Deep eutectic solvent self-assembled reverse nanomicelles for transdermal delivery of sparingly soluble drugs.

BACKGROUND: Transdermal delivery of sparingly soluble drugs is challenging due to their low solubility and poor permeability. Deep eutectic solvent (DES)/or ionic liquid (IL)-mediated nanocarriers are attracting increasing attention. However, most of them require the addition of auxiliary materials (such as surfactants or organic solvents) to maintain the stability of formulations, which may cause skin irritation and potential toxicity. RESULTS: We fabricated an amphiphilic DES using natural oxymatrine and lauric acid and constructed a novel self-assembled reverse nanomicelle system (DES-RM) based on the features of this DES. Synthesized DESs showed the broad liquid window and significantly solubilized a series of sparingly soluble drugs, and quantitative structure-activity relationship (QSAR) models with good prediction ability were further built. The experimental and molecular dynamics simulation elucidated that the self-assembly of DES-RM was adjusted by noncovalent intermolecular forces. Choosing triamcinolone acetonide (TA) as a model drug, the skin penetration studies revealed that DES-RM significantly enhanced TA penetration and retention in comparison with their corresponding DES and oil. Furthermore, in vivo animal experiments demonstrated that TA@DES-RM exhibited good anti-psoriasis therapeutic efficacy as well as biocompatibility. CONCLUSIONS: The present study offers innovative insights into the optimal design of micellar nanodelivery system based on DES combining experiments and computational simulations and provides a promising strategy for developing efficient transdermal delivery systems for sparingly soluble drugs.

Tyrosine phosphorylation of band 3 impairs the storage quality of suspended red blood cells in the Tibetan high-altitude polycythemia population.

Due to environmental hypoxia on the Tibetan Plateau, local residents often exhibit a compensative increase in hemoglobin concentration to maintain the body's oxygen supply. However, increases in hemoglobin and hematocrit (Hct) pose a serious challenge to the quality of stored suspended red blood cells (SRBCs) prepared from the blood of high-hemoglobin populations, especially populations at high altitude with polycythemia in Tibet. To explore the difference in storage quality of SRBCs prepared from plateau residents with a high hemoglobin concentration, blood donors were recruited from Tibet (> 3600 m) and Chengdu (≈ 500 m) and divided into a high-altitude control (HAC) group, high-altitude polycythemia (HAPC) group and lowland control (LLC) group according to their hemoglobin concentration and altitude of residence. The extracellular acidification rate (ECAR), pyruvate kinase (PK) activity and band 3 tyrosine phosphorylation were analyzed on the day of blood collection. Then, whole-blood samples were processed into SRBCs, and storage quality parameters were analyzed aseptically on days 1, 14, 21 and 35 of storage. Overall, we found that tyrosine 21 phosphorylation activated glycolysis by releasing glycolytic enzymes from the cytosolic domain of band 3, thus increasing glucose consumption and lactate accumulation during storage, in the HAPC group. In addition, band 3 tyrosine phosphorylation impaired erythrocyte deformability, accompanied by the highest hemolysis rate in the HAPC group, during storage. We believe that these results will stimulate new ideas to further optimize current additive solutions for the high-hemoglobin population in Tibet and reveal new therapeutic targets for the treatment of HAPC populations.

Polarization-insensitive tunable terahertz polarization rotator.

A rotation-angle variable polarization rotator is proposed and demonstrated using an all-dielectric metasurface doublet. Such a transmissive device can conveniently rotate the polarization of incident light by any desired angles by mechanically changing the relative angle of the double metasurface layers regardless of the incident state of polarization. Under certain conditions the device acts as a full phase modulator for the circularly polarized incident wave. Hence, it has a promising application in polarization and phase control.

Transmission and plasmonic resonances on quasicrystal metasurfaces.

