Enhancing the Antiproliferative Activity of Perillyl Alcohol against Glioblastoma Cell Lines through Synergistic Formulation with Natural Oils.

BACKGROUND: Due to its volatility, photostability, and gastrointestinal toxicity, Perillyl Alcohol (POH), a monoterpenoid component of various plant species, is a chemotherapeutic drug with insufficient efficacy. Many naturally occurring bioactive compounds have well-known antiproliferative properties, including sefsol, jojoba, tea tree, and moringa oils. OBJECTIVE: This study sought to develop an oil-based Self Nanoemulsifying Drug Delivery System (SNEDDS) using tween 80 as the surfactant and Dimethyl Sulfoxide (DMSO) or Polyethylene Glycol (PEG) 400 as the cosurfactant; the oils were used in a range of 10-20% to boost POH's anticancer efficacy. METHODS: The formulations' size, charge, and impact on the viability of glioma cell lines, ANGM-CSS and A172, were evaluated. RESULTS: The developed SNEDDS formulations ranged from 3 nm to 362 nm in size, with electronegative surface charges between 5.05 and 17.0 mV and polydispersity indices between 0.3 and 1.0. CONCLUSION: The findings indicated that the antiproliferative effect of POH-loaded Nanoemulsion (NE) could be used as a possible anticancer therapy for glioblastoma in vitro, particularly when paired with the tested natural oils. Before asserting that this delivery technique is appropriate for glioblastoma therapy, additional in vitro and in vivo investigations are required.

Incorporation of Perillyl Alcohol into Lipid-Based Nanocarriers Enhances the Antiproliferative Activity in Malignant Glioma Cells.

Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its potential anti-cancer activity against malignant glioma has been reported. The aim was to develop PA-loaded lipid-based nanocarriers (LNCs), and to investigate their anti-cancer activity against two different brain cell lines. Non-medicated and PA-loaded LNCs were prepared and characterized. The mechanism of cytotoxic activity of PA was conducted using a molecular docking technique. The cell viabilities against A172 and ANGM-CSS cells were evaluated. The results revealed that the average particle size of the prepared LNCs ranged from 248.67 ± 12.42 to 1124.21 ± 12.77 nm, the polydispersity index was 0.418 ± 0.043-0.509 ± 0.064, while the zeta potential ranged from -36.91 ± 1.31 to -15.20 ± 0.96 mV. The molecular docking studies demonstrated that the drug had binding activity to human farnesyltransferase. Following exposure of the two glioblastoma cell lines to the PA-loaded nanoformulations, MTS assays were carried out, and the data showed a far lower half-maximal inhibitory concentration in both cell lines when compared to pure drug and non-medicated nanocarriers. These results indicate the potential in vitro antiproliferative activity of PA-loaded LNCs. Therefore, the prepared PA-loaded nanocarriers could be used to enhance drug delivery across the blood-brain barrier (BBB) in order to treat brain cancer, especially when formulated in a suitable dosage form. The size, surface charge, and lipid composition of the LNCs make them promising for drug delivery across the BBB. Detailed pharmacokinetic and pharmacodynamic assessments, including the evaluation of BBB penetration, are necessary to better understand the compound's distribution and effects within the brain.

Incorporating valsartan in sesame oil enriched self-nanoemulsifying system-loaded liquisolid tablets to improve its bioavailability.

