Comparative Study of Latanoprost Drug Delivery Systems for Glaucoma Treatment and Their Interaction with the Tear Film Lipid Layer Models.

This study investigates the interaction of two approved and one newly developed latanoprost formulation with in vitro and in silico models of the tear film and tear film lipid layer (TFLL). Latanoprost, a prostaglandin analogue used for intraocular elevated pressure treatment, is topically delivered by nanocarriers within aqueous solutions or emulsions. The study focuses on the impact of these carriers on drug interactions with the tear film and their effect on the TFLL. Three different types of latanoprost carriers, micellar, nanoemulsion, and polymer-based, were compared, and each revealed distinct interaction patterns with the TFLL. Surface pressure kinetics demonstrated a rapid increase for the benzalkonium chloride formulation and a slow rise for the preservative-free variants. Visualization of the acellular in vitro TFLL model revealed different patterns of incorporation for each formulation, indicating unique interaction mechanisms. Molecular dynamics simulations further revealed different mechanisms of drug release in the TFLL between micellar and nanoemulsion formulations. In-depth examination highlighted the role of triglyceride molecules in replenishing the nonpolar layer of the TFLL, which suggests potential improvements in ocular surface compatibility by adjusting the quality and concentration of the oily phase. These findings suggest the potential for optimizing latanoprost formulations by tuning the oily phase-to-surfactant ratio and selecting suitable surfactants.

Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects.

Increasing evidence suggests that lysosomal dysfunction has a pathogenic role in neurodegenerative diseases. In particular, an increase in lysosomal pH has been reported in different cellular models of Parkinson's disease. Thus, targeting lysosomes has emerged as a promising approach. More specifically, regulating its pH could play a central role against the neurodegeneration process. To date, only a few agents specifically targeting lysosomal pH are reported in the literature, partly due to the challenge of crossing the Blood-Brain-Barrier (BBB), preventing drug penetration into the central nervous system (CNS). To develop chronic treatments for neurodegenerative diseases, crossing the BBB is crucial. We report herein the conception and synthesis of an innovative DNA derivative-based nanocarrier. Nucleolipids, carrying a biocompatible organic acid as an active ingredient, were designed and synthesized as prodrugs. They were successfully incorporated into an oil-in-water nanoemulsion vehicle to cross biological membranes and then release effectively biocompatible acidic components to restore the functional lysosomal pH of neuronal cells. Biological assays on a genetic cell model of Parkinson's disease highlighted the non-toxicity of such nucleolipids after cellular uptake and their ability (at c = 40 µM) to fully restore lysosomal acidity.

Improving the Physical and Oxidative Stability of Emulsions Using Mixed Emulsifiers: Casein-Octenyl Succinic Anhydride Modified Starch Combinations.

This study aims to investigate the influence of casein and octenyl succinic anhydride modified starch (OSAS) combinations on the physical and oxidative stability of fish oil-in-water emulsions. The interaction between casein and OSAS was manifested in changes in protein structure and hydrogen-bonding interaction. Casein-OSAS combinations could effectively inhibit droplet aggregation at pH 4 and attenuate droplet growth at a high CaCl2 concentration of 0.2 mol/L, compared with casein as an emulsifier. Nanoemulsions stabilized by casein-OSAS combinations or casein showed better oxidative stability compared with OSAS-stabilized emulsions. Therefore, casein-OSAS combinations can improve some physical properties of protein-based emulsions and oxidative stability of modified starch-based emulsions, suggesting protein-modified starch combinations are more promising in the emulsion-based food industry compared to each of the two emulsifiers alone.

Nanoemulsions in drug delivery: formulation to medical application.

Nanoscale oil-in-water emulsions (NEs), heterogeneous systems of two immiscible liquids stabilized by emulsifiers or surfactants, show great potential in medical applications because of their attractive characteristics for drug delivery. NEs have been explored as therapeutic carriers for hydrophobic compounds via various routes of administration. NEs provide opportunities to improve drug delivery via alternative administration routes. However, deep understanding of the NE manufacturing and functionalization fundamentals, and how they relate to the choice of administration route and pharmacological profile is still needed to ease the clinical translation of NEs. Here, we review the diversity of medical applications for NEs and how that governs their formulation, route of administration, and the emergence of increasing sophistication in NE design for specific application.

Enhanced brain penetration of pretomanid by intranasal administration of an oil-in-water nanoemulsion.

