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Zinc oxide nanoparticles (ZnONPs) have shown antidiabetic activity in multiple studies and can be produced by different plant-mediated ("green") methods. This study aimed to compare ZnONPs prepared via different "green" approaches (heating at high temperatures (400 °C) vs. low temperature (70 °C)). The low temperature method involved addition of suspending agents (Tween 80 or gum arabic) and pH variations followed by lyophilization. The study evaluated the hypoglycemic potential of ZnONPs with the best properties (quantity of capped agents and stability) compared to the plant extract per se. The ZnONP synthesis involved a mixture of zinc nitrate hexahydrate as the zinc precursor and a plant extract with high antioxidant activity as the capping agent supplier. The results of the studies showed that the procedure using high-temperature heating resulted in almost uncapped nanoparticles with phytocompounds (0.01 % of phenolic compounds) and nanoparticle sizes larger than 300 nm. The low-temperature method produced ZnONPs with high retention of capping agents (92.90 % of phenolic compounds) and a size of approximately 200 nm. The use of Tween 80 with pH adjustment between 9 and 10 resulted in more stable nanoparticles than with gum arabic. These nanoparticles prepared with Tween 80, exhibited a pronounced in vivo antihyperglycemic activity at a much lower dose (10 mg ZnO/kg capped by 0.31 mg phenolic compounds per kg) than the extracts alone (400 mg extract/kg) following an oral glucose tolerance test. These results demonstrated that green-synthesized ZnONPs with a high retention rate of phytochemicals can induce antihyperglycemic effects at a low dose.

There is a growing interest in the development of lipid-based nanocarriers for multiple purposes, including the recent increase of these nanocarriers as vaccine components during the COVID-19 pandemic. The number of studies that involve the surface modification of nanocarriers to improve their performance (increase the delivery of a therapeutic to its target site with less off-site accumulation) is enormous. The present review aims to provide an overview of various methods associated with lipid nanoparticle grafting, including techniques used to separate grafted nanoparticles from unbound ligands or to characterize grafted nanoparticles. We also provide a critical perspective on the usefulness and true impact of these modifications on overcoming different biological barriers, with our prediction on what to expect in the near future in this field.

Diabetes is a metabolic pathology with chronic high blood glucose levels that occurs when the pancreas does not produce enough insulin or the body does not properly use the insulin it produces. Diabetes management is a puzzle and focuses on a healthy lifestyle, physical exercise, and medication. Thus far, the condition remains incurable; management just helps to control it. Its medical treatment is expensive and is to be followed for the long term, which is why people, especially from low-income countries, resort to herbal medicines. However, many active compounds isolated from plants (phytocompounds) are poorly bioavailable due to their low solubility, low permeability, or rapid elimination. To overcome these impediments and to alleviate the cost burden on disadvantaged populations, plant nanomedicines are being studied. Nanoparticulate formulations containing antidiabetic plant extracts or phytocompounds have shown promising results. We herein aimed to provide an overview of the use of lipid- and inorganic-based nanoparticulate delivery systems with plant extracts or phytocompounds for the treatment of diabetes while highlighting their advantages and limitations for clinical application. The findings from the reviewed works showed that these nanoparticulate formulations resulted in high antidiabetic activity at low doses compared to the corresponding plant extracts or phytocompounds alone. Moreover, it was shown that nanoparticulate systems address the poor bioavailability of herbal medicines, but the lack of enough preclinical and clinical pharmacokinetic and/or pharmacodynamic trials still delays their use in diabetic patients.

Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.

Oral administration is the most commonly used route for drug delivery owing to its costeffectiveness,ease of administration, and high patient compliance. However, the absorption of orally delivered compounds is a complex process that greatly depends on the interplay between the characteristics of the drug/formulation and the gastrointestinal tract. In this contribution, we review the different preclinical models (in vitro, ex vivo and in vivo) from their development to application for studying the transport of drugs across intestinal barriers. This review also discusses the advantages and disadvantages of each model. Furthermore, the authors have reviewed the selection and validation of these models and how the limitations of the models can be addressed in future investigations. The correlation and predictability of the intestinal transport data from the preclinical models and human data are also explored. With the increasing popularity and prevalence of orally delivered drugs/formulations, the need of sophisticated preclinical models with higher predictive capacity for absorption of oral formulations used in clinical studies will be required. Keywords:Oral delivery