Valsartan (VST) is a poorly soluble antihypertensive drug characterized by its limited dissolution rate and low bioavailability. This study aims to improve VST solubility and dissolution rate via developing liquisolid tablets (LSTs) containing a self-nanoemulsifying drug delivery system (SNEDDS), which is expected to enhance VST bioavailability. This aim was achieved via two designs of experiment. The first was the simplex-lattice design to optimize VST-loaded-SNEDDS using sesame oil, Tween 80, and polyethylene glycol 400. The second was the 32-3-level factorial design to optimize the liquisolid system using the SNEDDS-loaded VST and Neusilin®US2 as a carrier and fumed silica as a coating material. Different excipient ratios (X1) and varioussuper-disintegrants (X2) were also used in developing the optimized VST-LSTs. Thein vitrodissolution of VST from LSTs was compared with the marketed product (Diovan®). Non-compartmental analysis of plasma data after extravascular input with the linear trapezoidal method was used to calculate thepharmacokinetic parameters of the optimized VST-LSTs compared with the marketed tablet in male Wistar rats. The optimized SNEDDS compromised 24.9% sesame oil, 33.3% surfactant, and 41.8% cosurfactant, giving 173.9 nm size and 63.9 mg/ml loading capacity. Also, the SNEDDS-loaded VST tablet revealed good quality attributes with the release of 75% of its content in 5 min and 100% within 15 min. On the other hand, the marketed product took 1 h for the entire drug to be released.Moreover, the maximum plasma concentration (Cmax) of the optimizedVST-LSTwas6585.33 ng/ml within 1 h (Tmax), compared to 2884.67 ng/ml within 2 h of the marketed tablet.The relative bioavailability of the SNEDDS-loaded VST tablet was 213.7% compared to that of the marketed tablet, indicating that this formulation approach could be applied for increasing solubility, dissolution behavior in GIT, and bioavailability of poorly water-soluble drugs.

Tailoring and optimization of a honey-based nanoemulgel loaded with an itraconazole-thyme oil nanoemulsion for oral candidiasis.

The use of essential oil-based nanoemulsions (NEs) has been the subject of extensive research on a variety of conditions affecting the oral cavity. NEs are delivery methods that improve the solubility and distribution of lipid medicines to the intended areas. Because of their antibacterial and antifungal properties, itraconazole and thyme oil-based self-nanoemulsifying drug delivery systems (ItZ-ThO-SNEDDS) were created to protect oral health against oral microorganisms. The ItZ-ThO-SNEDDS were created utilizing an extreme verices mixture design, and varying concentrations of ThO (10% and 25%), labrasol (40% and 70%), and transcutol (20% and 40%) were used. The ItZ-ThO-SNEDDS had droplet sizes of less than 250 nm, a drug-loading efficiency of up to 64%, and a fungal growth inhibition zone of up to 20 mm. The accepted design was used to obtain the ideal formulation, which contained ThO in the amount of 0.18 g/ml, labrasol 0.62 g/ml, and transcutol 0.2 g/ml. The best ItZ-ThO-SNEDDS formulation was incorporated into a honey-based gel, which demonstrated improved release of ItZ in vitro and improved transbuccal permeation ex vivo. In addition, when compared with various formulations tested in rats, the optimized loaded emulgel decreased the ulcer index. This study therefore demonstrated that the ItZ-ThO-SNEDDS could offer an effective defense against oral diseases caused by microbial infections.

Spanlastics as a Potential Platform for Enhancing the Brain Delivery of Flibanserin: In Vitro Response-Surface Optimization and In Vivo Pharmacokinetics Assessment.

Flibanserin was licensed by the United States Food and Drug Administration (FDA) as an oral non-hormonal therapy for pre-menopausal women with inhibited sexual desire disorder. However, it suffers from susceptibility to first-pass metabolism in the liver, low aqueous solubility, and degradation in the acidic stomach environment. Such hurdles result in a limited oral bioavailability of 33%. Thus, the aim of the study was to utilize the principles of nanotechnology and the benefits of an intranasal route of administration to develop a formulation that could bypass these drawbacks. A response-surface randomized D-optimal strategy was used for the formulation of flibanserin spanlastics (SPLs) with reduced size and increased absolute zeta potential. Two numerical factors were studied, namely the Span 60: edge activator ratio (w/w) and sonication time (min), in addition to one categorical factor that deals with the type of edge activator. Particle size (nm) and zeta potential (mV) were studied as responses. A mathematical optimization method was implemented for predicting the optimized levels of the variables. The optimized formulation was prepared using a Span: sodium deoxycholate ratio of 8:2 w/w; a sonication time of 5 min showed particle sizes of 129.70 nm and a zeta potential of -33.17 mV. Further in vivo assessment following intranasal administration in rats showed boosted plasma and brain levels, with 2.11- and 2.23-fold increases (respectively) compared to raw FLB. The aforementioned results imply that the proposed spanlastics could be regarded as efficient drug carriers for the trans-nasal delivery of drugs to the brain.

