Lymphatic Targeting Research Articles

Lymphatic targeting of cilnidipine by designing and developing a nanostructured lipid carrier drug delivery system

Objective The objective of current research is to design, develop, and optimize a cilnidipine (CLN) nanostructured lipid carrier (NLC)-based drug delivery system for the effective treatment of hypertension (HT). Significance Oral administration of CLN-loaded NLC (CLN NLC) containing glyceryl monostearate (GMS) as a solid and isopropyl myristate (IPM) as a liquid lipid may show remarkable lymphatic uptake through payer patches. Methods The emulsification probe sonication technique was used followed by optimization using 32 factorial designs. Results The optimized batch showed a mean particle size of 115.4 ± 0.22 nm with encapsulation efficiency of 98.32 ± 0.23%, polydispersity index (PDI) of 0.342 ± 0.03, and zeta potential (ZP, ζ) was −60.5 ± 0.24 which indicate excellent physical stability. In vitro studies showed a controlled release of CLN NLCs. Pharmacokinetics studies determined the C max of NLCs (373.47 ± 15.1) indicates 2.3-fold enhancement compared with plain drug (160.64 ± 7.63). Pharmacodynamic studies indicated that CLN NLCs were maintaining systolic blood pressure in a controlled manner without any signs of side effects. Conclusion CLN NLCs significantly improved lymphatic delivery and proved to be effective in the treatment and management of HT. It has been proved that CLN NLCs are found to be better than any traditional CLN dosage form due to enhancement in solubility, absorption, bioavailability, intestinal permeability, avoidance of first-pass metabolism, P-glycoprotein efflux and reduction in dose-related side effects, achievement of controlled and sustained release action.

Delivery of imiquimod to intestinal lymph nodes following oral administration

Intestinal lymph nodes are involved in the progression of colorectal cancer (CRC). Tumours suppress the activation of dendritic cells (DCs) in draining lymph nodes, diminishing anti-cancer immune response. Imiquimod (IMQ) facilitates DCs activation via toll-like receptor 7, suggesting that targeted delivery of IMQ to intestinal lymph nodes can improve the treatment of CRC. This study aims to enhance the delivery of IMQ to intestinal lymph nodes by a highly lipophilic prodrug approach. Amide prodrugs were synthesised by conjugating IMQ with saturated and unsaturated medium- to long-chain fatty acids. Their potential for intestinal lymphatic transport was assessed by their affinity to chylomicrons and solubility in long-chain triglycerides. Further selection of prodrug candidates was determined by resistance to enzymatic hydrolysis in intestinal lumen and release of IMQ in the lymphatics using fasting state simulated intestinal fluid supplemented with esterases, brush border enzyme vesicles and plasma. Key pharmacokinetic parameters and biodistribution in rats were assessed for the most promising compounds, prodrugs 5 and 8. The plasma concentration–time profile of IMQ following oral administration of the prodrugs was less erratic in comparison to the administration of unmodified IMQ. The lymph-to-plasma ratios of IMQ concentration increased 1.9- and 1.7-fold using prodrugs 5 and 8 in comparison to administration of unmodified IMQ, respectively. Importantly, the average concentration of IMQ in mesenteric lymph nodes (MLN) was 11.2- and 7.6-fold higher than in plasma following the administration of prodrugs 5 and 8, respectively. Additionally, the non-specific wide distribution of IMQ into various organs and tissues was reduced with prodrugs. This work suggests that the highly lipophilic prodrug approach can efficiently deliver IMQ to intestinal lymphatics. In addition, this study demonstrates the feasibility of an amide prodrug approach for intestinal lymphatic targeting.

Lipid Drug Conjugates in Pharmaceutical Formulations and Drug Delivery Systems

Abstract: Drugs that have been covalently altered with lipids are known as lipid-drug conjugates. Drug characteristics are altered and their lipophilicity is increased when lipids are conjugated to drug molecules. The conjugates exhibit a number of benefits, including increased oral bioavailability, improved lymphatic targeting, improved tumor targeting, and reduced cytotoxicity. Different conjugation techniques and chemical bridges can be utilized to create lipid-drug conjugates depending on the chemical makeup of medicines and lipids. For lipid-drug conjugates to function at their best, linkers and/or conjugation techniques are essential. They control how medications are released from lipid-drug conjugates. The numerous lipids utilized to make lipid-drug conjugates and the various conjugation techniques are outlined in this article. Although these conjugates can be delivered without a delivery vehicle, many of them are put into suitable delivery techniques. Drug loading into lipophilic parts of vehicles can be considerably improved by the lipid component in the conjugates, leading to combinations with significant drug content and superior stability.

