Development of a hydrogel containing bisabolol-loaded nanocapsules for the treatment of atopic dermatitis in a Balb/c mice model.

α-Bisabolol (αBIS), a plant-derived compound with anti-inflammatory properties, is potentially a therapeutic agent for Atopic dermatitis. However, its poor water solubility and photoinstability limit its topical application. Therefore, the present study, aimed to develop cationic polymeric nanocapsules of αBIS to improve its skin delivery, photostability, and therapeutic efficacy. The αBIS-loaded nanocapsules were prepared using the solvent displacement technique. A Box-Behnken (BB) design was employed to statistically optimize formulation variables and αBIS-loaded nanocapsules characterized by particle size, surface charge and encapsulation efficiency. The optimal formulation was selected, and the spherical shape of the nanocapsules was confirmed by scanning electron microscopy (SEM). Furthermore, hydrogel containing αBIS-loaded nanocapsules was prepared by thickening of nanocapsule suspension with Carbopol 934 and evaluated for rheology, in vitro drug release and skin permeation. Furthermore, a mice model of atopic dermatitis was used to evaluate the anti-inflammatory potential of the hydrogels. The optimal formulation displayed a spherical morphology under scanning electron microscopy (SEM) with an optimum particle size of 133.00 nm, polydispersity index (PDI) of 0.12, high EE% of 93 %, and improved optical stability of αBIS in the prepared nanocapsules compared to the free drug. The nano-based hydrogels demonstrated non-Newtonian pseudoplastic behavior and an increased αBIS in vitro release profile without causing skin irritation in rabbits. Drug retention within the dermis and epidermis layers significantly surpassed that of drug-free hydrogel. Moreover, in vivo histopathological studies and myeloperoxidase (MPO) enzyme activity, revealed that hydrogel containing bisabolol nanocapsules exhibited The best anti-inflammatory effect. The results showed that hydrogels containing bisabolol nanocapsules markedly alleviated dermatitis-related inflammation and reduced skin thickness in Balb/c mice. Our findings support nanocapsules as an effective drug delivery system to enhance αBIS stability, bioavailability, and therapeutic efficacy in AD treatment.

Quercetin-loaded nanoemulsions prevent Scopolamine-induced neurotoxicity in male rats.

Quercetin (QCT) is well-known as a neuroprotective agent due to its antioxidant capacities and reinstating mitochondrial functions. Scopolamine is commonly used as a model to induce Alzheimer's disease (AD-like) symptoms. The current study develops QCT-loaded nanoemulsion (QCT-NE) accompanied by evaluating its neuro-therapeutic effectiveness against SCO-induced neurotoxicity in male rats. The QCT-NE was prepared by the spontaneous emulsification technique and characterized by using particle size, zeta potential, drug loading, in vitro drug release behavior, and stability studies. In vivo studies were done on adult Wistar rats by applying the Morris water maze (MWM) test to study spatial memory and learning. The levels of lipid peroxidation and reduced glutathione were quantitatively determined to reveal the potential mechanism of SCO-induced oxidative stress. Finally, histological studies were performed using staining techniques. The QCT-NE particle size, zeta potential, polydispersity index (PDI), and DL were obtained at 172.4 ± 16.8 nm, -29 ± 0.26 mV, 0.3 ± 0.07, and 81.42 ± 9.14 %, respectively. The QCT and more effectively QCT-NE reduced the elevation of neurobehavioral abnormalities in the MWM test in SCO-exposed rats. The results of oxidative status showed that SCO significantly could increase the LPO and decrease the GSH levels in the rat's brain. However, QCT-NE treatment was more effective than free QCT to inhibit oxidative damage and was well correlated with histopathological findings. Taken together, QCT-NE, compared to QCT, was superior in ameliorating SCO-induced AD-like symptoms due to its better neuroprotective activity and can be considered a novel supplementary therapeutic agent in AD management.

The effect of conjugated estrogens vaginal cream and a combined vaginal cream of vitamins D and E in the treatment of genitourinary syndrome.