The control of light-matter interaction in metasurfaces offers an unexplored potential for the excitation and manipulation of light. Here, we combine experimental terahertz time-domain spectroscopy and near-field scanning terahertz microscopy to demonstrate the role of reciprocal vectors in the transmission and plasmonic resonances of quasicrystal metasurfaces. An investigation of two-dimensional metasurface structures with different rotationally symmetric quasicrystal arrangements demonstrates that the transmission minima resulting from Wood's anomaly are directly related to the surface plasmon resonances. We also find that the surface plasmon resonances of the quasicrystal metasurface were determined by the reciprocal vectors, which could be well explained by the coupling condition of the resonances, and the characteristic frequencies remain un-shifted under various slit sizes. Our findings demonstrate a new potential in developing novel plasmonic metasurfaces.

[Dexamethasone acetate microemulsions: formulation and effect on skin permeability].

The present project was designed to optimize the microemulsion (ME) formulation of oil in water (O/W) for dexamethasone acetate (DA), and examine its impact on DA percutaneous permeation. The saturated solubility of DA in different oils, surfactants and co-surfactants was tested. The ratio of surfactant to co-surfactant was selected by constructing pseudo three phase diagrams to investigate the maximal microemulsion area. In vitro permeation studies of DA from microemulsion and suspension were performed to optimize the formulation further. Differential scanning calorimetry(DSC) and attenuated total reflection flourier transformed infrared spectroscopy (ATR-FTIR) were performed to investigate the mechanism of microemulsion action on skin. The optimized formulation was composed of oleic acid/Labrasol/propylene glycol/water with 8/45/15/32 (w/w), and the DA loading was 0.75% (w/w). The permeation enhancement of microemusion was 6.00-fold as that of suspension, and the DA from microemulsion retained in the skin was 4.79-fold as that of suspension. DSC and ATR-FTIR results suggested that microemulsion could affect the intercellular lipid lamellae and keratin of the stratum corneum. The barrier function of stratum corneum was disordered by the microemulsion so that the dermal drug delivery was enhanced. Therefore, the optimized microemulsion enhanced DA percutaneous permeation significantly through the interaction of microemulsion with skin, microemulsion is a promising approach for DA percutaneous delivery.

Higher mortality in patients with right hemispheric intracerebral haemorrhage: INTERACT1 and 2.

BACKGROUND AND PURPOSE: Controversy exists over the prognostic significance of the affected hemisphere in stroke. We aimed to determine the relationship between laterality of acute intracerebral haemorrhage (ICH) and poor clinical outcomes. METHODS: A subsidiary analysis of the INTERACT Pilot and INTERACT2 studies--randomised controlled trials of patients with spontaneous acute ICH with elevated systolic blood pressure (BP), randomly assigned to intensive (target systolic BP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Outcomes were the combined and separate end points of death and major disability (modified Rankin scale (mRS) scores of 3-6, 6 and 3-5, respectively) at 90 days. RESULTS: A total of 2708 patients had supratentorial/hemispheric ICH and information on mRS at 90 days. Patients with right hemispheric ICH (1327, 49%) had a higher risk of death at 90 days compared to those with left hemispheric ICH after adjustment for potential confounding variables (OR, 1.77 (95% CI 1.33 to 2.37)). There were no differences between patients with right and left hemispheric ICH regarding the combined end point of death or major disability or major disability in the multivariable-adjusted models (1.07 (0.89 to 1.29) and 0.85 (0.72 to 1.01), respectively). CONCLUSIONS: Right hemispheric lesion was associated with increased risk of death in patients with acute ICH. The laterality of the ICH does not appear to affect the level of disability in survivors. TRIAL REGISTRATION NUMBER: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079.

[In vitro targeting effect of lactoferrin modified PEGylated liposomes for hepatoma cells].

