Search Results (32)

Drugs administered by means of extravascular routes of drug administration must be absorbed into the systemic circulation, which involves the movement of the drug molecules across biological barriers such as epithelial cells that cover mucosal surfaces or the stratum corneum that covers the skin. Some drugs exhibit poor permeation across biological membranes or may experience excessive degradation during first-pass metabolism, which tends to limit their bioavailability. Various strategies have been used to improve drug bioavailability. Absorption enhancement strategies include the co-administration of chemical permeation enhancers, enzymes, and/or efflux transporter inhibitors, chemical changes, and specialized dosage form designs. Models with physiological relevance are needed to evaluate the efficacy of drug absorption enhancement techniques. Various in vitro cell culture models and ex vivo tissue models have been explored to evaluate and quantify the effectiveness of drug permeation enhancement strategies. This review deliberates on the use of in vitro and ex vivo models for the evaluation of drug permeation enhancement strategies for selected extravascular drug administration routes including the nasal, oromucosal, pulmonary, oral, rectal, and transdermal routes of drug administration. Full article

Titanium dioxide (TiO₂), a white color food additive, is widely used in bakery products, candies, chewing gums, soups, and creamers. Concerns about its potential genotoxicity have recently emerged, particularly following the European Union’s ban on its usage as a food additive due to its genotoxicity potential. Conflicting in vitro and in vivo results regarding its genotoxicity highlight the need for further in-depth investigation. Moreover, food additives can interact with food components or biological matrices, potentially altering their biological responses and genotoxicity. In this study, we evaluated the interactions between two different sizes of additive TiO₂ particles and food or biological matrices, including albumin, fetal bovine serum (FBS), and glucose. The results showed that the hydrodynamic diameters of TiO₂ increased upon interaction with albumin or FBS, but not with glucose. The presence of albumin or FBS reduced TiO₂-induced cytotoxicity, oxidative stress, in vitro intestinal transport, and ex vivo intestinal absorption to untreated control levels, regardless of particle size. While TiO₂ caused DNA damage in intestinal Caco-2 cells, the interactions with albumin or FBS significantly reduced the DNA damage to levels comparable to untreated controls. The DNA damage was closely related to oxidative stress caused by TiO₂. These findings suggest that the interaction of TiO₂ with albumin or FBS, resulting in increased hydrodynamic diameters, mitigates its cytotoxicity, oxidative stress, intestinal transport, and genotoxicity. Further investigation is required to fully understand the potential genotoxicity of TiO₂ in food contexts. Full article

Intestinal digestion and absorption are complex processes; thus, it is a challenge to imitate them realistically. There are numerous approaches available, with different disadvantages and advantages. The simplest methods to mimic absorption are the non-cell-based transport models but these lack important characteristics of enterocytes of the intestine. Therefore, the most often used method is to measure absorption through viable mammalian cells (most commonly Caco-2 cells, cultured on membrane insert plates), which not only assures the incorporation of brush border enzymes (responsible for the final digestion of peptides and disaccharides), it also simulates the absorption process. This means that influx/efflux transporter-facilitated transport, carrier-mediated transport, endocytosis, and transcytosis is also imitated besides passive diffusion. Still, these also lack the complexity of intestinal epithelium. Organoids or ex vivo models are a better approach if we want to attain precision but the highest accuracy can be achieved with microfluidic systems (gut-on-a-chip models). We propose that more research is necessary, and food absorption should also be studied on gut-on-a-chips, especially with fragmented organoids. Our review supports the choices of a proper intestinal epithelium model, which may have a key role in functional food development, nutrition studies, and toxicity assessment. Full article

Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies. Full article

In piglets, it is observed that early weaning can lead to poor weight gain due to an underdeveloped gastrointestinal (GI) tract, which is unsuitable for an efficient absorption of nutrients. Short-chain fatty acids (SCFAs) such as butyrate have demonstrated their ability to improve intestinal development by increasing cell proliferation, which is vital during this transition period when the small and large intestinal tracts are rapidly growing. Previous reports on butyrate inclusion in feed demonstrated significantly increased feed intakes (FIs) and average daily gains (ADGs) during piglet weaning. Similar benefits in piglet performance have been observed with the inclusion of yeast cell wall in diets. A proprietary mix of yeast cell wall, SCFAs, and zinc proteinate (YSM) was assessed here in vitro to determine its impact on cellular growth, metabolism and appetite-associated hormones in ex vivo small intestinal pig cells and STC-1 mouse intestinal neuroendocrine cells. Intestinal cells demonstrated greater cell densities with the addition of YSM (150 ppm) compared to the control and butyrate (150 ppm) at 24 h. This coincided with the higher utilisation of both protein and glucose from the media of intestinal cells receiving YSM. Ghrelin (an appetite-inducing hormone) demonstrated elevated levels in the YSM-treated cells on a protein and gene expression level compared to the cells receiving butyrate and the control, while satiety hormone peptide YY protein levels were lower in the cells receiving YSM compared to the control and butyrate-treated cells across each time point. Higher levels of ghrelin and lower PYY secretion in cells receiving YSM may drive the uptake of protein and glucose, which is potentially facilitated by elevated gene transporters for protein and glucose. Greater ghrelin levels observed with the inclusion of YSM may contribute to higher cell densities that could support pig performance to a greater extent than butyrate alone. Full article

Direct nose-to-brain drug delivery offers the opportunity to treat central nervous system disorders more effectively due to the possibility of drug molecules reaching the brain without passing through the blood–brain barrier. Such a delivery route allows the desired anatomic site to be reached while ensuring drug effectiveness, minimizing side effects, and limiting drug losses and degradation. However, the absorption of intranasally administered entities is a complex process that considerably depends on the interplay between the characteristics of the drug delivery systems and the nasal mucosa. Various preclinical models (in silico, in vitro, ex vivo, and in vivo) are used to study the transport of drugs after intranasal administration. The present review article attempts to summarize the different computational and experimental models used so far to investigate the direct delivery of therapeutic agents or colloidal carriers from the nasal cavity to the brain tissue. Moreover, it provides a critical evaluation of the data available from different studies and identifies the advantages and disadvantages of each model. Full article

Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the “first pass effect” of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components of Tripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin–blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three−layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery. Full article

The treatment of central nervous system disorders, such as depression and anxiety, relies on the oral administration of drugs with antidepressant or anxiolytic action. Given the increased incidence of these diseases and the disadvantages of oral drug administration, studies are being performed with the aim of developing new ways of treatment in order to improve the effectiveness of the therapies that are applied. The intranasal pathway has gained interest as a route of administration for drugs to the intended target, the brain, due to its capability of direct transport to the central nervous system. In addition to the route of administration, nanoparticles have been studied as possible alternatives to conventional formulations, with the objective of improving drug bioavailability. The present work aimed to analyze the potential of intranasal nanoparticle administration for the treatment of depression and anxiety, using the analysis of several already performed studies. From the carried-out analysis, it was concluded that nanoparticle development takes into consideration the characteristics of the nasal mucosa to allow for enhanced drug absorption and permeability. The use of nanoparticles allows the protection of the drug from enzymatic degradation, and the modulation of its components provides advantages for intranasal administration. In vitro drug release and ex vivo drug permeation studies were conducted, demonstrating, in the majority of cases, an advantage in the use of these formulations. In vivo studies on rats or mice were also carried out, allowing the efficacy of the treatment with the developed formulations to be verified, with results proving very promising. Full article

