was recovered in cervical lymph over 8 h. Lymph/plasma concentration ratios of 3 H-albumin were also very high (up to 53:1). Together, these results indicate that 3 H-albumin is transported from the brain not only via lymphatic routes but also via the blood. Similar to other tissues, the lymphatics may thus play a significant role in the transport of macromolecules, including therapeutic proteins, from the brain but are unlikely to be a major transport pathway from the brain for small molecule drugs that are not lipophilic. Our rat cervical lymph cannulation model can be used to quantify the lymphatic drainage of different molecules and factors from the brain.

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances ( e.g. , ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.)

Lipoproteins (LPs) are circulating heterogeneous nanoparticles produced by the liver and intestines. LPs play a major role in the transport of dietary and endogenous lipids to target cells through cell membrane receptors or cell surface-bound lipoprotein lipase. The stability, biocompatibility, and selective transport of LPs make them promising delivery vehicles for various therapeutic and imaging agents. This review discusses isolation, manufacturing, and drug loading techniques used for LP-based drug delivery, as well as recent applications for diagnosis and treatment of cancer, atherosclerosis, and other life-threatening diseases. Unlabelled Image • Lipoproteins are circulating endogenous nanoparticles targeted to specific tissues. • Lipoproteins can be isolated from biological fluids or synthetically manufactured. • Therapeutic and imaging molecules can be loaded in lipoproteins. • Lipoprotein-based drug delivery is promising for e.g. cancer and atherosclerosis. • Challenges include cost-efficient, scalable, and standardized manufacturing. [ABSTRACT FROM AUTHOR]

Flavonoids are one of the major dietary polyphenols and have a variety of chemical structures. They are considered as functional food factors to have physiological effects to prevent various diseases. Dietary flavonoid aglycons are taken up are and converted to their corresponding conjugated metabolites by phase II enzymes in the enterocyte. The bioavailability of flavonoids affects their physiological function. Recently, we found dietary flavonoids are absorbed not only via the portal vein but also via the intestinal lymphatic pathways. Most of dietary nutrients are absorbed in the small intestine, and the intestinal lymphatic system is generally used to absorb lipids and lipophilic vitamins as the form of chylomicrons. In the case of lipophilic drugs, the lymphatic transport pathway makes the medicine avoid the first-pass metabolism in the liver and deliver the drugs as a more active form to the target tissues. In this review, the several reports on the lymphatic transport of flavonoids are summarized, mainly in the cause of quercetin and its derivatives. In addition, the potential of physiological importance of lymphatic flavonoid absorption will be discussed. [ABSTRACT FROM AUTHOR]

The aim of the present investigation was to fabricate and evaluate solid lipid nanoparticles (SLNs) of asenapine maleate (AM) to improve its oral bioavailability (BA). AM-SLNs were prepared by high speed homogenization followed by ultrasonication technique. The resultant SLNs exhibited particle size, zeta potential and entrapment efficiency of 114.3 ± 3.5 nm, −12.9 ± 3.8 mV, and 84.10% ± 2.90% respectively. In vitro release study of AM-SLNs showed 9.23% ± 2.72% and 92.09% ± 3.40% release of AM in pH 1.2 medium and phosphate buffer pH 6.8, respectively, indicating higher potential of lymphatic uptake. Cell viability study using Caco-2 cell line indicated non-toxicity of the carriers and drug. The uptake of AM-SLNs across Caco-2 cell line was time and energy dependent exhibiting clathrin-claveole mediated endocytosis transport. Cellular uptake of Coumarin loaded SLNs was effectively increased as compared to the dye solution. The pharmacokinetic results in rats showed 50.19-fold improvement in BA of AM after fabrication of SLNs. Collectively, all these findings demonstrated effectiveness of SLNs to improve therapeutic efficacy of AM in the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

In the present study, a water insoluble drug named silybin was encapsulated into self-nanoemulsifying drug delivery system (SNEDDS) following the preparation of silybin–phospholipid complex (SB–PC), then several methods were carried out to characterize SB–PC–SNEDDS and elucidate its mechanisms to improve the oral absorption of SB. Using a dynamic in vitro digestion model, the lipolysis of SB–PC–SNEDDS was proved to be mainly related with the property of its lipid excipients. SB–PC–SNEDDS could significantly enhance the transport of SB across Caco-2 cells, which may partly attribute to the increased cell membrane fluidity and the loss of tight junction according to the analysis results of fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and tight junction protein (ZO-1). The result of in situ perfusion showed the intestinal absorption of SB from high to low was SB–PC–SNEDDS, SB–PC, and SB. The extent of lymphatic transport of SB–PC and SB–PC–SNEDDS via the mesenteric duct was 12.2 and 22.7 folds of that of SB, respectively. In the lymph duct cannulated rats, the relative bioavailability (Fr) of SB–PC and SB–PC–SEDDS compared to SB was 1265.9% and 1802.5%, respectively. All the above results provided mechanistic support for oral absorption improvement of water insoluble drugs by the combination of PC and SNEDDS. [ABSTRACT FROM AUTHOR]

Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.

Huperzine A (Hup-A) is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P

Abstract Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4+CD25+Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases. Graphical abstract Unlabelled Image Highlights • Oral administration of WAY-252,623 with lipids increases GI lymphatic transport. • Lymphatic transport increases ABCA1 and Foxp3 expression in lymph lymphocytes. • Increased lymph transport of WAY-252,623 also increases Treg cell numbers in blood. • Lymph targeting strategies promote the immunomodulatory activity of WAY-252,623. [ABSTRACT FROM AUTHOR]

Abstract For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.

Candesartan Cilexetil (CC) is a prodrug widely used in the treatment of hypertension and heart failure, but it has some limitations, such as very poor aqueous solubility, high affinity to P-glycoprotein efflux mechanism, and hepatic first-pass metabolism. Therefore, it has very low oral bioavailability. In this study, glyceryl monostearate (GMS) and Capryol™ 90 were selected as solid and liquid lipids, respectively, to develop CC-NLC (nanostructured lipid carrier). CC was successfully encapsulated into NLP (CC-NLC) to enhance its oral bioavailability. CC-NLC was formulated using a hot homogenization-ultrasonication technique, and the physicochemical properties were characterized. The developed CC-NLC formulation was showed in nanometric size (121.6 ± 6.2 nm) with high encapsulation efficiency (96.23 ± 3.14%). Furthermore, it appeared almost spherical in morphology under a transmission electron microscope. The surgical experiment of the designed CC-NLC for absorption from the gastrointestinal tract revealed that CC-NLC absorption in the stomach was only 15.26% of that in the intestine. Otherwise, cellular uptake study exhibit that CC-NLCs should be internalized through the enterocytes after that transported through the systemic circulation. The pharmacokinetic results indicated that the oral bioavailability of CC was remarkably improved above 2-fold after encapsulation into nanostructured lipid carriers. These results ensured that nanostructured lipid carriers have a highly beneficial effect on improving the oral bioavailability of poorly water-soluble drugs, such as CC.