A lactoferrin-containing PEGylated liposome system (Lf-PLS) was developed and tested in vitro as a hepatoma-targeting drug delivery system. PEGylated liposomes (PLS) were successfully prepared using the thin film hydration method with peglipid post insertion. Lf was covalently conjugated onto the carboxyl terminal of DSPE-PEG2000-COOH on liposomes. Coumarin-6 was used to trace Lf-PLS with fluorescence. The cellular uptake of this system was carried out in asialoglycoprotein receptor (ASGPR) positive HepG2 cells via confocal microscopy and flow cytometry. The Lf-PLS liposome was observed as spherical or oval vesicles with the particle size around 130 nm, zeta potential about -30 mV and encapsulation efficiency more than 80%. The confocal microscopy images and flow cytometry data demonstrated that Lf-PLS resulted in significantly higher cell association by ASGPR positive HepG2 cells compared to PLS. The association between Lf-PLS and cells were dependent on the concentration, time and temperature, which was inhibited by pre-incubation with excessive free Lf. The results suggest that Lf-PLS has a good targeting effect on HepG2 cells in vitro. The targeting mechanism may be related to the specific binding of Lf and ASGPR on HepG2 cells, which guides Lf-PLS to the cell surface to induce an active endocytosis process. All these results demonstrated that Lf-PLS might be a potential drug delivery system in targeting hepatocellular carcinoma, which deserves more research on its targeting ability, antitumor efficiency, and metabolism in vivo for treatment of hepatomacellular carcinoma.

Association study identifying a new susceptibility gene (AUTS2) for schizophrenia.

Schizophrenia (SCZ) is a severe and debilitating mental disorder, and the specific genetic factors that underlie the risk for SCZ remain elusive. The autism susceptibility candidate 2 (AUTS2) gene has been reported to be associated with autism, suicide, alcohol consumption, and heroin dependence. We hypothesized that AUTS2 might be associated with SCZ. In the present study, three polymorphisms (rs6943555, rs7459368, and rs9886351) in the AUTS2 gene were genotyped in 410 patients with SCZ and 435 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and forced PCR-RFLP methods. We detected an association between SCZ and the rs6943555 genotype distribution (odds ratio (OR)=1.363, 95% confidence interval (CI): 0.848-2.191, p=0.001). The association remained significant after adjusting for gender, and a significant effect (p=0.001) was observed among the females. In the present study, rs6943555 was determined to be associated with female SCZ. Our results confirm previous reports which have suggested that rs6943555 might elucidate the pathogenesis of schizophrenia and play an important role in its etiology.

Application value of self-management manual combined with case management superiority model in postoperative management of nasopharyngeal carcinoma after radiotherapy.

OBJECTIVE: To explore the application value of the self-management manual combined with the case management model in postoperative management of nasopharyngeal carcinoma after radiotherapy. METHODS: Eighty-four patients with nasopharyngeal carcinoma admitted to Yingtan People's Hospital from May 2020 to April 2022 were retrospectively included in this study. They were divided into the experimental group (receiving self-management manual combined with case management mode scheme, n=42) and the control group (receiving continuous management after conventional nasopharyngeal carcinoma radiotherapy, n=42) according to mode differences. The cancer-related fatigue [Cancer Fatigue Scale (CFS)], comfort status [General Comfort Questionnaire (GCQ)], self-management efficacy [Chinese Strategies Used by People to Promote Health (C-SUPPH)], self-care ability (self-care ability measurement), pain score [Visual analogue scale (VAS)], and quality of life [European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30)] were compared between the two groups after 4 weeks of radiotherapy. The adverse reactions of the two groups were recorded. Combined with periodic review and follow-up records, the prognostic factors of the two groups of patients were analyzed. RESULTS: After treatment, the scores of physical fatigue (12.83±1.10), emotional fatigue (9.78±1.32), cognitive fatigue (5.62±1.31), and total score of CFS (28.24±2.26) in the experimental group were 12.83±1.10. The control group physical fatigue (13.90±1.25) points, emotional fatigue (10.55±1.40) points, cognitive fatigue (6.80±1.75) points, and total CFS (31.33±2.59) points in both groups were lower than before treatment. The experimental group was lower than the control group (ALL P<0.05). The physiological, psychological, spiritual, socio-cultural, and environmental scores of the experimental group were higher than those of the control group (all P<0.05). The scores of health knowledge, self-care skills, self-care responsibility, and self-concept score of patients in the experimental group were higher than the control group (all P<0.05). After intervention, the VAS score of the experimental group was lower than that of the control group (P<0.05). After intervention, the EORTC QLQ-C30 score of both groups increased significantly as compared with pre-intervention. The score in the experimental group was significantly higher than that in the control group [(80.05±10.72) vs (68.11±12.10), P<0.05]. Postoperative (various) adverse reactions in the experimental group were lower than the control group (all P<0.05). The factors influencing the prognosis of nasopharyngeal carcinoma patients were age, tumor stage, and intervention mode by Cox model analysis (all P<0.05). CONCLUSION: The self-management manual combined with the case management mode can alleviate cancer fatigue, improve postoperative self-management ability, self-care ability, and quality of life of patients with nasopharyngeal cancer radiotherapy, reduce the occurrence of adverse reactions and improve the prognosis of patients. It is worth promoting in clinical settings.

