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The aim of this study was to prepare sodium glycocholate liposomes (SGC-Lip) encapsulating semaglutide (Sml) to improve oral bioavailability and better exert hypoglycemic effect. In this paper, SGC-Lip was prepared by reverse-phase evaporation method with particle size around 140 nm, potential around -27 mV, rounded morphology and better stability. The hypoglycemic and intestinal uptake effects of SGC-Lip and cholesterol-containing liposomes (CH-Lip) were comparatively investigated in rats, and the oral safety of SGC-Lip was examined by cytotoxicity assay. The results indicate that SGC-Lip can achieve a hypoglycemic effect of 40% of the initial value within 12 hours, and the AAC 0-12h is approximately six times that of CH-Lip without sodium glycocholate. The results of the cytotoxicity tests indicate that SGC-Lip has good oral safety. SGC-Lip enhances the absorption of semaglutide in the small intestinal villi via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway with the highest penetration at the ileal site. In summary, the oral bioavailability of semaglutide can be improved by encapsulating semaglutide in SGC-Lip and utilizing the stabilizing and permeation-promoting effects of SGC on liposomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As a multi-target drug to treat ischemic stroke, N-butylphthalide (NBP) is extremely water-insoluble and exhibits limited oral bioavailability, impeding its wide oral application. Effective treatment of ischemic stroke by NBP requires timely and efficient drug exposure, necessitating the development of new oral formulations. Herein, liposomes containing biosurfactant sodium cholate (CA-liposomes) were systemically investigated as an oral NBP delivery platform because of its high biocompatibility and great potential for clinical applications. The optimized liposomes have a uniform hydrodynamic size of 104.30 ± 1.60 nm and excellent encapsulation efficiency (93.91 ± 1.10%). Intriguingly, NBP-loaded CA-liposomes produced rapid drug release and the cumulative release was up to 88.09 ± 4.04% during 12 h while that for NBP group was only 6.79 ± 0.99%. Caco-2 cell monolayer assay demonstrated the superior cell uptake and transport efficiency of NBP-loaded CA-liposomes than free NBP, which was mediated by passive diffusion via transcellular and paracellular routes. After oral administration to rats, NBP-loaded CA-liposomes exhibited rapid and almost complete drug absorption, with a t max of 0.70 ± 0.14 h and an absolute bioavailability of 92.65% while NBP suspension demonstrated relatively low bioavailability (21.7%). Meanwhile, NBP-loaded CA-liposomes produced 18.30-fold drug concentration in the brain at 5 min compared with NBP suspension, and the brain bioavailability increased by 2.48-fold. As expected, NBP-loaded CA-liposomes demonstrated significant therapeutic efficacy in a middle cerebral artery occlusion rat model. Our study provides new insights for engineering oral formulations of NBP with fast and sufficient drug exposure against ischemic stroke in the clinic.

This study demonstrates that significant perturbation of tween20:cholesterol(1:1) niosome membrane takes place even at premicellar concentration of bile salts. Here, 1-naphthol (1-NpOH), a known and sensitive excited state proton transfer (ESPT) probe, was used to understand the nature of perturbation of the membrane in an unbuffered medium. The significant decrease in 1-NpOH fluorescence intensity in niosome-bile salt mixed system at both lower (10 °C) and higher (50 °C) temperatures indicates the bile salts [sodium cholate (NaC) and sodium deoxycholate (NaDC)] induce perturbation of niosome membranes. Variations in the fluorescence lifetime values of both the prototropic emissions (neutral and anionic species) along with the proton transfer rate of 1-NpOH confirm the bile salts perturb up to the hydrophobic core domain of the niosomal membranes. Bile salts induce size change of the niosomal membrane is confirmed through dynamic light scattering study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Elastic liposoxy1mes (ELs) are biocompatible bilayer vesicular systems commonly used in the transdermal delivery of drugs. Compared with conventional liposomes (CLs), the strong deformation ability conferred by edge activators (EAs) is one of the most critical properties of ELs. However, due to limited research methods, little is known about the effect of EAs on the deformation abilities of vesicles. In this study, taking sodium cholate as an example, a multiscale study was carried to study the effect of EAs on the deformability of ELs, including in vitro diffusion experiment at macroscale, "vesicle-pore" model experiment at the microscale and flat patch model experiment at the molecular scale. As a result, it was found that sodium cholate could decrease the kc of DPPC bilayer, which enabled it to remain morphologically intact during a strong deformation process. Such kind of differences on deformation ability made pogostone ELs (contain sodium cholate) present a better permeation effect compared with that of pogostone CLs. All of these provide a multiscale and thorough understanding of the effect of sodium cholate on the deformation ability of ELs.

Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetration of drugs deep into the skin, which is aided by encapsulation within ultradeformable liposomes. Penetrability depends on the flexibility of the lipid membrane, which may be affected by the drugs. We have studied the biophysical effects of four anti-Leishmania drugs (miltefosine (Milt), amphotericin B (AmpB), indole (Ind), and imiquimod (Imiq)) on a soy phosphatidylcholine/sodium cholate membrane. Using diffuse X-ray scattering techniques, we determined bending modulus ( K C ) and chain order parameter ( S X-ray ) of the membrane at several drug concentrations. Form factor scattering data allowed construction of electron density profiles, which yielded bilayer thickness and area per lipid. Results show that AmpB had the largest effect on K C and S X-ray , causing the bilayer to lose integrity at high concentrations. Imiq and Ind induced slight membrane stiffening, whereas Milt had little effect. Imiq also notably decreased chain order at high concentrations. These results will aid in the design of new topical treatments, where Milt, Ind, and Imiq could be used at any concentration without affecting liposome integrity or physical properties, whereas AmpB should not be used at high concentrations.

In this study, novel paclitaxel (PTX) loaded hybrid liposomes for oral PTX delivery were prepared through incorporating PTX loaded polyion complex micelles comprised of positively charged Pluronic F127-Polyethylenimine (PF127-PEI) copolymer and negatively charged sodium cholate (CA) into liposomes consisted of phospholipid molecules. According to the results, this kind of PTX-loaded hybrid liposomes showed improved PTX encapsulation efficiency, sustained PTX release, and enhanced PTX absorption in intestine. The mechanism for enhancing absorption was demonstrated in connection with inhibition of the efflux mediated by multidrug resistance protein, intestinal P-gp. In pharmacokinetic study, the absolute oral bioavailability of PTX loaded in hybrid liposomes had reached to 37.91%. All of these results demonstrated that the application of this novel PTX loaded hybrid liposomes is a strategy with great potential for highly effective oral PTX delivery., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study is to investigate methotrexate-entrapped ultradeformable liposomes (MTX-UDLs) for potential transdermal application. MTX-UDLs were prepared by extrusion method with phosphatidylcholine as a bilayer matrix and sodium cholate or Tween 80 as an edge activator. The physicochemical properties of MTX-UDLs were determined in terms of particle size, polydispersity index, zeta potential, and entrapment efficiency. The deformability of MTX-UDLs was compared with that of methotrexate-entrapped conventional liposomes (MTX-CLs) using a steel pressure filter device. The skin permeation of MTX-UDLs was investigated using Franz diffusion cell, and the skin penetration depth of rhodamine 6G-entrapped UDLs was determined by confocal laser scanning microscopy. MTX-UDLs showed a narrow size distribution, with the particle size of ~100 nm. The deformability of MTX-UDLs was two to five times greater than that of MTX-CLs. The skin permeation of MTX-UDLs was significantly improved compared with MTX-CLs and free MTX solution. The optimized UDLs (phosphatidylcholine: Tween 80 =7:3, w/w) showed a higher fluorescence intensity than conventional liposomes at every increment of skin depth. Thus, the optimized UDLs could be promising nanocarriers for systemic delivery of MTX across skin.

The ultradeformable archaeosomes (UDA, made of total polar archaeolipids (TPA) extracted from the extreme halophile archaea Halorubrum tebenquichense:soybean phosphatidylcholine (SPC):sodium cholate (NaChol), 3:3:1 w:w), are promising topical adjuvants showing high deformability, an essential property for intact skin penetration up to the viable epidermis/dermis. To gain insights on UDA structure, the interactions between TPA, SPC and the edge activator NaChol, were assessed by electrospray ionization mass spectroscopy (ESI-MS) and confocal fluorescence microscopy of giant unilamellar vesicles (GUV). The non covalent heterodimers NaChol-SPC, NaChol-phosphatidylglycerophosphate methyl ether (PGPMe), NaChol-sulfated diglycosyl diphytanyl-glycerol diether (SDGD5) and SPC-PGPMe detected in the gas phase by ESI-MS after direct infusion of UDA, together with the homogeneous partition of FASTDiO and DiIC18 in GUV suggested that in these proportions, lipids and NaChol were miscible. We propose therefore, a model where in UDA the SPC diluted sufficient enough in the rich PGPMe TPA, so as to the low lateral mobility of molecules (typical of rich in PGPMe bilayers) was no longer experienced. We also found that 50μm deep within in vitro human skin canyons, the fluorescence of Alexa fluor 647-ovalbumin in UDL was ∼1.5 folds higher than in UDA, indicating a potential steric hindrance of the voluminous structure of PGPMe UDA bilayer, to the penetration of a particulate cargo such as the 7nm diameter ovalbumin. According to these observations, a further reduction in PGPMe - a lipid playing no immune role - content could help to improve the performance of UDA as topical adjuvants., (Copyright © 2014 Elsevier B.V. All rights reserved.)