AIM: To enhance the drug delivery to the brain with an oil-in-water nanoemulsion of pretomanid via intranasal (IN) administration. MATERIALS & METHODS: The study involved 70 male Sprague-Dawley rats (160-180 g) that received either 20 mg/kg body weight (b.w.) a nanoemulsion or a 20 mg/kg b.w. of pretomanid in solution via the IN route. The drug was quantified by liquid chromatography-tandem mass spectrometry to investigate whole tissue-drug concentrations, and mass spectrometric imaging to visualize drug localization in the brain. RESULTS: Nanoemulsion delivery concentrations of pretomanid in the brain reached peak concentrations (Cmax) of 12,062.3 ng/g that is significantly higher than the required therapeutic level. The mass spectrometric imaging analysis clearly showed a time dependent and uniform distribution in the brain. CONCLUSION: The results of this study show that IN delivery of oil-in-water nanoemulsion may be very promising for targeting anatomical tuberculosis reservoirs, such as the brain.

Effect of the coexistence of sodium caseinate and Tween 20 as stabilizers of food emulsions at acidic pH.

In the present investigation the properties of edible nanoemulsions were studied. Sodium caseinate represents a good candidate for food emulsion preparations thanks to its surface-active properties and because it is perceived as a natural product by consumers. Nevertheless, it is very sensitive to acidic pH close to its isoelectric point and, if used as emulsion stabilizer, this aspect can negatively affect the emulsion stability. In order to prevent this drawback, sodium caseinate was used in combination with a non-ionic surfactant (Tween 20) as emulsifier of oil/water nanoemulsions. For these reasons, nanoemulsions stabilized by Tween 20, sodium caseinate and by a blend of the two emulsifiers were studied and compared according to their response to pH variations. Nanoemulsions were characterized for size of the dispersed phase with variation of time and temperature, for their rheological properties, for surface charge as a function of pH and for protein fluorescence. Noticeably, it was ascertained that, at pH close to caseinate isoelectric point, emulsions stabilized with the blend of caseinate and Tween 20 were more stable, compared with emulsions stabilized only with sodium caseinate. Such behavior was explained according to the composition of the emulsifiers at the oil/water interface where, at acidic pH, the presence of Tween 20 ensured the steric stabilization thus improving the role of sodium caseinate as emulsion stabilizer.

Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers.

PURPOSE: Nanoemulsions have shown potential in delivering drug across epithelial and endothelial cell barriers, which express efflux transporters. However, their transport mechanisms are not entirely understood. Our goal was to investigate the cellular permeability of nanoemulsion-encapsulated drugs and apply mathematical modeling to elucidate transport mechanisms and sensitive nanoemulsion attributes. METHODS: Transport studies were performed in Caco-2 cells, using fish oil nanoemulsions and a model substrate, rhodamine-123. Permeability data was modeled using a semi-mechanistic approach, capturing the following cellular processes: endocytotic uptake of the nanoemulsion, release of rhodamine-123 from the nanoemulsion, efflux and passive permeability of rhodamine-123 in aqueous solution. RESULTS: Nanoemulsions not only improved the permeability of rhodamine-123, but were also less sensitive to efflux transporters. The model captured bidirectional permeability results and identified sensitive processes, such as the release of the nanoemulsion-encapsulated drug and cellular uptake of the nanoemulsion. CONCLUSIONS: Mathematical description of cellular processes, improved our understanding of transport mechanisms, such as nanoemulsions don't inhibit efflux to improve drug permeability. Instead, their endocytotic uptake, results in higher intracellular drug concentrations, thereby increasing the concentration gradient and transcellular permeability across biological barriers. Modeling results indicated optimizing nanoemulsion attributes like the droplet size and intracellular drug release rate, may further improve drug permeability.

An oil-in-water nanoemulsion enhances immunogenicity of H5N1 vaccine in mice.

To enhance the immunogenicity of the Influenza H5N1 vaccine, we developed an oil-in-water nanoemulsion (NE) adjuvant. NE displayed good temperature stability and maintained particle size. More importantly, it significantly enhanced IL-6 and MCP-1 production to recruit innate cells, including neutrophils, monocytes/macrophages and dendritic cells to the local environment. Furthermore, NE enhanced dendritic cell function to induce robust antigen-specific T and B cell immune responses. NE-adjuvanted H5N1 vaccine not only elicited significantly higher and long-lasting antibody responses, but also conferred enhanced protection against homologous clade 1 as well as heterologous clade 2 H5N1 virus challenge in young as well as in aged mice. The pre-existing immunity to seasonal influenza did not affect the immunogenicity of NE-adjuvanted H5N1 vaccine.