Diagnostic performance of microRNA-29a in active pulmonary tuberculosis: a systematic review and meta-analysis.

BACKGROUND: In recent years, more and more studies have shown that microRNA-29a (miRNA-29a) can be used as a potential biomarker for active tuberculosis, but the results of these studies are not consistent. OBJECTIVE: To comprehensively evaluate the value of miRNA-29a in the diagnosis of active tuberculosis by meta-analysis. METHODS: The databases of CNKI, WanFang, PubMed, The Cochrane Library, Web of Science and EMBASE were searched for relevant studies. Studies were screened strictly according to inclusion and exclusion criteria. QUADAS-2 scale was used to evaluate the quality of the included studies. Data were extracted and analyzed by Meta-DiSc 1.4 and Stata 16.0 software. RESULTS: 13 articles were included, including a total of 1598 subjects, including 872 active tuberculosis patients and 726 controls. The combined sensitivity and specificity of miRNA-29a in the diagnosis of active tuberculosis were 78 % and 76 %, respectively, and the area under the overall summary receiver operating characteristic curve was 0.8564. CONCLUSION: miRNA-29a can be used as a biomarker for the diagnosis of active tuberculosis.

Oxymatrine-fatty acid deep eutectic solvents as novel penetration enhancers for transdermal drug delivery: Formation mechanism and enhancing effect.

Transdermal delivery of drugs is commonly limited by low skin permeability. The aim of the study was to synthesize deep eutectic solvents (DESs) based on oxymatrine (OMT) and fatty acids with various alkyl chain lengths (LCFAs) as novel vehicles, to solubilize the water-insoluble drug and enhance percutaneous penetration. Quercetin (QUE) was selected as a model drug. Combining differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and molecular simulations demonstrated that the formation of DESs was mediated by charge-assisted hydrogen bonding. Physicochemical properties including stability, viscosity, and solubilization capacity were also studied. Subsequently, the effect of three stable DESs on drug release and skin permeability was evaluated. The results showed that QUE was solubilized well and presented a different sustained release behavior in DESs. Meanwhile, DESs enhanced the skin permeation of OMT and QUE, which was influenced by alkyl chain lengths of LCFAs, whereas DES consisting of lauric acid (LA) exhibited the highest enhancing effect. FTIR, DSC, and molecular docking further demonstrated consistency between micro molecular mechanism and macro penetration behavior. Additionally, HaCaT cells treated with DESs showed high cell viability, suggesting their good skin safety. Taken together, OMT-LCFA DESs would be a promising penetration enhancer for transdermal drug delivery, which also provides guidance for the design of new DESs.

Combining the In Silico and In Vitro Assays to Identify Strobilanthes cusia Kuntze Bioactives against Penicillin-Resistant Streptococcus pneumoniae.

Leaves of Strobilanthes cusia Kuntze (S. cusia) are a widely used alexipharmic Traditional Chinese Medicine (TCM) in southern China for the prevention of cold and respiratory tract infectious diseases. One of the most common bacterial pathogens in the respiratory tract is the gram-positive bacterium Streptococcus pneumoniae. The antibiotic resistance of colonized S. pneumoniae makes it a more serious threat to public health. In this study, the leaves of S. cusia were found to perform antibacterial effects on the penicillin-resistant S. pneumoniae (PRSP). Confocal assay and Transmission Electron Microscopy (TEM) monitored the diminished cell wall integrity and capsule thickness of the PRSP with treatment. The following comparative proteomics analysis revealed that the glycometabolism-related pathways were enriched for the differentially expressed proteins between the samples with treatment and the control. To further delve into the specific single effective compound, the bio-active contents of leaves of S. cusia were analyzed by UPLC-UV-ESI-Q-TOF/MS, and 23 compounds were isolated for anti-PRSP screening. Among them, Tryptanthrin demonstrated the most promising effect, and it possibly inhibited the N-glycan degradation proteins, as suggested by reverse docking analysis in silico and further experimental verification by the surface plasmon resonance assay (SPR). Our study provided a research foundation for applications of the leaves of S. cusia as a TCM, and supplied a bio-active compound Tryptanthrin as a candidate drug skeleton for infectious diseases caused by the PRSP.