Impact of conjugation to different lipids on the lymphatic uptake and biodistribution of brush PEG polymers

Delivery to peripheral lymphatics can be achieved following interstitial administration of nano-sized delivery systems (nanoparticles, liposomes, dendrimers etc) or molecules that hitchhike on endogenous nano-sized carriers (such as albumin). The published work concerning the hitchhiking approach has mostly focussed on the lymphatic uptake of vaccines conjugated directly to albumin binding moieties (ABMs such as lipids, Evans blue dye derivatives or peptides) and their subsequent trafficking into draining lymph nodes. The mechanisms underpinning access and transport of these constructs into lymph fluid, including potential interaction with other endogenous nanocarriers such as lipoproteins, have largely been ignored. Recently, we described a series of brush polyethylene glycol (PEG) polymers containing end terminal short-chain or medium-chain hydrocarbon tails (1C2 or 1C12, respectively), cholesterol moiety (Cho), or medium-chain or long-chain diacylglycerols (2C12 or 2C18, respectively). We evaluated the association of these materials with albumin and lipoprotein in rat plasma, and their intravenous (IV) and subcutaneous (SC) pharmacokinetic profiles. Here we fully detail the association of this suite of polymers with albumin and lipoproteins in rat lymph, which is expected to facilitate lymph transport of the materials from the SC injection site. Additionally, we characterise the thoracic lymph uptake, tissue and lymph node biodistribution of the lipidated brush PEG polymers following SC administration to thoracic lymph cannulated rats. All polymers had moderate lymphatic uptake in rats following SC dosing with the lymph uptake higher for 1C2-PEG, 2C12-PEG and 2C18-PEG (5.8%, 5.9% and 6.7% dose in lymph, respectively) compared with 1C12-PEG and Cho-PEG (both 1.5% dose in lymph). The enhanced lymph uptake of 1C2-PEG, 2C12-PEG and 2C18-PEG appeared related to their association profile with different lipoproteins. The five polymers displayed different biodistribution patterns in major organs and tissues in mice. All polymers reached immune cells deep within the inguinal lymph nodes of mice following SC dosing. The ability to access these immune cells suggests the potential of the polymers as platforms for the delivery of vaccines and immunotherapies. Future studies will focus on evaluating the lymphatic targeting and therapeutic potential of drug or vaccine-loaded polymers in pre-clinical disease models.

Lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy.

Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.

Comprehensive strategy of white analytical chemistry and analytical quality by design to sensitive spectrofluorimetric method for in-vitro drug release kinetic study of Ibrutinib-loaded nanostructured lipid carriers for leukemia via lymphatic targeting

Ibrutinib (IBR) is a drug classified as BCS class II, characterized by low solubility and high permeability. However, its oral bioavailability is limited to a mere 2.9% due to significant first-pass metabolism. To address this challenge, researchers developed IBR-NLCs (Nanostructured Lipid Carriers) using a DoE-based hot melted ultrasonication method to enhance its bioavailability and drug release profile. While various methods exist for IBR analysis in pharmaceutical formulations, human plasma, and rat plasma, a sensitive spectrofluorimetric method has not been reported for estimating IBR. To facilitate in-vitro drug release kinetic studies of IBR-NLCs, a sensitive and green spectrofluorimetric method was developed, combining principles of white analytical chemistry and analytical quality by design. This approach included a fractional factorial design for screening of method variables and a Box-Behnken design for method optimization. The developed method underwent rigorous validation following ICH guidelines. The developed method was applied to assess the in-vitro drug release kinetic study of IBR-NLCs in comparison to marketed formulations. Remarkably, the optimized IBR-NLCs exhibited sustained release of IBR which helps to decrease dose and dose frequency. The whiteness and greenness profiles of published and proposed method have been assessed using analytical greenness calculator, green analytical procedure index software, national environmental method index standards, and eco-scale assessment tool. The results confirmed that the proposed method is sensitive, eco-friendly, cost-effective, speedy, and user-friendly, making it an excellent choice for IBR estimation in NLCs. In summary, the developed method for drug release kinetic study of BR-NLCs, utilizing principles of white analytical chemistry and analytical quality by design, has not only improved drug release profile but also resulted in an efficient and environmentally friendly analytical approach.