Synthesis and Characterization of Calcium Alginate-Based Microspheres Entrapped with TiO2 Nanoparticles and Cinnamon Essential Oil Targeting Clinical Staphylococcus aureus.

It is important to create new generations of materials that can destroy multidrug-resistant bacterial strains, which are a serious public health concern. This study focused on the biosynthesis of an essential oil entrapped in titanium dioxide (TiO2) calcium alginate-based microspheres. In this research, calcium alginate-based microspheres with entrapped TiO2 nanoparticles and cinnamon essential oil (CI-TiO2-MSs) were synthesized, using an aqueous extract of Nigella sativa seeds for TiO2 nanoparticle preparation, and the ionotropic gelation method for microsphere preparation. The microspheres obtained were spherical, uniformly sized, microporous, and rough surfaced, and they were fully loaded with cinnamon essential oil and TiO2 nanoparticles. The synthesized microspheres were analyzed for antibacterial activity against the clinical multidrug-resistant strain of Staphylococcus aureus. Disc diffusion and flow cytometry analysis revealed strong antibacterial activity by CI-TiO2-MSs. The synthesized CI-TiO2-MSs were characterized by the SEM/EDX, X-ray diffraction, and FTIR techniques. Results showed that the TiO2 nanoparticles were spherical and 99 to 150 nm in size, whereas the CI-TiO2-MSs were spherical and rough surfaced. Apoptosis analysis and SEM micrography revealed that the CI-TiO2-MSs had strong bactericidal activity against S. aureus. The in vitro antibacterial experiments proved that the encapsulated CI-TiO2-MSs had strong potential for use as a prolonged controlled release system against multidrug-resistant clinical S. aureus.

The Humanised NPY-mRFP RBL Reporter Cell Line Is a Fast and Inexpensive Tool for Detection of Allergen-Specific IgE in Human Sera.

Rat basophilic leukaemia (RBL) cells have been used for decades as a model of high-affinity Immunoglobulin E (IgE) receptor (FcεRI) signalling. Here, we describe the generation and use of huNPY-mRFP, a new humanised fluorescent IgE reporter cell line. Fusion of Neuropeptide Y (NPY) with monomeric red fluorescent protein (mRFP) results in targeting of fluorescence to the granules and its fast release into the supernatant upon IgE-dependent stimulation. Following overnight sensitisation with serum, optimal release of fluorescence upon dose-dependent stimulation with allergen-containing extracts could be measured after 45 min, without cell lysis or addition of any reagents. Five substitutions (D194A, K212A, K216A, K226A, and K230A) were introduced into the FcεRIα cDNA used for transfection, which resulted in the removal of known endoplasmic reticulum retention signals and high surface expression of human FcεRIα* in huNPY-mRFP cells (where * denotes the penta-substituted variant), comparable to the ~500,000 FcεRIα molecules per cell in the RS-ATL8 humanised luciferase reporter, which is a human FcεRIα/FcεRIγ double transfectant. The huNPY-mRFP reporter was used to demonstrate engagement of specific IgE in sera of Echinococcus granulosus-infected individuals by E. granulosus elongation factor EgEF-1ß and, to a lesser extent, by EgEF-1δ, which had been previously described as IgE-immunoreactive EgEF-1ß/δ.

2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-ß1 and p-ERK1/2 Axis.