Co-Delivery of Loxoprofen and Tofacitinib by Photothermal Microneedles for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is an autoimmune disease of synovial inflammation that affects populations worldwide. Transdermal drug delivery systems for treating RA have increased but remain challenging. We fabricated a dissolving microneedle (MN) system with photothermal (PT) polydopamine (PDA) to co-load the non-steroidal anti-inflammatory drug loxoprofen (Lox) and the Janus kinase inhibitor tofacitinib (Tof), with the aim of co-delivering Lox and Tof directly to the articular cavity, aided by the combination of MN and PT. In vitro and in vivo permeation studies showed that the PT MN significantly promoted drug permeation and retention in the skin. An in vivo visualization of the drug distribution in the articular cavity showed that the PT MN significantly promoted drug retention in the articular cavity. Importantly, compared to the intra-articular injection of Lox and Tof, the application of the PT MN to a carrageenan/kaolin-induced arthritis rat model exhibited superior performance in reducing joint swelling, muscle atrophy, and cartilage destruction. Furthermore, the PT MN downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α, IL-1ß, iNOS, JAK2, JAK3, and STAT3. The results show that the PT MN transdermal co-delivery of Lox and Tof is a new synergetic therapy with high compliance and good therapeutic efficacy for RA.

Active pharmaceutical ingredient-ionic liquids assisted follicular co-delivery of ferulic acid and finasteride for enhancing targeted anti-alopecia.

Androgenetic alopecia (AGA) is the primary hair loss with impairing patients' quality of life. Finasteride (FIN) is an SRD5A2 inhibitor for AGA treatment, but oral FIN causes systemic adverse effects. Topical FIN delivery is anticipated to overcome this problem. Ferulic acid (FA) is a natural phenolic acid with vascular remodeling and anti-inflammatory effects. Herein, an active pharmaceutical ingredient ionic liquid (API IL) based on choline and FA (CF-IL) is for the first time constructed to load FIN for fabricating FIN CF-IL. CF-IL aims to act as carriers and cargos and enhance hair follicle (HF) co-delivery of FA and FIN for synergistic anti-alopecia. Thermal and spectroscopic analysis combined with quantum chemistry calculations and molecular dynamics confirm the formation of CF-IL. The CF-IL simultaneously increases the solubility of FA (∼648-fold) and FIN (∼686-fold), enhances the permeation and retention of FIN and FA through the follicular pathway, and promotes cellular uptake. FIN CFIL regulates the abnormal mRNA expressions in dihydrotestosterone-irritated hDPCs, and promotes hair regrowth in AGA mice in a combined manner with FIN and FA. These findings suggest that FA-based API IL is a promising approach for percutaneously co-delivering FA and FIN to HF, providing an enhanced targeting treatment for AGA.

[In vivo imaging in tumor-bearing animals and pharmacokinetics of PEGylated liposomes modified with RGD cyclopeptide].

