Anti-depressant effect of Naringenin-loaded hybridized nanoparticles in diabetic rats via PPARγ/NLRP3 pathway.

Naringenin (NAR) has various biological activities but low bioavailability. The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21 ± 0.02), highest entrapment efficiency (98.7 ± 2.01%), as well as an acceptable particle size and zeta potential of 415.2 ± 9.54 nm and 52.8 ± 1.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4 °C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg/kg), NAR-HNPs (50 mg/kg) and NAR (50 mg/kg) + peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662 (1mg/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR-γ gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-γ/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.

Synergistic approach for acne vulgaris treatment using glycerosomes loaded with lincomycin and lauric acid: Formulation, in silico, in vitro, LC-MS/MS skin deposition assay and in vivo evaluation.

This study aims to develop a pharmaceutical formulation that combines the potent antibacterial effect of lincomycin and lauric acid against Cutibacterium acnes (C. acnes), a bacterium implicated in acne. The selection of lauric acid was based on an in silico study, which suggested that its interaction with specific protein targets of C. acnes may contribute to its synergistic antibacterial and anti-inflammatory effects. To achieve our aim, glycerosomes were fabricated with the incorporation of lauric acid as a main constituent of glycerosomes vesicular membrane along with cholesterol and phospholipon 90H, while lincomycin was entrapped within the aqueous cavities. Glycerol is expected to enhance the cutaneous absorption of the active moieties via hydrating the skin. Optimization of lincomycin-loaded glycerosomes (LM-GSs) was conducted using a mixed factorial experimental design. The optimized formulation; LM-GS4 composed of equal ratios of cholesterol:phospholipon90H:Lauric acid, demonstrated a size of 490 ± 17.5 nm, entrapment efficiency-values of 90 ± 1.4 % for lincomycin, and97 ± 0.2 % for lauric acid, and a surface charge of -30.2 ± 0.5mV. To facilitate its application on the skin, the optimized formulation was incorporated into a carbopol hydrogel. The formed hydrogel exhibited a pH value of 5.95 ± 0.03 characteristic of pH-balanced skincare and a shear-thinning non-Newtonian pseudoplastic flow. Skin deposition of lincomycin was assessed using an in-house developed and validated LC-MS/MS method employing gradient elution and electrospray ionization detection. Results revealed that LM-GS4 hydrogel exhibited a two-fold increase in skin deposition of lincomycin compared to lincomycin hydrogel, indicating improved skin penetration and sustained release. The synergistic healing effect of LM-GS4 was evidenced by a reduction in inflammation, bacterial load, and improved histopathological changes in an acne mouse model. In conclusion, the proposed formulation demonstrated promising potential as a topical treatment for acne. It effectively enhanced the cutaneous absorption of lincomycin, exhibited favorable physical properties, and synergistic antibacterial and healing effects. This study provides valuable insights for the development of an effective therapeutic approach for acne management.

Chrysin loaded nanovesicles ameliorated diabetic peripheral neuropathy. Role of NGF/AKT/GSK-3ß pathway.

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Chrysin (CHY) has many biological properties but poor oral bioavailability. This study investigates the effect of CHY and CHY-loaded nanovesicles (CHY-NVs) on streptozotocin (STZ)-induced DPN in rats. CHY-NVs were prepared by using film hydration method. The formula with the best entrapment efficiency%, lowest particle size, highest zeta potential, and highest in vitro CHY released profile was selected, characterized by Differential scanning calorimetry, Fourier transformation infrared spectroscopy analysis, and examined by Transmission electron microscope. Acute toxicity test, pharmacokinetic study and experimental model of diabetes mellitus were performed on the selected formulation. Wistar rats were considered diabetic by administration of a single intraperitoneal dose of STZ (50 mg/kg). 48 h after STZ administration, hyperglycemic rats were randomly assigned into four groups, one group of untreated hyperglycemic rats and the other three groups received daily oral doses of unloaded NVs, CHY-NVs (25 mg/kg), and CHY-NVs (50 mg/kg), respectively for 21 days. Moreover, five additional groups of healthy rats received: distilled water (control), free CHY, unloaded NVs, and CHY-NVs respectively for 21 days. CHY and CHY-NVs maintained body weight and reduced STZ-induced behavioral changes in rotarod, hind paw cold allodynia, tail cold allodynia, tail flick, and hot plate tests. CHY and CHY-NVs lowered blood glucose, glycated hemoglobin, elevated serum reduced glutathione (GSH), and reduced plasma malondialdehyde (MDA) levels. CHY-NVs elevated phosphatidylinositol 3-kinase (Pi3k), phosphorylated protein kinase B (p-AKT), and reduced nuclear factor kappa B (NF-κB), interleukin-6 (IL-6) in sciatic nerve homogenate. CHY and CHY-NVs increased nerve growth factor (NGF) and decreased glycogen synthase kinase-3ß (GSK-3ß) gene expressions in the sciatic nerve. In conclusion, CHY and CHY-NVs ameliorated STZ-induced DPN behavioral and histopathological changes via attenuating hyperglycemia, exerting anti-oxidant, anti-inflammatory effects, activating NGF/p-AKT/GSK-3ß pathway, and its anti-apoptotic effect. The best pharmacokinetic profile and therapeutic effect was observed in rats treated with CHY-loaded NVs.