With the aim of improving the antioxidant activity of polyphenols from blueberries (Vaccinium myrtillus) on skin targets after topical application, ethanolic extracts from three blueberry varieties (named Millenia, O'Neal, and Blue Crisp) were loaded into ultradeformable liposomes. These nanocarriers are known to be capable of penetrating through the stratum corneum reaching its deeper layers and the viable epidermis. On the other hand, blueberries contain large amounts of polyphenols, whose antioxidant properties as tissue protectors against processes mediated by reactive oxygen species have been extensively proved. Blueberries are usually consumed as edible products, but their antioxidant compounds are poorly absorbed. The antioxidant properties of the extracts were screened before and after being loaded into ultradeformable liposomes made of soy phosphatidylcholine and sodium cholate, of nearly 100 nm in size at 0.223 extract/lipid w/w. The ethanolic extract-loaded ultradeformable liposomes (nanoberries) from Millenia variety retained an 85% of the antioxidant capacity of the free extract and showed low cytotoxicity on HaCaT cells (less than 20%) at active concentration against free radicals.

Ultradeformable archaeosomes (UDA) are vesicles made of soybean phosphatidylcholine (SPC), sodium cholate (NaChol) and polar lipids from Halorubrum tebenquichense (3:1:3 wt/wt). Although ultradeformable liposomes (UDL, made of SPC and NaChol at 6:1 wt/wt) and UDA were neither captured nor caused cytotoxicity on keratinocytes, UDA was avidly captured by macrophages, their viability being reduced by 0.4-1.6 mg/mL phospholipids by 25 to 60%. Instead, UDL were poorly captured and caused no toxicity. Balb/C mice immunized by the topical route with four doses of ovalbumin (OVA)-loaded UDA, at 75 μg OVA/600 μg phospholipids (125 nm mean size and -42 mV zeta potential), induced IgG titers tenfold to 100-fold higher than those immunized with OVA-loaded UDL at the same dosage. Both matrices penetrate to the same skin depth (nearly 10 μm after 1 hour on excised human skin), being the higher topical adjuvancy and higher phagocytic uptake of UDA related to its glycolipid content., From the Clinical Editor: This work summarizes key findings related to the development of ultradeformable archaeosomes as vehicles utilized in transdermal delivery systems with improved skin penetration., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The potentiality of ultradeformable vesicles as a possible topical delivery system for asiaticoside, a natural compound obtained from Centella asiatica was evaluated, because this compound exhibits collagen biosynthesis promoting activity. Ultradeformable vesicles were prepared by the extrusion technique; these vesicles were composed of Phospholipon 100 and different molar fractions of sodium cholate as the edge activator. The physicochemical properties of the ultradeformable vesicles were investigated through differential scanning calorimetry and light scattering techniques. The potential cyctotoxicity and biological activity of asiaticoside-loaded ultradeformable vesicles were evaluated on primary human dermal fibroblast cells by determining the extracellular lactic dehydrogenase activity, the cellular viability and the biosynthetic production of collagen. In vitro permeation experiments through human stratum corneum and epidermis membranes were also carried out. Ultradeformable vesicles having sodium cholate molar fraction of 0.2 proved to be the most suitable topical carriers for asiaticoside. A sodium cholate content of >0.2 was observed to be cytotoxic probably due to its co-existence with other lipid aggregates, an example being mixed micelles. Asiaticoside-loaded ultradeformable vesicles with a sodium cholate molar fraction of 0.2 elicited the greatest degree of collagen biosynthesis in human fibroblasts. Ultradeformable vesicles provided the greatest in vitro skin permeation of asiaticoside showing a 10-fold increase with respect to the free drug solution and favoured an increase in in vivo collagen biosynthesis. Ultradeformable vesicles are therefore suitable carriers for the pharmaceutical and cosmetic application of the natural agent asiaticoside., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study aimed at preparing and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearyl amine (STA)] and surfactants [poly-24-oxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepared using four different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2%-5% mol/mol additives. Differential scanning calorimetry thermograms revealed that the additives completely abolished gel/liquid transition suggesting that the bilayer membranes could accommodate the additives. The volume diameters D (4, 3) of the prepared niosomes were significantly [p < 0.05, analysis of variance (ANOVA)] dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 ± 1.40 and 5.37 ± 1.40 μ m, respectively. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepared niosomes significantly (p < 0.01, ANOVA) controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepared niosomal formulations were found practically nonirritant when applied onto the surface of a 10-day-old hen's chorioallantoic membrane., (Copyright © 2011 Wiley-Liss, Inc.)