Zinc oxide (ZnO) nanoparticles (NPs) are used as a food additive Zn supplement due to the role of Zn in biological functions. They are directly added to complex processed foods or Zn-fortified functional foods. Hence, the interactions between ZnO NPs and nutritional or functional components can occur. In this study, the effects of ZnO NP interactions with two polyphenols (quercetin and rutin) on cytotoxicity, antioxidant activity, ex vivo intestinal absorption, and solubility were evaluated. Moreover, the characterization on the interactions was carried out by analyzing crystallinity, surface chemical bonding, chemical composition, and surface chemistry. The results demonstrate that the interactions caused higher cytotoxicity, ex vivo intestinal transport, and solubility of ZnO NPs than pristine ZnO NPs but did not affect antioxidant activity nor intestinal absorption of the polyphenols. The interaction effects were more evident by ZnO NPs interacted with quercetin than with rutin. The crystallinity of ZnO NPs was not influenced, but the degree of exposure of the chemical bondings, elemental compositions, and chemical group intensities on the surface of ZnO NPs, quercetin, or rutin were quenched or decreased to some extent by the interactions, especially by ZnO NPs interacted with quercetin. It is, therefore, concluded that the interactions affect chemical characteristics and surface chemical sates of ZnO NPs, quercetin, or rutin, which can cause high cytotoxicity, intestinal absorption, and solubility of ZnO NPs. Further study is required to elucidate the mechanism of action of the interactions. Full article

Isolated secondary metabolites asperidine B (preussin) and asperidine C, produced by the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, were found to exhibit inhibitory effects against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and oxidative stress in an in vitro assay. Whether or not the known pyrrolidine asperidine B and the recently isolated piperidine asperidine C have lipid-lowering effects remains unknown. Thus, this study aimed to investigate the hypocholesterolemic effects of asperidines B and C and identify the mechanisms involved in using in vitro, ex vivo, and in vivo models. The results show that both compounds interfered with cholesterol micelle formation by increasing bile acid binding capacity, similar to the action of the bile acid sequestrant drug cholestyramine. However, only asperidine B, but not asperidine C, was found to inhibit cholesterol uptake in Caco-2 cells by up-regulating LXRα without changing cholesterol transporter NPC1L1 protein expression. Likewise, reduced cholesterol absorption via asperidine-B-mediated activation of LXRα was also observed in isolated rat jejunal loops. Asperidine B consistently decreases plasma cholesterol absorption, similar to the effect of ezetimibe in rats. Therefore, asperidine B, the pyrrolidine derivative, has therapeutic potential to be developed into a type of cholesterol absorption inhibitor for the treatment of hypercholesterolemia. Full article

Based on glucose (G) transporters (GLUTs), structuring nanoparticles with G as a target are an effective strategy to enhance oral bioavailability and anti-tumor effects of drugs. A novel drug delivery system using G-modified zein (GZ) nanoparticles loaded with docetaxel (DTX) (DTX-GNPs) was prepared and characterized in vitro and in vivo via assessment of cellular uptake, absorption site, pharmacokinetics, ex vivo distribution, and anti-tumor effects. The DTX-GNPs were approximately 120 nm in size. Compared with DTX-NPs, G modification significantly enhanced cellular uptake of DTX-GNPs by 1.22 times in CaCo-2 cells, which was related to GLUT mediation and the enhancement of endocytosis pathways via clathrin, micropinocytosis, and caveolin. Compared to DTX-NPs, G modification significantly enhanced DTX-NP absorption in the jejunum and ileum, delayed plasma concentration peak time, prolonged the average residence time in vivo, and increased oral bioavailability (from 43.82% to 96.04%). Cellular uptake and oral bioavailability of DTX were significantly affected by the G modification ratio. Compared with DTX-NPs, G modification significantly reduced drug distribution in the liver, lungs, and kidneys and increased tumor distribution and tumor growth inhibition rate without obvious systemic toxicity. This study demonstrated the potential of GZ-NPs as nanocarriers for DTX to enhance oral bioavailability and anti-tumor effects. Full article