Biostability enhancement of oil core - polysaccharide multilayer shell via photoinitiator free thiol-ene 'click' reaction.

Layer-by-layer of polyelectrolytes has emerged as one of the easiest and most controlled techniques to deposit ultrathin polymer layers mainly driven by electrostatic interactions. However, this kind of interaction results to be weak and easily breakable in physiological environment. Here we report on the preparation of nanocapsules completely made of natural biomaterials: a lipophilic core (soybean oil and egg lecithin as surfactant) as nanometric template and a polysaccharide-based multilayer shell (glycol chitosan and heparin) covalently cross-linked. We first modified glycol chitosan with a thiol moiety and heparin with an alkene moiety, respectively, and then we built a polymer multilayer film with a covalent cross-linkage among layers, exploiting the light initiated thiol-ene reaction, known as click chemistry. We showed the possibility to perform the covalent cross-linkage without any photoinitiator or metal catalyst, thus avoiding cytotoxic effects and further purification steps. The so realized nanocapsules resulted to be stable and completely biocompatible and, therefore, of interest for the biotechnology fields, mainly for drug delivery.

Photothermal-Responsive Single-Walled Carbon Nanotube-Based Ultrathin Membranes for On/Off Switchable Separation of Oil-in-Water Nanoemulsions.

Oil-contaminated wastewater threatens our environment and health, especially that stabilized by surfactants. Conventional separation protocols become invalid for those surfactant-stabilized nanoemulsions due to their nanometer-sized droplets and extremely high stability. In this paper, photothermal-responsive ultrathin Au nanorods/poly(N-isopropylacrylamide-co-acrylamide) cohybrid single-walled carbon nanotube (SWCNT) nanoporous membranes are constructed. Such membranes are capable of separating oil-in-water nanoemulsions with a maximum flux up to 35 890 m(2)·h(-1)·bar(-1) because they feature hydrophilicity, underwater oleophobicity, and nanometer pore sizes. It is remarkable that the permeation flux can be simply modulated by light illumination during the process of separation, due to the incorporation of thermal-responsive copolymers and Au nanorods. Meanwhile, it shows ultrahigh separation efficiency (>99.99%) and desired antifouling and recyclability properties. We anticipate that our ultrathin photothermal-responsive SWCNT-based membranes provide potential for the generation of point-of-use water treatment devices.

Comparative Biodistribution and Pharmacokinetic Analysis of Cyclosporine-A in the Brain upon Intranasal or Intravenous Administration in an Oil-in-Water Nanoemulsion Formulation.

The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.

Enhancement of the antimicrobial properties of bacteriophage-K via stabilization using oil-in-water nano-emulsions.

Bacteriophage therapy is a promising new treatment that may help overcome the threat posed by antibiotic-resistant pathogenic bacteria, which are increasingly identified in hospitalized patients. The development of biocompatible and sustainable vehicles for incorporation of viable bacterial viruses into a wound dressing is a promising alternative. This article evaluates the antimicrobial efficacy of Bacteriophage K against Staphylococcus aureus over time, when stabilized and delivered via an oil-in-water nano-emulsion. Nano-emulsions were formulated via thermal phase inversion emulsification, and then bacterial growth was challenged with either native emulsion, or emulsion combined with Bacteriophage K. Bacteriophage infectivity, and the influence of storage time of the preparation, were assessed by turbidity measurements of bacterial samples. Newly prepared Bacteriophage K/nano-emulsion formulations have greater antimicrobial activity than freely suspended bacteriophage. The phage-loaded emulsions caused rapid and complete bacterial death of three different strains of S. aureus. The same effect was observed for preparations that were either stored at room temperature (18-20°C), or chilled at 4°C, for up to 10 days of storage. A response surface design of experiments was used to gain insight on the relative effects of the emulsion formulation on bacterial growth and phage lytic activity. More diluted emulsions had a less significant effect on bacterial growth, and diluted bacteriophage-emulsion preparations yielded greater antibacterial activity. The enhancement of bacteriophage activity when delivered via nano-emulsions is yet to be reported. This prompts further investigation into the use of these formulations for the development of novel anti-microbial wound management strategies.