Zwitterionic peptide pendant as a homing agent to achieve lymphatic targeting antigen-specific immunotherapy of allergenic protein

Targeting the lymphatic route has gained extensive attention in drug delivery due to its potential to reduce drug dosage and improve therapeutic effects. However, the lack of an effective targeting path limits the development of relevant treatments. Herein, we reported a zwitterionic peptide pendant conjugation strategy to render protein drugs with lymphatic targeting capability, which merited subsequent allergen-specific immunotherapy (AIT). The zwitterionic peptide pendant of alternatively repeated glutamic acid (E) and lysine (K) sequences was conjugated to the causative allergenic protein tropomyosin (TM) through recombinant protein expression. The recombinant TM-EK exhibited a decreased immunogenicity and improved lymphatic targeting efficacy. It was found that the TM-EK could effectively induce the mice to achieve immune tolerance to TM and had no noticeable toxic or side effects on major organs. The proposed zwitterionic peptide strategy provided a new approach to developing lymphatic targeting protein drugs and facilitating the improvement of immunotherapies.

β-glucan-modified nanoparticles with different particle sizes exhibit different lymphatic targeting efficiencies and adjuvant effects

Particle size and surface properties are crucial for lymphatic drainage (LN), dendritic cell (DC) uptake, DC maturation, and antigen cross-presentation induced by nanovaccine injection, which lead to an effective cell-mediated immune response. However, the manner in which the particle size and surface properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) affect this immune response is unknown. We prepared 50, 100, and 200 nm of MSNs that adsorbed ovalbumin antigen (OVA) while modifying β-glucan to enhance immunogenicity. The results revealed that these MSNs with different particle sizes were just as efficient in vitro, and MSNs with β-glucan modification demonstrated higher efficacy. However, the in vivo results indicated that MSNs with smaller particle sizes have stronger lymphatic targeting efficiency and a greater ability to promote the maturation of DCs. The results also indicate that β-glucan-modified MSN, with a particle size of ∼100 nm, has a great potential as a vaccine delivery vehicle and immune adjuvant and offers a novel approach for the delivery of multiple therapeutic agents that target other lymph-mediated diseases.

Fabrication of TPGS decorated Etravirine loaded lipidic nanocarriers as a neoteric oral bioavailability enhancer for lymphatic targeting

Etravirine (ERVN) is a potential NNRTI (non-nucleoside reverse transcriptase inhibitor) in treating HIV infection. It possesses extremely low oral bioavailability. The present research aims to optimize the formulation and characterization of TPGS-enriched ERVN-loaded lipid-based nanocarriers (NLCs) for HIV-infected patients. The formulation, ERVN–TPGS–NLCs, was optimized by central composite rotational design using a modified-solvent emulsification process. Various characterization parameters of NLCs were evaluated, including globule size of 121.56 ± 2.174 nm, PDI of 0.172 ± 0.042, the zeta potential of − 7.32 ± 0.021 mV, %EE of 94.42 ± 8.65% of ERVN and %DL was 8.94 ± 0.759% of ERVN and spherical shape was revealed by TEM. PXRD was also performed to identify the crystallinity of the sample. In-vitro drug release showed % a cumulative drug release of 83.72 ± 8.35% at pH 1.2 and 90.61 ± 9.11% at pH 6.8, respectively, whereas the % cumulative drug release from drug suspension (ERVN-S) was found to be 21.13 ± 2.01% at pH 1.2 and 24.84 ± 2.51 at pH 6.8 at the end of 48 h. Further, the intestinal permeation study and confocal microscope showed approximately three-fold and two-fold increased permeation in ERVN–TPGS–NLCs and ERVN-NLCs across the gut sac compared to ERVN-S. Hemolysis compatibility and lipolysis studies were performed to predict the in-vivo fate of the formulation. The pharmacokinetic study revealed a 3.13-fold increment in the relative bioavailability, which agrees with the ex-vivo studies, and lymphatic uptake was validated by using cycloheximide along with designed formulation, which showed the impact of lymphatic uptake in AUC. This study ensures that ERVN–TPGS–NLCs take lymphatic uptake to minimize the first-pass metabolism followed by improved oral bioavailability of ERVN. Thus, the enhanced bioavailability of ERVN can reduce the high dose of ERVN to minimize the adverse effects related to dose-related burden.Graphical abstract