Low aqueous solubility and poor oral bioavailability are limiting factors in the oral delivery of voxelotor, an antisickling agent. To overcome these limitations, a voxelotor self-nanoemulsifying drug delivery system was developed. Various oils, surfactants, and cosurfactants were screened for their solubilization potential for the drug. The area of nanoemulsification was identified using a ternary phase diagram. An experimental mixture design and a desirability function were applied to select SNEDDSs that contain a maximum amount of lipids and a minimum amount of surfactant, and that possess optimal emulsification properties (i.e., droplet sizes, polydispersity index (PDI), emulsification time, and transmittance percentage). The optimized SNEDDS formulation was evaluated for the self-emulsifying time (32 s), droplet size (35 nm), and zeta potential (-8 mV). In vitro dissolution studies indicated a 3.1-fold improvement in drug solubility from the optimized SNEDDS over pure drug powder. After 60 min of in vitro lipolysis, 88% of the voxelotor loaded in the SNEDDS remained in the aqueous phase. Cytotoxicity evaluation, using Caco-2 cells, indicated the safety of the formulation at 0.9 mg/mL. The transport of the voxelotor SNEDDS across Caco-2 monolayers was significantly enhanced compared to that of the free drug. Compared to the drug suspension, the developed SNEDDS enhanced the oral bioavailability (1.7-fold) of voxelotor in rats. The results suggest that further development of SNEDDSs for the oral delivery of voxelotor is needed.

The present invention relates to a lipid nanocapsule for oral administration comprising a solid lipid outer shell and a lipophilic liquid inner core comprising reverse micelles loaded with one or more incretin mimetics. The present invention also relates to the use of lipid nanocapsules for treating and/or preventing a disorder associated with a GLP-1 dysfunction.

Approximately one third of newly discovered drug molecules show insufficient water solubility and therefore low oral bio-availability. Self-nano-emulsifying drug-delivery systems (SNEDDSs) are one of the emerging strategies developed to tackle the issues associated with their oral delivery. SNEDDSs are composed of an oil phase, surfactant, and cosurfactant or cosolvent. SNEDDSs characteristics, their ability to dissolve a drug, and in vivo considerations are determinant factors in the choice of SNEDDSs excipients. A SNEDDS formulation can be optimized through phase diagram approach or statistical design of experiments. The characterization of SNEDDSs includes multiple orthogonal methods required to fully control SNEDDS manufacture, stability, and biological fate. Encapsulating a drug in SNEDDSs can lead to increased solubilization, stability in the gastro-intestinal tract, and absorption, resulting in enhanced bio-availability. The transformation of liquid SNEDDSs into solid dosage forms has been shown to increase the stability and patient compliance. Supersaturated, mucus-permeating, and targeted SNEDDSs can be developed to increase efficacy and patient compliance. Self-emulsification approach has been successful in oral drug delivery. The present review gives an insight of SNEDDSs for the oral administration of both lipophilic and hydrophilic compounds from the experimental bench to marketed products.

The specialized microfold cells (M cells) in the follicle-associated epithelium (FAE) of intestinal Peyer's patches serve as antigen-sampling cells of the intestinal innate immune system. Unlike 'classical' enterocytes, they are able to translocate diverse particulates without digesting them. They act as pathways for microorganism invasion and mediate food tolerance by transcellular transport of intestinal microbiota and antigens. Their ability to transcytose intact particles can be used to develop oral drug delivery and oral immunization strategies. This protocol describes a reproducible and versatile human M-cell-like in vitro model. This model can be exploited to evaluate M-cell transport of microparticles and nanoparticles for protein, drug or vaccine delivery and to study bacterial adherence and translocation across M cells. The inverted in vitro M-cell model consists of three main steps. First, Caco-2 cells are seeded at the apical side of the inserts. Second, the inserts are inverted and B lymphocytes are seeded at the basolateral side of the inserts. Third, the conversion to M cells is assessed. Although various M-cell culture systems exist, this model provides several advantages over the rest: (i) it is based on coculture with well-established differentiated human cell lines; (ii) it is reproducible under the conditions described herein; (iii) it can be easily mastered; and (iv) it does not require the isolation of primary cells or the use of animals. The protocol requires skills in cell culture and microscopy analysis. The model is obtained after 3 weeks, and transport experiments across the differentiated model can be carried out over periods of up to 10 h.