(1) Background: Type 2 diabetes (T2D) is associated with a duodenal hypermotility in postprandial conditions that favors hyperglycemia and insulin resistance via the gut-brain axis. Enterosynes, molecules produced within the gut with effects on the enteric nervous system, have been recently discovered and pointed to as potential key modulators of the glycemia. Indeed, targeting the enteric nervous system that controls gut motility is now considered as an innovative therapeutic way in T2D to limit intestinal glucose absorption and restore the gut-brain axis to improve insulin sensitivity. So far, little is known about the role of glucose on duodenal contraction in fasted and fed states in normal and diabetic conditions. The aim of the present study was thus to investigate these effects in adult mice. (2) Methods: Gene-expression level of glucose transporters (SGLT-1 and GLUT2) were quantified in the duodenum and jejunum of normal and diabetic mice fed with an HFD. The effect of glucose at different concentrations on duodenal and jejunal motility was studied ex vivo using an isotonic sensor in fasted and fed conditions in both normal chow and HFD mice. (3) Results: Both SGLT1 and GLUT2 expressions were increased in the duodenum (47 and 300%, respectively) and jejunum (75% for GLUT2) of T2D mice. We observed that glucose stimulates intestinal motility in fasted (200%) and fed (400%) control mice via GLUT2 by decreasing enteric nitric oxide release (by 600%), a neurotransmitter that inhibits gut contractions. This effect was not observed in diabetic mice, suggesting that glucose sensing and mechanosensing are altered during T2D. (4) Conclusions: Glucose acts as an enterosyne to control intestinal motility and glucose absorption through the enteric nervous system. Our data demonstrate that GLUT2 and a reduction of NO production could both be involved in this stimulatory contracting effect. Full article

Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853). Full article

Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat experimental model. The PEGylated edge activator combined with the conventional components of chylomicrons (CMs) amplify the transport of the drug across the intestine and its circulation period, hence its therapeutic impact. The implementation of variables in the in vitro characterization of the vesicles was investigated. Using Design Expert^® software, a 2⁴ factorial design was conducted, and the resulting PCM formulations were fabricated utilizing a thin-film hydration technique. The efficacy of the formulations was assessed according to their zeta potential (ZP), entrapment efficiency percentage (EE%), amount of drug released after 8 h (Q8h), and particle size (PS) data. Formulation F9, which was deemed to be the optimal formula, used compritol as the lipidic core together in defined amounts with phosphatidylcholine (PC) and Brij52. Computer-aided studies revealed that MH alone in a suspension had both diminished intestinal permeability and absorption, but was enhanced when loaded in PCMs. This was affirmed by the superiority of formulation F9 results in ex vivo permeation and pharmacokinetic studies. Furthermore, formulation F9 had a superior safety profile and antiviral activity over a pure MH suspension. Molecular-docking studies revealed the capability of MH to inhibit MERS-CoV 3CL^pro, the enzyme shown to exhibit a crucial role in viral replication. Additionally, F9 suppressed both MERS-CoV-induced histopathological alteration in lung tissue and resulting oxidative and inflammatory biomarkers. Collectively, the results reported herein affirmed the potential of PCMs as nanocarriers for the effective oral administration of MH as an antiviral. Full article

This work aimed to develop lomustine (LOM) and n-propyl gallate (PG)-loaded liposomes suitable for targeting glioblastoma multiforme (GBM) via the auspicious nose-to-brain drug delivery pathway. The therapeutical effect of LOM, as a nitrosourea compound, can be potentiated by PG suitable for enhanced anti-cancer therapy. Nose-to-brain delivery of PG and LOM combined in liposomes can overcome the poor water solubility, absorption properties, and toxicity issues in the systemic circulation. Optimization and characterization of the liposomal carrier with binary drug contents were carried out in order to achieve adequate encapsulation efficiency, loading capacity, drug release, and ex vivo permeation. The optimized liposome co-encapsulated with both drugs showed suitable Z-average (127 ± 6.9 nm), size distribution (polydispersity index of 0.142 ± 0.009), zeta potential (−34 ± 1.7 mV), and high encapsulation efficacy (63.57 ± 1.3% of PG and 73.45 ± 2.2% of LOM, respectively) meeting the acceptance criteria of nose-to-brain transport for both drugs. MTT assays of PG-LOM formulations were also conducted on NIH/3T3 (murine embryonic fibroblast), U87 (glioblastoma), and A2780 (ovarian cancer) cell lines indicating reduced an antiproliferative effect on all types of cells. Our results supported the use of this novel combination of LOM and PG in a liposomal formulation as a promising carrier for glioblastoma targeting via the intranasal route. Full article