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes.

The role of advanced drug delivery strategies in drug repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. Although the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug-targeting approaches to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. SIGNIFICANCE STATEMENT: The World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.

Dendritic Cell-Mimicking Nanoparticles Promote mRNA Delivery to Lymphoid Organs.

Spleen and lymphoid organs are important targets for messenger RNA (mRNA) delivery in various applications. Current nanoparticle delivery methods rely on drainage to lymph nodes from intramuscular or subcutaneous injections. In difficult-to-transfect antigen-presenting cells (APCs), such as dendritic cells (DCs), effective mRNA transfection remains a significant challenge. In this study, a lymphatic targeting carrier using DC membranes is developed, that efficiently migrated to lymphoid organs, such as the spleen and lymph nodes. The nanoparticles contained an ionizable lipid (YK009), which ensured a high encapsulation efficacy of mRNA and assisted mRNA with endosomal escape after cellular uptake. Dendritic cell-mimicking nanoparticles (DCMNPs) showed efficient protein expression in both the spleen and lymph nodes after intramuscular injections. Moreover, in immunized mice, DCMNP vaccination elicited Spike-specific IgG antibodies, neutralizing antibodies, and Th1-biased SARS-CoV-2-specific cellular immunity. This work presents a powerful vaccine formula using DCMNPs, which represents a promising vaccine candidate for further research and development.

Recent Progress in the Oral Delivery of Therapeutic Peptides and Proteins: Overview of Pharmaceutical Strategies to Overcome Absorption Hurdles.

Proteins and peptides have secured a place as excellent therapeutic moieties on account of their high selectivity and efficacy. However due to oral absorption limitations, current formulations are mostly delivered parenterally. Oral delivery of peptides and proteins (PPs) can be considered the need of the hour due to the immense benefits of this route. This review aims to critically examine and summarize the innovations and mechanisms involved in oral delivery of peptide and protein drugs. Comprehensive literature search was undertaken, spanning the early development to the current state of the art, using online search tools (PubMed, Google Scholar, ScienceDirect and Scopus). Research in oral delivery of proteins and peptides has a rich history and the development of biologics has encouraged additional research effort in recent decades. Enzyme hydrolysis and inadequate permeation into intestinal mucosa are the major causes that result in limited oral absorption of biologics. Pharmaceutical and technological strategies including use of absorption enhancers, enzyme inhibition, chemical modification (PEGylation, pro-drug approach, peptidomimetics, glycosylation), particulate delivery (polymeric nanoparticles, liposomes, micelles, microspheres), site-specific delivery in the gastrointestinal tract (GIT), membrane transporters, novel approaches (self-nanoemulsifying drug delivery systems, Eligen technology, Peptelligence, self-assembling bubble carrier approach, luminal unfolding microneedle injector, microneedles) and lymphatic targeting, are discussed. Limitations of these strategies and possible innovations for improving oral bioavailability of protein and peptide drugs are discussed. This review underlines the application of oral route for peptide and protein delivery, which can direct the formulation scientist for better exploitation of this route.

Effective Attenuation of Arteriosclerosis Following Lymphatic-Targeted Delivery of Hyaluronic Acid-Decorated Rapamycin Liposomes.