The immunosuppressant cyclosporine A (CSA) has been linked to serious renal toxic effects. Although 2-methoxyestradiol (2ME) possesses a wide range of pharmacological abilities, it suffers poor bioavailability after oral administration. The purpose of this study was to evaluate the potential of 2ME loaded D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles to prevent CSA-induced nephrotoxicity in rats. A 2ME-TPGS was prepared and showed particle size of 44.3 ± 3.5 nm with good entrapment efficiency and spherical structures. Male Wistar rats were divided into 5 groups, namely: Control, Vehicle, CSA, CSA + 2ME-Raw, and CSA + 2ME-Nano. CSA was injected daily at a SC dose of 20 mg/kg. Both 2ME-Raw and 2ME-Nano were given daily at oral doses of 5 mg/kg. Treatments continued for three successive weeks. 2ME-TPGS exerted significant protective effects against CSA nephrotoxicity. This was evidenced in ameliorating deterioration of renal functions, attenuation of pathological changes in kidney tissues, exerting significant anti-fibrotic, antioxidant, and anti-inflammatory effects together with significant anti-apoptotic effects. Western blot analyses showed both 2ME-Raw and 2ME-Nano significantly inhibited protein expression of TGF-ß1 and phospho-ERK (p-ERK). It was observed that 2ME-TPGS, in almost all experiments, exerted superior protective effects as compared with 2ME-Raw. In conclusion, 2ME loaded in a TPGS nanocarrier possesses significant protective activities against CSA-induced kidney injury in rats. This is attributable to 2ME anti-fibrotic, antioxidant, anti-inflammatory, and anti-apoptotic activities which are mediated at least partly by inhibition of TGF-ß1/p-ERK axis.

Colon Targeted Eudragit Coated Beads Loaded with Optimized Fluvastatin-Scorpion Venom Conjugate as a Potential Approach for Colon Cancer Therapy: In Vitro Anticancer Activity and In Vivo Colon Imaging.

Preclinical studies suggest that most of statins or 3­hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors possess pleiotropic anticancer activity. The aim of the present work was to investigate the conjugation of the statin fluvastatin (FLV) with scorpion venom (SV), a natural peptide with proven anticancer properties, to enhance FLV cytotoxic activity and prepare colon targeted FLV-SV nanoconjugate beads for management of colon cancer. Response surface design was applied for the optimization of FLV-SV nanoconjugates. FLV-SV particle size and zeta potential were selected as responses. Cytotoxicity of optimized FLV-SV nanoconjugates was carried out on Caco2 cell line. Colon targeted alginate coated Eudragit S100 (ES100) beads for the optimized formula were prepared with the utilization of barium sulfate (BaSO4) as radiopaque contrast substance. Results revealed that optimized FLV-SV nanoconjugates showed a size of 71.21 nm, while the zeta potential was equal to 29.13 mV. Caco2 cells were considerably more sensitive to the FLV-SV formula (half-maximal inhibitory concentration (IC50) = 11.91 µg/mL) compared to SV and FLV used individually, as shown by values of IC50 equal to 30.23 µg/mL and 47.68 µg/mL, respectively. In vivo imaging of colon targeted beads, carried out by employing real-time X-ray radiography, confirmed the efficiency of colon targeted beads. Overall our results indicate that the optimized FLV-SV nanoconjugate loaded alginate coated ES100 beads could represent a promising approach for colon cancer with efficient colon targeting ability.

Design and Development of Neomycin Sulfate Gel Loaded with Solid Lipid Nanoparticles for Buccal Mucosal Wound Healing.

Drug administration to the wound site is a potential method for wound healing. The drug retention duration should be extended, and drug permeability through the buccal mucosal layer should be regulated. Oral wounds can be caused by inflammation, ulcers, trauma, or pathological lesions; if these wounds are not treated properly, they can lead to pain, infection, and subsequent undesirable scarring. This study aimed to develop Kolliphor-407 P-based gel containing neomycin sulfate (NES) loaded in solid lipid nanoparticles (SLNs) and enhance the antimicrobial activity. By considering lipid concentrations and achieving the lowest particle size (Y1) and maximum entrapment (EE-Y2) effectiveness, the formulation of NES-SLN was optimized using the Box-Behnken design. For the selected responses, 17 runs were formulated (as anticipated by the Design-Expert software) and evaluated accordingly. The optimized formulation could achieve a particle size of 196.25 and EE of 89.27% and was further utilized to prepare the gel formulation. The NES-SLN-G formula was discovered to have a smooth, homogeneous structure and good mechanical and rheological properties. After 24 h of treatment, NES-SLN-G showed a regulated in vitro drug release pattern, excellent ex vivo permeability, and increased in vitro antibacterial activity. These findings indicate the potential application of NES-SLN-loaded gels as a promising formulation for buccal mucosal wound healing.