The hydroxycamptothecin (HCPT) PEGylated liposomes (HCPT-LP) were modified with RGD cyclopeptide formed the tumor-targeting liposomes (HCPT-RGD-LP). HCPT-LP and HCPT-RGD-LP were injected intravenously with single dose of 5 mg x kg(-1) to rats. The drug concentration in plasma was determined and the pharmacokinetic behaviour was compared. The HCPT distribution in heart, liver, spleen, lung, kidney and plasma of mice was investigated following intravenous administration of HCPT-LP and HCPT injection. The nude mice implanted human hepatoma HepG2 cells were studied by in vivo imaging. The fluorescent probe was DiR and the nude mice were injected with DiR PEGylated liposomes (DiR-LP) and DiR-LP modified with RGD cyclopeptide (DiR-RGD-LP). The results showed that there was no significant difference (P > 0.05) of main pharmacokinetic parameters t1/2beta, CL, V(c), AUC(0-48 h), AUC(0-inifinity), MRT(0-48 h), MRT(0-infinity) between HCPT-RGD-LP and HCPT-LP. HCPT-LP had a remarkably better long-circulating effect than HCPT injection in mice and the concentration of HCPT was highest in liver. The DiR accumulation in tumors of DiR-RGD-LP was higher than that of DiR-LP by the visualized fluorescence of in vivo imaging. It indicated that such PEGylated liposomes modified with RGD cyclopeptide could improve the tumor targeting efficacy.

[Tetrahydropalmatine's permeative properties of acupoint and non-acupoint transdermal administration of Baijiezi Tufang in vitro and in vivo].

OBJECTIVE: To study tetrahydropalmatine's permeative properties of acupoint and non-adupoint transdermal administration of baijiezi tufang in vitro and in vivo. METHOD: Taking tetrahydropalmatine as an evaluative component to assess the permeative of baijiezi tufang in acupoint skin and non-acupoint skin with the modified Franz diffusion cell method and in vivo penetration studies. The content of tetrahydropalmatine was determined by a HPLC method. RESULT: The 24 hours cumulative permeation amount through acupoint skin was (13.53 +/- 3.92) microg x cm(-2), about 4 times higher than non-acupoint skin. The steady-state infiltration rates of tetrahydropalmatine in acupoint skin was (0.659 1 microg x cm(-2) x h(-1)), 4.5 times higher than non-acupoint skin. The content in acupoint skin was signally higher than that in non-acupoint skin (P < 0.05). An accumulation of fluorescence can be clearly seen in the four layers: stratum corneum > viable epidermis > dermis > subcutaneous. CONCLUSION: In vitro and in vivo studies show that the permeation of baijiezi tufang in acupoint skin was better than in non-acupoint skin, following a higher cumulative amount and skin content.

Chitosan/hyaluronan nanogels co-delivering methotrexate and 5-aminolevulinic acid: A combined chemo-photodynamic therapy for psoriasis.

Psoriasis does not respond adequately to the monotherapy, tailoring combined strategies for synergistical treatment remains challenging. We fabricated chitosan/hyaluronan nanogels to co-load methotrexate (MTX) and 5-aminoleavulinic acid (ALA), i.e., MTX-ALA NGs, for a combined chemo-photodynamic therapy for psoriasis. Compared with MTX-ALA suspension, the NGs enhanced the penetration and retention of MTX and ALA through and into the skin in vitro and in vivo (p < 0.001). NGs enhanced the cellular uptake (p < 0.001), protoporphyrin IX conversion (p < 0.001), and reactive oxygen species generation (3.93-fold), subsequently exerted the synergistical anti-proliferation and apoptosis on lipopolysaccharide-irritated HaCaT cells with the apoptosis rate of 78.6%. MTX-ALA NGs efficiently ameliorated the skin manifestations and down-regulated the proinflammatory cytokines of TNF-α and IL-17A in imiquimod-induced psoriatic mice (p < 0.001). Importantly, MTX-ALA NGs reduced the toxicities of oral MTX to the liver and kidney. The results support that MTX-ALA NG is a convenient, effective, and safe combined chemo-photodynamic strategy for psoriasis treatment.

Spin-Decoupled Interference Metasurfaces for Complete Complex-Vectorial-Field Control and Five-Channel Imaging.

Light is a complex vectorial field characterized by its amplitude, phase, and polarization properties, which can be further represented by four basic parameters, that is, amplitudes and phases of two orthogonally polarized components. Controlling these parameters simultaneously and independently at will using metasurfaces are essential in arbitrarily manipulating the light propagation. However, most of the studies so far commonly require a great number of different meta-atoms or rely on diffraction under oblique incidence, which lack convenience and flexibility in design and implementation. Here, a new metasurface paradigm is proposed that can completely manipulate the amplitudes and phases of two spin components based on the interference effect, where only two different meta-atoms are applied. For proof-of-concept demonstration, two five-channel meta-holograms for imaging and information encryption are designed and experimentally characterized. The interference method provides a simple route toward compact complex and multifunctional meta-devices.