Innovated pirfenidone loaded lecithin nanocapsules for targeting liver fibrosis: Formulation, characterization and in vivo study.

Increasing interest in developing antifibrotic therapies became a paramount priority due to the globally raised incidence of deaths secondary to hepatic cirrhosis. This work deals with the development of innovative antifibrotic pirfenidone -loaded lecithin core nanocapsules. This with the intention to target the liver and to increase the drug bioavailability, reducing drug liver toxicity, and studying the associated hepatic microenvironment changes. PFD-loaded lecithin nanocapsules (PFD-LENCs) were prepared using the natural lipoid S45 for its dual benefits of being both a lipid and an amphiphilic surfactant. The selected formulation exhibited in vitro sustained drug release up to 24 h compared to free PFD, which is consistent with the studied pharmacokinetic profile. The studied cytotoxicity of PFD as well as PFD-LENCs exhibited negligible cytotoxicity in normal oral epithelial cells. For exploring the capability of the PFD-LENCs in reaching the liver; in vivo tracing using CLSM, in vivo biodistribution to the vital organs were conducted and electron microscopic examination for depicting nanoparticles in liver tissue was performed. Results revealed the capability of the prepared fluorescent LENC2 in reaching the liver, PFD-LENCs detection in the Disse space of the liver and the significant accumulation of PFD-LENCs in liver tissue compared to the other tested organs. The assessment of the necro-inflammatory, antioxidant and the anti-fibrotic effect of PFD-LENCs (50 & 100 mg/kg) exhibited a significant decrease of liver enzymes, TNF-α, TGF-ß, Col-1, α-SMA, and TIMP-1, and a significant increase of catalase enzyme and MMP2 compared to free PFD. EM studies, revealed often detection of dendritic cells in PFD-LENCs (100 mg/kg) treated mice and abnormal collagen structure which can represent an adjunct contribution to the antifibrotic mechanism of PFD-LENCs. In conclusion, the development of this innovative PFD loaded lecithin nanocapsules achieved a targeting ability to the liver, controlled drug release, thereby increase the PFD therapeutic value in downregulating hepatic fibrosis in adjunct with the reduction of liver toxicity.

Nanolipogel Loaded with Tea Tree Oil for the Management of Burn: GC-MS Analysis, In Vitro and In Vivo Evaluation.

The GC-MS analysis of tea tree oil (TTO) revealed 38 volatile components with sesquiterpene hydrocarbons (43.56%) and alcohols (41.03%) as major detected classes. TTO efficacy is masked by its hydrophobicity; nanoencapsulation can address this drawback. The results showed that TTO-loaded solid lipid nanoparticles (SLN1), composed of glyceryl monostearate (2% w/w) and Poloxamer188 (5% w/w), was spherical in shape with a core-shell microstructure. TTO-SLN1 showed a high entrapment efficiency (96.26 ± 2.3%), small particle size (235.0 ± 20.4 nm), low polydispersity index (0.31 ± 0.01), and high negative Zeta potential (-32 mV). Moreover, it exhibited a faster active agent release (almost complete within 4 h) compared to other formulated TTO-SLNs as well as the plain oil. TTO-SLN1 was then incorporated into cellulose nanofibers gel, isolated from sugarcane bagasse, to form the 'TTO-loaded nanolipogel' which had a shear-thinning behavior. Second-degree thermal injuries were induced in Wistar rats, then the burned skin areas were treated daily for 7 days with the TTO-loaded nanolipogel compared to the unmedicated nanolipogel, the TTO-loaded conventional gel, and the normal saline (control). The measurement of burn contraction proved that TTO-loaded nanolipogel exhibited a significantly accelerated skin healing, this was confirmed by histopathological examination as well as quantitative assessment of inflammatory infiltrate. This study highlighted the success of the proposed nanotechnology approach in improving the efficacy of TTO used for the repair of skin damage induced by burns.

Computational Investigation to Design Ofloxacin-Loaded Hybridized Nanocellulose/Lipid Nanogels for Accelerated Skin Repair.