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis.

Background: Recently, the combination of durvalumab and tremelimumab, two immune checkpoint inhibitors, for the treatment of different types of cancers has been considered; however, its overall effects, including its safety, are still unclear and need to be further investigated. Objectives: The aim of the present systematic review and meta-analysis was to investigate the safety and tolerability of this combination of drugs. Methods: A systematic review of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, was conducted by employing online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. The selection of eligible publications was made following a staged screening and selection process. The software RevMan 5.4 was used to run the quantitative analysis and forest plots, while the Cochrane tool was employed for risk of bias assessment. Results: From the retrieved 157 results, 9 randomized controlled trials involving 3060 patients were included. By comparing the combination of durvalumab and tremelimumab vs. durvalumab monotherapy, it was observed that: adverse events (AEs) ≥ Grade 3 incidence was 32.6% (536/1646) vs. 23.8% (336/1414) (Z = 2.80; p = 0.005; risk ratio (RR) = 1.44), reduced appetite incidence was 10.8% (154/1427) vs. 8.3% (108/1305) (Z = 2.26; p = 0.02; RR = 1.31), diarrhea was reported in 15.6% (229/1473) vs. 8.1% (110/1352) (Z = 5.90; p < 0.00001; RR = 1.91), rash incidence was equal to 11.1% (160/1441) vs. 6.5% (86/1320) (Z = 4.35; p <0.0001; RR = 1.75), pruritis was 13.6% (201/1473) vs. 7.7% (104/1352) (Z = 5.35; p < 0.00001; RR = 1.83), fever was 10.5% (42/399) vs. 6.6% (22/330) (Z = 2.27; p = 0.02; RR = 1.77), discontinuation rate was 18% (91/504) vs. 3% (36/434) (Z = 4.78; p < 0.00001; RR = 2.41), and death rate was 2.6% (13/504) vs. 0.7% (3/434) (Z = 1.90; p = 0.06; RR = 2.77). Conclusions: It was observed that the combined (durvalumab and tremelimumab) vs. monotherapy (durvalumab) is associated with a higher risk of treatment discontinuation, mortality, fever, diarrhea, rash, pruritis, and reduced appetite. This information is relevant and should be disclosed, especially to patients that are currently enrolled in clinical trials considering this combined therapy.

Liposome-Encapsulated Tobramycin and IDR-1018 Peptide Mediated Biofilm Disruption and Enhanced Antimicrobial Activity against Pseudomonas aeruginosa.

The inadequate eradication of pulmonary infections and chronic inflammation are significant complications in cystic fibrosis (CF) patients, who usually suffer from persistent and frequent lung infections caused by several pathogens, particularly Pseudomonas aeruginosa (P. aeruginosa). The ability of pathogenic microbes to protect themselves from biofilms leads to the development of an innate immune response and antibiotic resistance. In the present work, a reference bacterial strain of P. aeruginosa (PA01) and a multidrug-resistant isolate (MDR 7067) were used to explore the microbial susceptibility to three antibiotics (ceftazidime, imipenem, and tobramycin) and an anti-biofilm peptide (IDR-1018 peptide) using the minimum inhibition concentration (MIC). The most effective antibiotic was then encapsulated into liposomal nanoparticles and the IDR-1018 peptide with antibacterial activity, and the ability to disrupt the produced biofilm against PA01 and MDR 7067 was assessed. The MIC evaluation of the tobramycin antibacterial activity showed an insignificant effect on the liposomes loaded with tobramycin and liposomes encapsulating tobramycin and IDR-1018 against both P. aeruginosa strains to free tobramycin. Nevertheless, the biofilm formation was significantly reduced (p < 0.05) at concentrations of ≥4 µg/mL and ≤32 µg/mL for PA01 and ≤32 µg/mL for MDR 7067 when loading tobramycin into liposomes, with or without the anti-biofilm peptide compared to the free antibiotic, empty liposomes, and IDR-1018-loaded liposomes. A tobramycin concentration of ≤256 µg/mL was safe when exposed to a lung carcinoma cell line upon its encapsulation into the liposomal formulation. Tobramycin-loaded liposomes could be a potential candidate for treating lung-infected animal models owing to the high therapeutic efficacy and safety profile of this system compared to the free administration of the antibiotic.