Drug access to the CNS is hindered by the presence of the blood-brain barrier (BBB), and the intranasal route has risen as a non-invasive route to transport drugs directly from nose-to-brain avoiding the BBB. In addition, nanoparticles (NPs) have been described as efficient shuttles for direct nose-to-brain delivery of drugs. Nevertheless, there are few studies describing NP nose-to-brain transport. Thus, the aim of this work was (i) to develop, characterize and validate in vitro olfactory cell monolayers and (ii) to study the transport of polymeric- and lipid-based NPs across these monolayers in order to estimate NP access into the brain using cell penetrating peptide (CPPs) moieties: Tat and Penetratin (Pen). All tested poly(d,l-lactide-co-glycolide) (PLGA) and nanostructured lipid carrier (NLC) formulations were stable in transport buffer and biocompatible with the olfactory mucosa cells. Nevertheless, 0.7% of PLGA NPs was able to cross the olfactory cell monolayers, whereas 8% and 22% of NLC and chitosan-coated NLC (CS-NLC) were transported across them, respectively. Moreover, the incorporation of CPPs to NLC surface significantly increased their transport, reaching 46% of transported NPs. We conclude that CPP-CS-NLC represent a promising brain shuttle via nose-to-brain for drug delivery.

Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro- and cardio-protective effects of CsA (CiCloMulsion®; NeuroSTAT®) are being tested in phase II and III trials respectively and NeuroSTAT® received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor® EL free formulations and address variable bioavailability and toxicity issues of CsA. This review is an attempt to highlight the progress made so far and the room available for further improvements to realize the maximum benefits of CsA.

Unraveling the mechanisms of nanoparticle transport across the intestinal barrier is essential for designing more efficient nanoparticles for oral administration. The physicochemical parameters of the nanoparticles (e.g., size, surface charge, chemical composition) dictate nanoparticle fate across the intestinal barrier. This review aims to address the most important findings regarding polymeric and lipidic nanoparticle transport across the intestinal barrier, including the evaluation of critical physicochemical parameters of nanoparticles that affect nanocarrier interactions with the intestinal barrier.

Single-layer protamine and double layer polysialic acid (PSA)/protamine nanocapsules (NCs) were designed in order to be used as carriers to facilitate the transport of macromolecules across the intestinal epithelium. The rational for the design of these NCs was based on that protamine is a non-toxic yet potent cell-penetrating peptide, capable of translocating protein cargos through cell membranes, while PSA is a low molecular weight polysaccharide used to enhance the stability of macromolecules and nanocarriers. The aim of this work was to study in vitro the mechanism of interaction of these NCs with different intestinal cell models (Caco-2, Caco-2/Raji mimicking follicle associated epithelium and Caco-2/HT29-MTX to study the effect of mucus). For this, a fluorescent marker, TAMRA was covalently linked to protamine. The interaction and transport of the NCs with the Caco-2 cells was found to be concentration, temperature and size dependent. In all cases, the double layer PSA-protamine NCs exhibited a significantly higher transport compared to protamine NCs. On the other hand, the transport of the NCs was significantly higher in the co-culture (Caco-2/Raji monolayer) compared to the monoculture model (Caco-2 monolayer), implying that M cells are involved in the transport of these nanosystems. The formulations, administered intra-jejunally to healthy rats (4h fasting) resulted in a moderate reduction of the glucose levels (20% reduction), which lasted for up to 4h. This work raises prospects that protamine-based nanocapsules may have the potential as oral peptide delivery nanocarriers.