The pharmaceutical application of biomaterials has attained a great success. Rapid wound healing is an important goal for many researchers. Hence, this work deals with the development of nanocellulose crystals/lipid nanogels loaded with ofloxacin (OFX) to promote skin repair while inhibiting bacterial infection. Ofloxacin-loaded hybridized nanocellulose/lipid nanogels (OFX-HNCNs) were prepared and evaluated adopting a computational method based on regression analysis. The optimized nanogels (OFX-HNCN7) showed a spherical outline with an encapsulation efficiency (EE), particle size (PS) and zeta potential (ZP) values of 97.53 ± 1.56%, 200.2 ± 6.74 nm and -26.4 ± 0.50 mV, respectively, with an extended drug release profile. DSC examination of OFX-HNCN7 proved the amorphization of the encapsulated drug into the prepared OFX-HNCNs. Microbiological studies showed the prolonged inhibition of bacterial growth by OFX-HNCN7 compared to the free drug. The cytocompatibility of OFX-HNCN7 was proved by Sulforhodamine B assay. Tissue repair was evaluated using the epidermal scratch assay based on cell migration in human skin fibroblast cell line, and the results depicted that cell treated with OFX-HNCN7 showed a faster and more efficient healing compared to the control. In overall, the obtained findings emphasize the benefits of using the eco-friendly bioactive nanocellulose, hybridized with lipid, to prepare a nanocarrier for skin repair.

Development of Lecithin/Chitosan Nanoparticles for Promoting Topical Delivery of Propranolol Hydrochloride: Design, Optimization and In-Vivo Evaluation.

Propranolol (PPL) administered orally is considered as the first line drug for the treatment of infantile hemangioma, however several systemic adverse effects limit its use. For this reason, our work tackles the development and evaluation of PPL loaded chitosan nanoparticles (NPs), as an effective alternative for the treatment of infantile hemangioma. PPL -NPs were prepared using the double emulsion technique and the influence of the formulation variables on drug entrapment efficiency (EE), particle size (PS), percent released after 24 h (%R24h) and zeta potential (ZP) were optimized using full factorial design. Two systems, namely F3 and F28 showing highest E.E., ZP and %R24h with lowest PS, were fully characterized for DSC and TEM and incorporated into hydrogel with adequate viscosity. After ensuring safety for the selected nanoparticle, the hydrogel containing the optimized system was applied topically to rats. The in-vivo skin deposition in rats showed an accumulation of propranolol from the lecithin/chitosan nanocarrier by 1.56-1.91-fold when compared to the drug solution. The obtained result was further supported by the confocal laser scanning microscopy which showed fluorescence across the skin. PPL-HCL-loaded lecithin/chitosan nanoparticles could be considered as a potential candidate for treating infantile hemangiomas (IH) by maintaining therapeutic concentration topically while minimizing systemic side effects.

Promising bioadhesive ofloxacin-loaded polymeric nanoparticles for the treatment of ocular inflammation: formulation and in vivo evaluation.

Our work tackles the combined advantages of both nanotechnology and the bioadhesive gel properties which were utilized to design an ocular drug delivery system that is capable to treat ocular inflammation. Nanoparticles encapsulating an antibiotic drug, ofloxacin, were fabricated using emulsion solvent evaporation technique adopting 23 full factorial design to evaluate the effect of formulation parameters: that is to say, the molecular weight of the polymer (polycaprolactone), amount of Kolliphor P188, and presence of the charge inducer (chitosan hydrochloride) on the measured responses: drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The results show that the optimized LPCL-NP2 formulation (composed of low molecular weight polycaprolactone, 500 mg of Kolliphor P188, 0.25% chitosan hydrochloride, and 50 mg ofloxacin)  displayed a sphere shape with EE%, PS, PDI, and ZP values of 89.73 ± 0.04%, 195.4 ± 13.17 nm, 0.323 ± 0.01, and 55.4 ± 0.66 mV, respectively. DSC study confirmed the amorphous nature of the drug. The optimized nanoparticle formulation was then further incorporated into the following two ocular formulations: gel (LPCL-NP2-G4) and in situ forming gel (LPCL-NP2-ISG4). The penetration of optimized ocular formulations was assessed by confocal laser scanning microscopy. The antimicrobial study was conducted  for the following three ocular formulations: LPCL-NP2 presented as eye drops, LPCL-NP2-G4, and LPCL-NP2-ISG4 as well as the market product using rabbits which were infected in their eyes with Escherichia coli. Results revealed that rabbits treated with LPCL-NP2-ISG4 demonstrated a remarkable antibacterial efficacy and evident low bacterial growth which was additionally assured by the histopathological examination of eye biopsies compared with the other investigated groups. Thus, a novel ofloxacin-loaded nanoparticle formulation based on polycaprolactone is presented in the form of mucoadhesive non-irritating in situ forming ocular gel possessing a superior antibacterial activity. Graphical abstract.