The activation of lymphatic vessel function is the crux to resolving atherosclerosis (AS), a chronic inflammatory disease. Rapamycin (RAPA) recently has attracted considerable attention as a potent drug to induce atherosclerotic plaque attenuation. The objective of this work was to develop a ligand-decorated, RAPA-loaded liposome for lymphatic-targeted delivery of drugs to improve abnormal lymphatic structure and function, resulting in highly effective regression of atherosclerotic plaques. Hyaluronic acid-decorated, RAPA-loaded liposomes (HA-RL) were fabricated by emulsion-solvent evaporation. The average size, zeta potential, entrapment efficiency were characterized, and the stability and drug release in vitro were investigated. Furthermore, the in vitro and in vivo lymphatic targeting ability were evaluated on lymphatic endothelial cells and LDLR-/- mice, and the efficiency of this nano-system in inducing the attenuation of atherosclerotic plaques was confirmed. HA-RL had a size of 100 nm, over 90% drug encapsulation efficiency, the storage stability was distinguished, demonstrating a slow release from the lipid nano-carriers. The mean retention time (MRT) and elimination half-life (t1/2β) achieved from HA-RL were 100.27±73.08 h and 70.74±50.80 h, respectively. HA-RL acquired the most prominent efficacy of lymphatic-targeted delivery and atherosclerotic plaques attenuation, implying the successful implementation of this novel drug delivery system in vivo. HA-RL exhibited the most appreciable lymphatic targeting ability and best atherosclerotic plaques attenuation efficiency, opening a new paradigm and promising perspective for the treatment of arteriosclerosis.

A novel oral biomimetic delivery system enhancing both the mucosal and systemic immunity of influenza virus vaccine

Oral vaccines hold great promise for preventing major infectious diseases, but their development is limited by various gastrointestinal tract (GIT) barriers and the low proportion of intestinal microfold (M) cells. Here, inspired by the specific absorption pathway of dietary fat, a novel bionic intestinal lymphatic delivery system based on large mesoporous silica nanoparticles (LMSN) was developed for oral delivery of H1N1 influenza split vaccine (SV). Encouragingly, LMSN with triglyceride biomimetic structure and encapsulated by double-end palmitic acid esterified PEG (PEG-DP), namely TGLMSN@PEG-DP, exhibited high intestinal epithelium permeability and excellent lymphatic targeting ability. Additionally, TGLMSN, which acting as both antigen carrier and adjuvant, significantly enhanced the ability of SV to stimulate dendritic cells maturation. The results demonstrated that TGLMSN@PEG-DP vigorously augmented SV-induced antigen-specific systemic and mucosal immunity, compared to oral SV alone. To our knowledge, this is the first study to customize mesoporous silica nanocarriers to load SV and deliver vaccines to mesenteric lymph nodes (MLNs) mainly through the intestinal epithelium cells (IECs) pathway rather than M cells route alone. This work will not only improve the existing influenza vaccination methods, but also open up a new avenue for the design of vaccines against pathogens infected via mucosal route.

Self-micro Emulsifying Drug Delivery via Intestinal Lymphatics: A Lucrative Approach to Drug Targeting.

The intestinal lymphatics are considered one of the most specialized pathways, which promote the absorption of various agents such as vitamins, lipids, xenobiotics, and lipophilic substances. The intestinal lymphatics have provided various advantages like bypassing first-pass effects, and improved bioavailability. The oral delivery of poor hydrophilic drugs can be improved by employing a lipid-based formulation strategy. Self-micro emulsifying drug delivery systems (SMEDDS) are one of the vivacious strategies based on lipid-based drug delivery that have shown their effects by improving the solubility and bioavailability of the therapeutic agents. This review is an insight into the functions, targets, mechanisms, and carriers involved in intestinal lymphatics. Also, the review illustrates the types, formulation requirements, and mechanism of action of SMEDDS in detail. In addition, it describes the targeting, types, physicochemical properties, biological barriers, and benefits of lymphatic targeting in therapy. Finally, the marketed formulations and future aspects of SMEDDS formulations are addressed.

Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons.

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.

Arrangement of Indocyanine Green in a 1.5-Nanometer Channel to Achieve High-Efficiency Imaging of the Intestinal Lymphatic System.