In vitro study of transdermal penetration and iontophoresis of hepatitis B vaccines through rat skin.

In vitro percutaneous delivery of hepatitis B vaccines was investigated in order to assess the penetration of vaccine under passive diffusion and iontophoresis conditions. The study was carried out using Franz vertical diffusion cell through the hairless abdominal skin of Sprague-Dawley (SD) rats. Enzyme-linked immunosorbent assay (ELISA) was used to determine the cumulative amount of permeation and the retention amount of drug in skin. Passive diffusion alone resulted in less skin permeation and retention of hepatitis B vaccines, only (2.1 +/- 0.1) ng x cm(-2) and (2.3 +/- 0.1) ng x cm(-2) after 24 h when the initial concentration of vaccine in the donor compartment was 23 microg x mL(-1) and 46 microg x mL(-1), respectively. After removing the stratum corneum, the permeation and retention amount of hepatitis B vaccines increased to (383.7 +/- 86.2) ng x cm(-2) and (16.8 +/- 4.6) ng x cm(-2), respectively, 171.6-folds and 2.1-folds more than that from its intact skin with the drug loaded at 46 microg x mL(-1). Iontophoresis induced a significant increase of cumulative and retention amount of hepatitis B vaccines through the skin (P < 0.05). Application of iontophoresis significantly enhanced the permeation of hepatitis B vaccines (P < 0.05) by 2.7-folds and 6.6-folds for the intact skin, and by 1.6-folds and 1.8-folds for the tape-stripped skin with initial drug loading of 23 microg x mL(-1) and 46 microg x mL(-1), respectively. Iontophoresis also significantly increased the amount of drug retained in the skin. After applying iontophoresis for 6 h, the amount of skin retention was nearly the same as passive diffusion for 24 h both from intact skin [(16.8 +/- 4.6) ng x cm(-2) vs (13.3 +/- 5.4) ng x cm(-2)] (P > 0.05) and tape-stripped skin [(36.7 +/- 14.1) ng x cm(-2) vs (26.8 +/- 11.2) ng x cm(-2)] (P > 0.05). Overall, these findings revealed that the transportation efficiency of bioactive substance like hepatitis B vaccines may be improved by iontophoresis, which can be potentially used in the field of transcutaneous immunization.

Co-delivery of methotrexate and nicotinamide by cerosomes for topical psoriasis treatment with enhanced efficacy.

Psoriasis is an immune-mediated skin disorder that affects populations worldwide. Methotrexate (MTX) is a cytotoxic drug with powerful anti-proliferative and anti-inflammatory effects that has gained prominence in treating inflammatory diseases including psoriasis. However, low solubility and side effects through oral administration hinder its systemic application. In this study, we developed a novel niosomes based on ceramide (cerosomes) to co-deliver MTX and nicotinamide (NIC), i.e., MTX/NIC cerosomes, for topically treating psoriasis with the aim to enhancing the efficacy and reducing the toxicity. NIC significantly solublized MTX by forming hydrogen bonds with MTX. In vitro and in vivo permeation studies showed that the cerosomes significantly promoted drug permeation through and retention in the skin, and the enhancing mechanism was clarified by Fourier transform infraredand Raman spectroscopy. MTX/NIC cerosomes exhibited strong anti-proliferation effect on lipopolysaccharide- irritated HaCaT cells by arresting the cell cycle at S phase and inducing apoptosis. Importantly, compared to MTX oral administration, topical application of MTX/NIC cerosomes on imiquimod (IMQ)-induced psoriatic mouse model exhibited a superior performance in ameliorating skin lesions, reducing spleen index and epidermal thickness, and downregulating the mRNA expression levels of proinflammatory cytokines including TNFα, IL-23, IL-17A, IL-6, IL-1ß, and IL-22. Taken together, MTX/NIC cerosomes is a promising approach for psoriasis topical treatment.