Development of 3D-Printed, Liquisolid and Directly Compressed Glimepiride Tablets, Loaded with Black Seed Oil Self-Nanoemulsifying Drug Delivery System: In Vitro and In Vivo Characterization.

Glimepiride is characterized by an inconsistent dissolution and absorption profile due to its limited aqueous solubility. The aim of this study was to develop glimepiride tablets using three different manufacturing techniques, as well as to study their quality attributes and pharmacokinetics behavior. Black seed oil based self-nanoemulsifying drug delivery system (SNEDDS) formulation was developed and characterized. Glimepiride liquisolid and directly compressed tablets were prepared and their pre-compression and post-compression characteristics were evaluated. Semi-solid pastes loaded with SNEDDS were prepared and used to develop three-dimensional printing tablets utilizing the extrusion technique. In vivo comparative pharmacokinetics study was conducted on Male Wistar rats using a single dose one-period parallel design. The developed SNEDDS formulation showed a particle size of 45.607 ± 4.404 nm, and a glimepiride solubility of 25.002 ± 0.273 mg/mL. All the studied tablet formulations showed acceptable pre-compression and post-compression characteristics and a difference in their in vitro drug release behavior. The surface of the liquisolid and directly compressed tablets was smooth and non-porous, while the three-dimensional printing tablets showed a few porous surfaces. The inner structure of the liquisolid tablets showed some cracks and voids between the incorporated tablet ingredients while that of the three-dimensional printing tablets displayed some tortuosity and a gel porous-like structure. Most of the computed pharmacokinetic parameters improved with the liquisolid and three-dimensional printed tablets. The relative bioavailabilities of the three-dimensional printed and liquisolid tablets compared to commercial product were 121.68% and 113.86%, respectively. Therefore, the liquisolid and three-dimensional printed tablets are promising techniques for modifying glimepiride release and improving in vivo performance but more clinical investigations are required.

Development, optimization, and evaluation of a nanostructured lipid carrier of sesame oil loaded with miconazole for the treatment of oral candidiasis.

Candida albicans is the fungus responsible for oral candidiasis, a prevalent disease. The development of antifungal-based delivery systems has always been a major challenge for researchers. This study was designed to develop a nanostructured lipid carrier (NLC) of sesame oil (SO) loaded with miconazole (MZ) that could overcome the solubility problems of MZ and enhance its antifungal activity against oral candidiasis. In the formulation of this study, SO was used as a component of a liquid lipid that showed an improved antifungal effect of MZ. An optimized MZ-loaded NLC of SO (MZ-SO NLC) was used, based on a central composite design-based experimental design; the particle size, dissolution efficiency, and inhibition zone against oral candidiasis were chosen as dependent variables. A software analysis provided an optimized MZ-SO NLC with a particle size of 92 nm, dissolution efficiency of 88%, and inhibition zone of 29 mm. Concurrently, the ex vivo permeation rate of the sheep buccal mucosa was shown to be significantly (p < .05) higher for MZ-SO NLC (1472 µg/cm2) as compared with a marketed MZ formulation (1215 µg/cm2) and an aqueous MZ suspension (470 µg/cm2). Additionally, an in vivo efficacy study in terms of the ulcer index against C. albicans found a superior result for the optimized MZ-SO NLC (0.5 ± 0.50) in a treated group of animals. Hence, it can be concluded that MZ, through an optimized NLC of SO, can treat candidiasis effectively by inhibiting the growth of C. albicans.

Carbopol emulgel loaded with ebastine for urticaria: development, characterization, in vitro and in vivo evaluation.

Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.

Development, Optimization, and In Vitro Evaluation of Novel Oral Long-Acting Resveratrol Nanocomposite In-Situ Gelling Film in the Treatment of Colorectal Cancer.