The complications of inflammatory bowel diseases (IBDs) seriously endanger people’s health, such as bleeding, polyp hyperplasia, and even cancer. Although the precise pathophysiology of IBD is unknown, alterations in the intestinal lymphatic network, such as lymphangiogenesis and lymphatic vessel dysfunction, are well-established features. Therefore, the development of a reliable technology is urgently required, with a stereoscopic, deep, and high-resolution technology for IBD lymphatic targeting imaging in clinical practice. However, indocyanine green, the only clinically approved imaging agent by the Food and Drug Administration, can easily cause self-aggregation or be interfered with by microenvironments, causing fluorescence quenching, which seriously affects the imaging and detective capabilities. Herein, indocyanine green molecules are arranged in a 1.5-nanometer one-dimensional channel (TpPa-1@ICG). Based on this specified structure, the fluorescence enhancement effect is observed in the TpPa-1@ICG resultant, and the fluorescence intensity is enhanced by 27%. In addition, the ICG-incorporated porous solid reveals outstanding solvent (dichloromethane, tetrahydrofuran, etc.) and thermal (>300 °C) stability. After modifying the target molecules, TpPa-1@ICG showed excellent imaging ability for intestinal lymphatic vessels, providing a new imaging tool for IBDs research.

Development of andrographolide-loaded solid lipid nanoparticles for lymphatic targeting: Formulation, optimization, characterization, in vitro, and in vivo evaluation.

Andrographolide, the primary bioactive constituent of Andrographis paniculata, is a promising natural substance with numerous pharmacotherapy uses. Low water solubility, short half-life, and low permeability necessitate the development of a delivery system that enhances its entrapment efficiency, bioavailability, lymphatic targeting, and by-pass hepatic effect. The andrographolide-loaded solid lipid nanoparticles were fabricated by melt-emulsification and ultrasonication and optimized with Design-Expert software. In the optimal formulation, Glycerol monostearate as the solid lipid and Poloxamer 407 and Span 60 as surfactants were used. Optimum AND-SLN was observed to have a mean particle size, polydispersity index, zeta potential, and entrapment efficiency of 193.84nm, 0.211, - 22.8mV, and 83.70% respectively. An optimized formulation was characterized by examining surface morphology, X-ray diffraction, and differential scanning calorimetry. In vitro studies have shown sustained drug release from AND-SLN for up to 24h. The stability studies showed that there was no significant change in the mean particle size and entrapment efficiency after storage at 4 ± 2°C and 25 ± 2°C/60 ± 5% RH. In in vivo pharmacokinetics studies, AND-SLN was found to have enhanced bioavailability and specificity in the spleen and thymus compared to plasma, providing evidence that the formulations could enhance target specificity and bioavailability in comparison to pure drugs. The H&E staining of the liver, spleen, and thymus treated with the AND-SLN revealed no signs of damage histopathologically. Thus, AND-SLN possess a high potential for improved efficacy and are an efficient vehicle for delivering drugs to the lymphatic system.

Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol

Although natural sesame oil has been shown to facilitate the lymphatic delivery and oral bioavailability of the highly lipophilic drug cannabidiol (CBD), considerable variability remains an unresolved challenge. Vegetable oils differ substantially in composition, which could lead to differences in promotion of intestinal lymphatic transport of lipophilic drugs. Therefore, the differences in composition of sesame, sunflower, peanut, soybean, olive and coconut oils and their corresponding role as vehicles in promoting CBD lymphatic targeting and bioavailability were investigated in this study. The comparative analysis suggests that the fatty acids profile of vegetable oils is overall similar to the fatty acids profile in the corresponding chylomicrons in rat lymph. However, arachidonic acid (C20:4), was introduced to chylomicrons from endogenous nondietary sources. Overall, fatty acid composition of natural vegetable oils vehicles affected the intestinal lymphatic transport and bioavailability of CBD following oral administration in this work. Olive oil led to the highest concentration of CBD in the lymphatic system and in the systemic circulation in comparison to the other natural vegetable oils following oral administration in rats.

Baicalein self-microemulsion based on drug-phospholipid complex for the alleviation of cytokine storm.

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-γ, 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.