Background and Aim: Genitourinary syndrome occurs due to a decrease in ovarian hormones; this can have a significant negative impact on women's interpersonal relationships and sexual function. The present study aimed at comparing the therapeutic effect of conjugated estrogens vaginal cream and a combined vaginal cream of vitamins D and E in the treatment of genitourinary syndrome in postmenopausal women. Methods: This study was conducted as a double-blind randomized clinical trial (RCT). As many as 64 postmenopausal women suffering from genitourinary syndrome were randomly divided into study and control groups. The study group was treated with a combined vaginal cream of vitamins D and E, and the control group was treated with conjugated estrogens vaginal creams for 12 weeks. The patients were visited at the beginning of being admitted, the fourth week, the 12th week, and four weeks after the treatment and their information was recorded by checklists and a sexual function questionnaire. The data were finally analyzed by SPSS-25 at a significant level of 0.05. Result: At four visits, libido, orgasm, and frequency of sexual intercourses, as well as vaginal symptoms such as burning, itching, dryness, and dyspareunia were improved in both groups (P <.05). However, there was no difference between the two groups in terms of the frequency of severity of these symptoms during the four visits (P >.05). Investigating the female sexual function index showed that using vitamin D and E vaginal creams, like the use of conjugated estrogens vaginal creams, improves sexual function in women (P <.01). Conclusion: According to the results, it can be concluded that the combined vaginal cream of vitamins D and E is a suitable alternative to vaginal estrogens in relieving the symptoms of genitourinary syndrome in postmenopausal women, especially those who are unable to use hormone therapy or have little compatibility with this therapy.

Budesonide-Loaded Hyaluronic Acid Nanoparticles for Targeted Delivery to the Inflamed Intestinal Mucosa in a Rodent Model of Colitis.

The aim of the present study was to investigate the therapeutic potential of budesonide- (BDS-) loaded hyaluronic acid nanoparticles (HANPs) for treatment of inflammatory bowel disease (IBD) using an acute model of colitis in rats. The therapeutic efficacy of BDS-loaded HANPs in comparison with an aqueous suspension of the drug with the same dose (30 µg/kg) was investigated 48 h following induction of colitis by intrarectal administration of acetic acid 4% in rats. Microscopic and histopathologic examinations were conducted in inflamed colonic tissue. Tissue concentration of tumor necrosis factor (TNF)-α was assessed by ELISA assay kit, while the activity of myeloperoxidase (MPO) was measured spectrophotometrically. Results from in vivo evaluations demonstrated that administrations of BDS-HANPs ameliorated the general endoscopic appearance, quite close to the healthy animals with no signs of inflammation and reduced the cellular infiltration, as well as the TNF-α level, and the MPO activity. It was found that delivery by BDS-loaded HANPSs alleviated the induced colitis significantly better than the same dose of the free drug. These data further suggest the potential of HANPs as a targeted drug delivery system to the inflamed colon mucosa.

Effectiveness of sodium bicarbonate and zinc chloride mouthwashes in the treatment of oral mucositis and quality of life in patients with cancer under chemotherapy.

AIM: The purpose of the study is to evaluate the effectiveness of sodium bicarbonate and zinc chloride mouthwashes on oral mucositis and quality of life in patients undergoing chemotherapy. DESIGN: The present study was a randomized controlled trial study. METHODS: One hundred forty-four patients with a cancer diagnosis were randomly assigned into three groups: sodium bicarbonate mouthwash (n = 48), zinc chloride mouthwash (n = 48) and placebo group (n = 48). The severity of mucositis and quality of life were examined blindly at the baseline and 3-week follow-up. RESULTS: The grade of oral mucositis decreased at the end of the third weeks in the sodium bicarbonate and zinc chloride groups rather than the placebo group (p < .001). The severity of oral mucositis in the sodium bicarbonate and zinc chloride groups decreased from end of the first week until third week (p < .001). In addition, there was significant difference in the severity of oral mucositis among the groups at the end of the second (p = .014) and the third weeks (p < .001). Also, there was a statistically significant difference in quality of life scores between the sodium bicarbonate and zinc chloride mouthwash with the placebo group (p < .001). CONCLUSION: Zinc chloride and sodium bicarbonate mouthwashes were effective in treating and reducing the severity of oral mucositis, and subsequently improving quality of life in patients with cancer under chemotherapy. Therefore, we can recommend zinc chloride and sodium bicarbonate at the beginning of chemotherapy to improve oral health and promoting quality of life in these patients.

Design and Optimization of Cationic Nanocapsules for Topical Delivery of Tretinoin: Application of the Box-Behnken Design, In Vitro Evaluation, and Ex Vivo Skin Deposition Study.

Cationic nanocapsules represent a promising approach for topical delivery purposes. We elaborated on a novel formulation based on the cationic nanocapsules to enhance the pharmacodynamic efficacy, user compliance, and photostability of tretinoin (TTN). To achieve this goal, TTN nanocapsules were prepared by the nanoprecipitation method. In order to statistically optimize formulation variables, a Box-Behnken design, using Design-Expert software, was employed. Three independent variables were evaluated: total weight of the cationic acrylic polymer (X 1), oil volume (X 2), and TTN amount (X 3). The particle size and encapsulation efficiency percent (EE%) were selected as dependent variables. The optimal formulation demonstrated spherical morphology under scanning electron microscopy (SEM), optimum particle size of 116.3 nm, and high EE% of 83.2%. TTN-loaded nanocapsules improved photostability compared to its methanolic solution. The in vitro release study data showed that tretinoin was released in a sustained manner compared to the free drug. The ex vivo skin permeation study demonstrated that greater drug deposition into the epidermal region rather than the deep skin was observed with a gel containing TTN-loaded nanocapsules than that of drug solution, respectively. The skin irritation test revealed that the nanoencapsulation of the drug decreased its irritancy compared to the free drug. These results revealed the promising potential of cationic nanocapsules for topical delivery of tretinoin.