This study aimed to develop and evaluate sustained-release (SR) long-acting oral nanocomposites in-situ gelling films of resveratrol (Rv) to treat colorectal cancer. In these formulations, Rv-Soy protein (Rv-Sp) wet granules were prepared by the kneading method and then encapsulated in the sodium alginate (NA) dry films. The prepared nanocomposite in-situ gels films were characterized using dynamic light scattering, Fourier-transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. The optimized formulations were further evaluated based on drug encapsulation efficiency, pH-drug release profile, swelling study, and storage time effects. The optimized formulation was tested for its anticancer activity against colorectal cancer cells using the cytotoxicity assessment, apoptosis testing, cell cycle analysis, gene expression analysis, and protein estimation by the reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay methods, respectively. The optimum film showed encapsulation efficiency of 97.87% ± 0.51 and drug release of 14.45% ± 0.043 after 8 h. All physiochemical characterizations confirmed, reasoned, and supported the drug release experiment's findings and the encapsulation assay. The Rv nanocomposite formulation showed concentration-dependent cytotoxicity enhanced apoptotic activity as compared to free Rv (p < 0.05). In addition, Rv nanocomposite formulation caused a significant increase in Bcl-2-associated protein X (Bax) and a decrease in expression of B-cell lymphoma 2, interleukin 1 beta, IL-6, and tumor necrosis factor-alpha (Bcl2, IL-1ß, IL-6, and TNF-α respectively) compared to that of free Rv in HCT-116 cells. These results suggest that long-acting Rv nanocomposite gels could be a promising agent for colorectal cancer treatment.

Phyto-Phospholipid Conjugated Scorpion Venom Nanovesicles as Promising Carrier That Improves Efficacy of Thymoquinone against Adenocarcinoma Human Alveolar Basal Epithelial Cells.

Lung cancer is a dangerous type of cancer in men and the third leading cause of cancer-related death in women, behind breast and colorectal cancers. Thymoquinone (THQ), a main compound in black seed essential oils, has a variety of beneficial effects, including antiproliferative, anti-inflammatory, and antioxidant properties. On the other hand, scorpion venom peptides (SV) induce apoptosis in the cancer cells, making it a promising anticancer agent. THQ, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess THQ's cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human alveolar epithelial cells (A549). Several nanovesicles were prepared and optimized using factorial experimental design. The optimized phytosome formulation contained 79.0 mg of PL and 170.0 mg of SV, with vesicle size and zeta potential of 209.9 nm and 21.1 mV, respectively. The IC50 values revealed that A549 cells were significantly more sensitive to the THQ formula than the plain formula and THQ. Cell cycle analysis revealed that THQ formula treatment resulted in significant cell cycle arrest at the S phase, increasing cell population in this phase by 22.1%. Furthermore, the THQ formula greatly increased cell apoptosis (25.17%) when compared to the untreated control (1.76%), plain formula (11.96%), or THQ alone (13.18%). The results also indicated that treatment with THQ formula significantly increased caspase-3, Bax, Bcl-2, and p53 mRNA expression compared to plain formula and THQ. In terms of the inflammatory markers, THQ formula significantly reduced the activity of TNF-α and NF-κB in comparison with the plain formula and THQ only. Overall, the findings from the study proved that a phytosome formulation of THQ could be a promising therapeutic approach for the treatment of lung adenocarcinoma.

Development of an Icariin-Loaded Bilosome-Melittin Formulation with Improved Anticancer Activity against Cancerous Pancreatic Cells.