L cells have attracted particular interest because of the pleiotropic effects of their secreted peptides (i.e., glucagon-like peptide (GLP) 1 and 2, peptide YY (PYY)). L cells express different G-protein-coupled receptors (GPCRs) that can be activated by endogenous ligands found in the gut lumen. We herein hypothesized that lipid-based nanoparticles could mimic endogenous ligands and thus activate GLP-1 secretion in type 2 diabetes mellitus treatment. To assess this hypothesis, lipid-based nanoparticles (nanostructured lipid carriers (NLC), lipid nanocapsules (LNC), and liposomes) and PLGA nanoparticles were added to the L cells and GLP-1 secretion was quantified. Among these nanoparticles, only NLC resulted effective at inducing GLP-1 secretion in both murine and human L cells in vitro. The mRNA expression of proglucagon showed that this effect was due to an increased GLP-1 secretion and not to an increased GLP-1 synthesis. The mechanism by which NLC triggered GLP-1 secretion by L cells revealed an extracellular interaction of NLC, exerting a physiological GLP-1 secretion. We herein demonstrate that nanomedicine can be used to induce GLP-1 secretion from murine and human L cells.

Over the last years, the interest of the pharmaceutical industry in the use of therapeutic peptides in diabetes treatment has been increased. However, these are restricted to parenteral administration. In order to mimic the natural physiological response, many efforts have been made towards oral peptide delivery in diabetes treatment. This review article aims to give an overview on the progress in the nanomedicine field towards the design and optimization of nanoparticle-based drug delivery systems capable of overcoming the harsh gastrointestinal environment and achieving an adequate bioavailability following oral administration. The reported data clearly illustrate the promise of nanomedicine for antidiabetic oral peptide delivery.

Nanotechnology has emerged as a promising strategy toward inflammatory bowel disease (IBD) treatment. Nano-sized drug delivery systems exhibit an increased accumulation in inflamed tissues due to their nanometer size and present the ability to overcome the challenging inflamed colonic barriers (i.e. thick mucus layer, disrupted epithelium, altered colonic transit time). Moreover, nanocarriers are able to increase the amount of drug present at the colonic site decreasing their associated systemic side effects and increasing their efficacy. This review aims to analyze the nanoparticulate systems that have been evaluated for IBD treatment based on (i) the strategy followed towards an increased colonic accumulation and/or permeation, (ii) the small or biopharmaceutical antiinflammatory drug encapsulated within the nanocarriers and (iii) the polymer(s) used for their preparation, highlighting the profits and the drawbacks of each of the candidates based on reported results.

The main objectives of the present study were (i) to evaluate the effect of the mucus layer on saquinavir-loaded nanostructured lipid carriers (SQV-NLCs) uptake and (ii) to evaluate the mucopenetrating properties of dextran-protamine (Dex-Prot) coating on NLCs as per SQV permeability enhancement. Three different NLC formulations differing on particle size and surfactant content were obtained and coated with Dex-Prot complexes. SQV permeability was then evaluated across Caco-2 cell monolayers (enterocyte-like model) and Caco-2/HT29-MTX cell monolayers (mucus model). In the Caco-2 monolayers, Dex-Prot-NLCs increased up to 9-fold SQV permeability in comparison to uncoated nanoparticles. In the Caco-2/HT29-MTX monolayers, Dex-Prot-NLCs presenting a surface charge close to neutrality significantly increased SQV permeability. Hence, Dex-Prot complex coating is a promising strategy to ensure successful nanoparticle mucus-penetration, and thus, an efficient nanoparticle oral delivery. To our knowledge, this is the first time that Dex-Prot coating has been described as a nanoparticle muco-penetration enhancer across the intestinal mucus barrier.

Nanoparticles for medical applications are frequently administered via parenteral administration. In this study, the tissue distribution of three lipid formulations based on Nanostructured Lipid Carriers (NLCs) after intravenous administration to rats was evaluated. NLCs were prepared by a high pressure homogenization method and varied in terms of particle size, surface charge, and surfactant content. The (99m)Tc radiolabeled NLCs were intravenously administered to rats, and radioactivity levels in blood and tissues were measured. Cmax, AUC0-24, and MRT0-24 were obtained from the radioactivity level versus time profiles. The radiolabeled nanocarriers exhibited a long circulation time since radioactivity was detected in blood even 24 h post-injection. No differences on the MRT values in blood among the NLCs were observed, in spite of the different particle size and surface charge. The highest radioactivity levels were measured in the kidney, followed by the bone marrow, the liver, and the spleen. In the kidney, there was a higher accumulation of the positive nanoparticles, and in the liver, uptake of negative nanoparticles was higher than positive ones. NLCs with the largest particle size showed a higher uptake in the lung and lower accumulation in liver and bone marrow, in comparison with the smaller ones.