Effectiveness of zinc chloride mouthwashes on oral mucositis and weight of patients with cancer undergoing chemotherapy.

BACKGROUND: Oral mucositis is one of the most emerging and debilitating complications of chemotherapy during the treatment period, which strongly affects the nutritional status and physical and mental condition of these patients. Zinc increased protein synthesis and improved cell membrane stability so passible effective in prevent and treat oral mucositis and promote oral health. Therefore, this study aimed to evaluate the effect of zinc chloride mouthwash on the prevention, incidence, and severity of oral mucositis in cancer patients undergoing chemotherapy. METHODS: The present study was a randomized control trial study. 96 patients with a cancer diagnosis selected from one oncology clinic in the west of Iran. Then they assigned randomly to the zinc chloride group and placebo group. The patients in each group should rinse their mouths every 8 h two times and each time 2 min with 7.5 ml from mouthwash. The severity of mucositis and weight loss examined blindly at the baseline and 3-week follow-up. RESULTS: The incidence and severity of oral mucositis between groups were significant higher at the end of the second (p < 0.002) and third (p < 0.001) week. The mucositis severity decreased well during the third weeks in the zinc chloride group. The difference in the weight loss was significant higher between the zinc chloride and the placebo group (p < 0.01). CONCLUSION: Zinc chloride mouthwash was effective in preventing and reducing the severity of oral mucositis and improving weight in patients undergoing chemotherapy. Trial registration We can therefore recommend more studies examine the effects zinc chloride as preventive care at the beginning of chemotherapy to improve oral health and subsequently preventing weight loss in these patients.

Peptide functionalized poly ethylene glycol-poly caprolactone nanomicelles for specific cabazitaxel delivery to metastatic breast cancer cells.

Metastatic cancer is responsible for 90% of deaths in world. Usage of nano-carriers improve the delivery and efficacy of chemotherapeutic agents. Recent studies suggest that decoration of the surface of nano-carriers with various targeting agents may further improve their overall therapeutic efficacy. Using specified peptides in targeted drug delivery is a key point in recent researches. In this study, tumor metastasis targeting (TMT) homing peptide was applied as a targeting group to improve specific drug delivery to tumor cells. TMT peptide is conjugated to poly ethylene glycol-poly caprolactone (PEG-PCL) micellar nanoparticles as carriers for targeted delivery of cabazitaxel to metastatic breast cancer cells. Synthesis of PEG-PCL copolymer was performed by amidation reaction between carboxylic acid group of PEG and amine group of PCL. Nanomicelles were prepared via solvent evaporation method. TMT peptide was covalently conjugated onto nanomicelles through the amine group of PEG. TMT-PEG-PCL nanoparticles were analyzed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), dynamic light scattering (DLS), gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR). Toxicity and cellular uptake of nanomicelles were investigated by in vitro cytotoxicity assays and confocal scanning microscopy in MCF-7 (non-metastatic breast cancer cells) and MDA-MB-231 (metastatic breast cancer cells). The final nanomicelles had about 110nm mean size and encapsulation efficiency of 82.5%. Treatment of metastatic breast cancer cells with targeted nanomicelles significantly increased the necrosis rate to 65%, compared to 33% in non-targeted nanomicelles and 8% in control group. The MDA-MB-231 cells treated with targeted nanomicelles exhibited a strong increase in the fluorescence intensity of coumarin in comparison to the cells treated with non-targeted nanomicelles (p<0.001). It could be concluded that the present carrier has the potential to be considered in treatment of metastatic breast cancer cells.

Self assembled hyaluronic acid nanoparticles as a potential carrier for targeting the inflamed intestinal mucosa.

To develop a nanoparticulate drug carrier for targeting of the inflamed intestinal mucosa, amphiphilic hyaluronic acid (HA) conjugates were synthesized, which could form self-assembled nanoparticles (NPs) in aqueous solution and budesonide (BDS) was loaded into the HANPs. Their particle sizes were in the range of 177 to 293nm with negative surface charge. The model of inflammatory CACO-2 cells was utilized to investigate the therapeutic potential of budesonide loaded HA nanocarriers. The highest expression of CD44 receptors was found on inflamed Caco-2 cells, as determined by flow cytometry. FITC-labeled HANPs revealed greater uptake in inflamed CACO-2 cells compared to untreated CACO-2 and CD44-negative cell lines, NIH3T3. BDS loaded HANPs displayed almost no toxicity indicating HANPs are excellent biocompatible nano-carriers. BDS loaded HANPs demonstrated higher anti-inflammatory effect on IL-8 and TNF-α secretion in inflamed cell model compared to the same dose of free drug. These results revealed the promising potential of HA nanoparticles as a targeted drug delivery system for IBD treatment.