Detergent removal from mixed micelles was combined with preparative size exclusion chromatography (SEC) on Sephacryl S 500 HR to prepare unilamellar and spherical liposomes of defined sizes between 50 and 100 nm with a very narrow size distribution (RSD of vesicle diameter between 13% and 25%). For neutral phosphatidylcholine and negatively charged phosphatidylcholine/phosphatidylglycerol liposome preparations, efficient sizing at the preparative scale was demonstrated by analyzing isolated SEC peak fractions with cryo-transmission electron microscopy and dynamic light scattering. The number-weighted average vesicle diameters obtained using both methods are in very good agreement for fractions of low polydispersity.

The aim of this work was to develop a system that can deliver siRNA into cells present in the human epidermis. More specifically, we wanted to block the expression of a specific Myosin Va exon F containing isoform that is physiologically involved in melanosome transport in human melanocytes. Therefore, we prepared and investigated the capacity of ultradeformable cationic liposomes (UCLs) to deliver siRNA in hard-to-transfect human primary melanocytes. UCLs were formulated from different w:w ratios (6:1, 8:1 and 10:1) of the cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and the edge activator sodium cholate. Subsequently, UCL/siRNA complexes were prepared and their particle size, surface charge, deformability, cytotoxicity, transfection efficiency and long-term stability were tested. The best results were obtained with UCLs composed of a DOTAP/NaChol ratio of 6:1 (w:w) which are promising for future in vivo experiments.

Polysaccharide-coated liposomes have been studied for their potential use for peptide drug delivery by the oral route because they are able to minimize the disruptive influences on peptide drugs of gastrointestinal fluids. The aim of this work was to synthesize and characterize a modified polysaccharide, O-palmitoylscleroglucan (PSCG), and to coat unilamellar liposomes for oral delivery of peptide drugs. To better evaluate the coating efficiency of PSCG, also scleroglucan (SCG)-coated liposomes were prepared. We studied the surface modification of liposomes and the SCG- and PSCG-coated liposomes were characterized in terms of size, shape, zeta potential, influence of polymer coating on bilayer fluidity, stability in serum, in simulated gastric and intestinal fluids and against sodium cholate and pancreatin. Leuprolide, a synthetic superpotent agonist of luteinizing hormone releasing hormone (LHRH) receptor, was chosen as a model peptide drug. After polymer coating the vesicle dimensions increased and the zeta potential shifted to less negative values. These results indicate that both SCG- and PSCG-coated liposomes surface and DSC results showed that PSCG was anchored on the liposomal surface. The stability of coated-liposomes in SGF, sodium cholate solution and pancreatin solution was increased. From this preliminary in vitro studies, it seems that PSCG-coated liposomes could be considered as a potential carrier for oral administration.

Objective: To prepare tanshinone transfersome (TTs) and evaluate its deformability., Methods: The transfersomes were prepared by film dispersion method followed by sonication, and their physical properties, morphology, content, entrapment efficiency, particle size, polydispersity, and Zeta potential were investigated. The stability and deformability of TTs were studied. Liposomes with different molar ratios of cholate and lecithin were compared for their permeability under external pressure., Results: The prepared TF were spherical vesicles with content of 1.0192+/-0.075 mg/ml, entrapment efficiency of (62.3+/-0.08)%, particle size of 110 nm, polydispersity of 0.19 and Zate potential of -15.0 mV. The TTs remained stable during light-proof preservation for 3 months at 4 degrees C, and sodium cholate contributed to the flexibility of the lecithin vesicles., Conclusion: TTs prepared by film dispersion method has good entrapment efficiency and stability. The vesicles possess high deformability in relation to the molar ratio of sodium cholate to lecithin and the external pressure.

The interactions of the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC) in 0.1 M NaCl (pH 7.4) with membranes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) and mixtures of DPPC and DPPG at molar ratios of 3:1 and 1:1 were studied by means of high-sensitivity isothermal titration calorimetry (ITC), dynamic light scattering (DLS), and differential scanning calorimetry (DSC). The partition coefficients and the transfer enthalpies for the incorporation of bile salt molecules into the phospholipid membranes were determined by ITC. The vesicle-to-micelle transition was investigated by ITC, DLS, and DSC. The phase boundaries for the saturation of the vesicles and their complete solubilization established by ITC were in general agreement with DLS data, but systematic differences could be seen due to the difference in detected physical quantities. Electrostatic repulsion effects between the negatively charged bile salt molecules and the negatively charged membrane surfaces are not limiting factors for the vesicle-to-micelle transition. The membrane packing constraints of the phospholipid molecules and the associated spontaneous curvature of the vesicles play the dominant role. DPPG vesicles are transformed by the bile salts into mixed micelles more easily or similarly compared to DPPC vesicles. The saturation of mixed DPPC/DPPG vesicles requires less bile salt, but to induce the solubilization of the liposomes, significantly higher amounts of bile salt are needed compared to the concentrations required for the solubilization of the pure phospholipid systems. The different solubilization behavior of DPPC/DPPG liposomes compared to the pure liposomes could be due to a specific "extraction" of DPPG into the mixed micelles in the coexistence region.