Formulation and Evaluation of Novel Hybridized Nanovesicles for Enhancing Buccal Delivery of Ciclopirox Olamine.

Ciclopirox olamine (CPO) is a topical wide-spectrum antimycotic agent that possesses antifungal, antibacterial and anti-inflammatory activities. Loading CPO into a hybridized vesicular system is expected to enhance its buccal permeation and hence, therapeutic activity, whereas the frequent administration and side effects are reduced. Vesicular systems with high penetration ability were prepared based on cholesterol, Lipoid S45 or Phospholipon 90H, with span 60 while incorporating a penetration enhancer (Labrafac or labrasol) followed by full assessment of their size, entrapment efficiency, and drug release profiles. The optimum formulation, composed of Lipoid S45 and Labrafac, possessed the smallest vesicle size (346.1 nm), highest entrapment efficiency (94.4%), and sustained CPO release pattern, and was characterized for its morphology and thermal properties. This powerful mixture of the penetration enhancers (Lipoid S45 and Labrafac) in the designed hybridized vesicles was thoroughly investigated for their characteristics after being incorporated in bioadhesive gel. Moreover, enhanced antifungal activity was demonstrated either upon testing the designed formulation on agar plates or in vivo upon treating infected rabbits with the proposed formulation. Results suggest that the presented bioadhesive gel incorporating the CPO-loaded vesicles can be a promising delivery system that can offer a prolonged localized antifungal treatment with enhanced therapeutic effect.

Cubic liquid crystalline nanoparticles containing a polysaccharide from Ulva fasciata with potent antihyperlipidaemic activity.

The present study involves the preparation of cubic liquid crystalline nanoparticles (cubsomes) for liver targeting to assess the potential of a formulated bioactive polysaccharide isolated from the hot aqueous extract of Ulva fasciata as an alternative natural agent with anti-hyperlipidaemic activity. Cubosomal nanoparticles were prepared by disrupting the cubic gel phase of the polysaccharide and water in the presence of a surfactant. Different lipid matrices and stabilizers were tested. All the formulations were in the nanosize range and showed sufficient negative charge to inhibit the aggregation of the cubosomes. Drug entrapment efficiencies (EEs%) were determined and in vitro release studies were performed. Transmission electron microscopy (TEM) and differential scanning calorimetry were used to analyze the loaded cubosomal nanoparticles containing glyceryl monostearate (GMO 2.25 g), poloxamer 407 (0.25 g) and 50 mg of the polysaccharide. A preclinical study comparing the cubic liquid crystalline nanoparticles containing polysaccharide to fluvastatin as a reference drug in hyperlipidaemic rats was conducted. The rats treated with the polysaccharide- loaded cubosomes showed significant decreases in total cholesterol (TC), triglycerides (TG) and total lipid (TL) compared to the untreated HL rats. In addition, oxidative stress and antioxidant biomarkers were measured in the HL rats. Compared to the untreated HL rats, the cubosome treated rats showed a significant reduction in malondialdehyde (MDA), whereas insignificant changes were detected in nitric oxide (NO), glutathione (GSH) levels and total antioxidant capacity (TAC). Further, vascular and intercellular adhesion molecules (VCAM, ICAM), and myeloperoxidase were demonstrated. A histopathological examination was conducted to study the alterations in histopathological lesions and to document the biochemical results. In conclusion, this study demonstrates the superiority of using a natural lipid regulator such as polysaccharide loaded cubosomes instead of fluvastatin.

A potential antibacterial wound dressing of cefadroxil chitosan nanoparticles in situ gel: Fabrication, in vitro optimization and in vivo evaluation.

Wound healing following skin injury is a natural phenomenon that usually lacks quality, rapidity, and aesthetics. Thus, the purpose of this study was to fabricate a new easily applied in situ gel of cefadroxil (CDX) loaded chitosan nanoparticles (CDX-CSNPs) that could promote wound healing, capable of inhibiting the possible accompanying bacterial infection. The nanoparticles were prepared by double emulsion technique and the influence of formulation parameters on drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were investigated using a full factorial design. The results show that the optimized CDX-CSNP1 composed of low molecular weight chitosan (0.2%w/v) was spherical with EE%, PS, PDI and ZP of 84.25 ±â€¯0.02, 408.30 ±â€¯53.17 nm, 0.458 ±â€¯0.048 and 22.80 ±â€¯0.57 mV, respectively. DSC and XRD studies confirmed the amorphous nature of the drug. After ensuring the safety and non toxicity of CDX-CSNP1 in situ gel through cytotoxic study, the antibacterial activity was evaluated using a rat skin infection model against Staphylococcus aureus. Compared to the rats treated with free CDX, the CDX-CSNP1 treated group revealed a remarkable accelerated wound healing process and bacterial clearance which was further confirmed by the histopathological examination of skin biopsies.