Preparation and optimization of N-trimethyl-O-carboxymethyl chitosan nanoparticles for delivery of low-molecular-weight heparin.

The aim of this study was preparation, optimization and in vitro characterization of nanoparticles composed of 6-[O-carboxymethyl]-[N,N,N-trimethyl] (TMCMC) for oral delivery of low-molecular-weight heparin. The chitosan derivative was synthesized. Nanoparticles were prepared using the polyelectrolyte complexation method. Box-Behnken response surface experimental design methodology was used for optimization of nanoparticles. The morphology of nanoparticles was studied using transmission electron microscopy. In vitro release of enoxaparin from nanoparticles was determined under simulated intestinal fluid. The cytotoxicity of nanoparticles on a Caco-2 cell line was determined, and finally the transport of prepared nanoparticles across Caco-2 cell monolayer was defined. Optimized nanoparticles with proper physico-chemical properties were obtained. The size, zeta potential, poly-dispersity index, entrapment efficiency and loading efficiency of nanoparticles were reported as 235 ± 24.3 nm, +18.6 ± 2.57 mV, 0.230 ± 0.03, 76.4 ± 5.43% and 12.6 ± 1.37%, respectively. Morphological studies revealed spherical nanoparticles with no sign of aggregation. In vitro release studies demonstrated that 93.6 ± 1.17% of enoxaparin released from nanoparticles after 600 min of incubation. MTT cell cytotoxicity studies showed no cytotoxicity at 3 h post-incubation, while the study demonstrated concentration-dependent cytotoxicity after 24 h of exposure. The obtained data had shown that the nanoparticles prepared from trimethylcarboxymethyl chitosan may be considered as a good candidate for oral delivery of enoxaparin.

Protein corona hampers targeting potential of MUC1 aptamer functionalized SN-38 core-shell nanoparticles.

Nanoparticles have been considered to improve delivery and physicochemical characteristics of bioactive agents in recent years. In this study, a core-shell chitosan nanoparticulate system was prepared for the targeted delivery of SN-38. SN-38, an active metabolite of camptothecin, conjugated to hyaluronic acid (HA) was used as the shell of chitosan nanoparticles decorated with MUC1 aptamer. The conjugation was confirmed by UV and (1)H NMR techniques. Targeting efficiency was evaluated by confocal microscopy and flow cytometry. It was shown that MUC1 decoration increased the uptake of nanoparticles by HT29 cells, MUC1 positive cell line, while CHO as MUC1 negative cell line showed no enhanced uptake of decorated nanoparticles. Compared to non-targeted nanoparticles, flow cytometric annexin V/PI analyses showed that the nanoparticles exert cytotoxicity through apoptosis. It was, however, shown that protein corona adsorption at the surface of nanoparticles hampered the cytotoxicity of nanoparticles, as there was no difference between the cytotoxicity of targeted and non-targeted nanoparticles, when treated with bovine serum albumin prior to cytotoxicity study.

Controlled-release drug delivery system based on fluocinolone acetonide-cyclodextrin inclusion complex incorporated in multivesicular liposomes.

Multivesicular liposomes (MVLs) have been widely studied for encapsulation of hydrophilic drugs due to their structural properties and large aqueous inner cavities. In this study, to investigate MVLs and their potential application for incorporation of hydrophobic drugs, new drug delivery system for fluocinolone acetonide (FA), as a lipophilic model drug, was developed combining the advantages of cyclodextrin inclusion complexes (CD-IC) and multivesicular liposomes. FA was complexed with several CDs to form inclusion complex (FA-CD-IC) and then FA-CD-IC was incorporated into MVLs by reverse-phase evaporation method. Physicochemical characterization of drug-CD-IC, at a molar ratio of 1:1 (drug to CD) was studied using 1HNMR, FT-IR, DSC and UV spectroscopy. The influence of various types of CDs on the aqueous solubility of FA, encapsulation efficiency and release profile in MVLs was studied. The results revealed the formation of inclusion complexes between the drug and CDs. Both the CD's type and proportion played an important role in the physicochemical properties of the systems. The inclusion complex of the drug with hydroxypropyl-ß-cyclodextrin exhibited the most appropriate loading and sustained-release profile over prolonged periods. The results reveal the promising potential of MVLs as a stable drug delivery system to release the drug in a sustained manner for the treatment of ocular inflammatory disease.