Pancreatic cancer currently represents a severe issue for the entire world. Therefore, much effort has been made to develop an effective treatment against it. Emerging evidence has shown that icariin, a flavonoid glycoside, is an effective anti-pancreatic cancer drug. Melittin, as a natural active biomolecule, has also shown to possess anticancer activities. In the present study, with the aim to increase its effectiveness against cancerous cells, icariin-loaded bilosome-melittin (ICA-BM) was developed. For the selection of an optimized ICA-BM, an experimental design was implemented, which provided an optimized formulation with a particle size equal to 158.4 nm. After estimation of the release pattern, the anti-pancreatic cancer efficacy of this new formulation was evaluated. The MTT assay was employed for the determination of half maximal inhibitory concentration (IC50), providing smaller IC50 for ICA-BM (2.79 ± 0.2 µM) compared to blank-BM and ICA-Raw (free drug) against PNAC1, a human pancreatic cancer cell line isolated from a pancreatic carcinoma of ductal cell origin. Additionally, cell cycle analysis for ICA-BM demonstrated cell arrest at the S-phase and pre-G1 phase, which indicated a pro-apoptotic behavior of the new developed formulation. The pro-apoptotic and anti-proliferative activity of the optimized ICA-BM against PNAC1 cells was also demonstrated through annexin V staining as well as estimation of caspase-3 and p53 protein levels. It can be concluded that the optimized ICA-BM formulation significantly improved the efficacy of icariin against cancerous pancreatic cells.

Development and Evaluation of Repurposed Etoricoxib Loaded Nanoemulsion for Improving Anticancer Activities against Lung Cancer Cells.

In the present work, novel modality for lung cancer intervention has been explored. Primary literature has established the potential role of cyclooxygenase-2 (COX-2) inhibitor in regression of multiple forms of carcinomas. To overcome its poor water solubility and boost anticancer activity, etoricoxib (ETO) was chosen as a therapeutic candidate for repurposing and formulated into a nanoemulsion (NE). The prepared ETO loaded NE was characterized for the surface charge, droplet size, surface morphology, and in vitro release. The optimized ETO loaded NE was then investigated for its anticancer potential employing A549 lung cancer cell line via cytotoxicity, apoptotic activity, mitochondrial membrane potential activity, cell migration assay, cell cycle analysis, Caspase-3, 9, and p53 activity by ELISA and molecular biomarker analysis through RT-PCR test. The developed ETO-NE formulation showed adequate homogeneity in the droplet size distribution with polydispersity index (PDI) of (0.2 ± 0.03) and had the lowest possible droplet size (124 ± 2.91 nm) and optimal negative surface charge (-8.19 ± 1.51 mV) indicative of colloidal stability. The MTT assay results demonstrated that ETO-NE exhibited substantial anticancer activity compared to the free drug. The ETO-NE showed a substantially potent cytotoxic effect against lung cancer cells, as was evident from the commencement of apoptosis/necrotic cell death and S-phase cell cycle arrests in A549 cells. The study on these molecules through RT-PCR confirmed that ETO-NE is significantly efficacious in mitigating the abundance of IL-B, IL-6, TNF, COX-2, and NF-kB as compared to the free ETO and control group. The current study demonstrates that ETO-NE represents a feasible approach that could provide clinical benefits for lung cancer patients in the future.

Phytosomes as an Emerging Nanotechnology Platform for the Topical Delivery of Bioactive Phytochemicals.

The emergence of phytosome nanotechnology has a potential impact in the field of drug delivery and could revolutionize the current state of topical bioactive phytochemicals delivery. The main challenge facing the translation of the therapeutic activity of phytochemicals to a clinical setting is the extremely low absorption rate and poor penetration across biological barriers (i.e., the skin). Phytosomes as lipid-based nanocarriers play a crucial function in the enhancement of pharmacokinetic and pharmacodynamic properties of herbal-originated polyphenolic compounds, and make this nanotechnology a promising tool for the development of new topical formulations. The implementation of this nanosized delivery system could enhance the penetration of phytochemicals across biological barriers due to their unique physiochemical characteristics, improving their bioavailability. In this review, we provide an outlook on the current knowledge of the biological barriers of phytoconstituents topical applications. The great potential of the emerging nanotechnology in the delivery of bioactive phytochemicals is reviewed, with particular focus on phytosomes as an innovative lipid-based nanocarrier. Additionally, we compared phytosomes with liposomes as the gold standard of lipid-based nanocarriers for the topical delivery of phytochemicals. Finally, the advantages of phytosomes in topical applications are discussed.