Fabrication and application of targeted ciprofloxacin nanocarriers for the treatment of chronic bacterial prostatitis.

Pathogenic bacteria cause chronic bacterial prostatitis (CBP). CPB is characterized by urinary tract infection and persistence of pathogenic bacteria in prostatic secretion. Owing to poor blood supply to the prostate gland and limited drug penetration, CBP treatment is difficult. Transferosomes are ultradeformable vesicles for nanocarrier applications, which have become an important area of nanomedicine. Such carriers are specifically targeted to the pathological area to provide maximum therapeutic efficacy. It consists of a lipid bilayer soybean lecithin phosphatidylcholine (PC), an edge activator Tween 80 with various ratios, and a chloroform/methanol core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or among the lipid bilayer. Due to their exceptional flexibility, which enables them to squeeze themselves through narrow pores that are significantly smaller than their size, they can be a solution. One formulation (Cipro5 PEG) was selected for further in vitro analysis and was composed of phosphatidylcholine (PC), Tween 80, and polyethylene glycol-6 stearate (PEG-6 stearate) in a ratio of 3:3:1 in a chloroform/methanol mixture (1:2 v/v). In vitro, the results showed that PEGylated transferosomes had faster drug release, higher permeation, and increased bioavailability. The transferosomes were quantified with a particle size of 202.59 nm, a zeta potential of-49.38 mV, and a drug entrapment efficiency of 80.05%. The aim of this study was to investigate drug targeting. Therefore, Monoclonal antibody IgG was coupled with Cipro5 PEG, which has specificity and selectivity for conjugated nanoparticles. In vivo, a total of twenty-five adult Wistar rats were obtained and randomly divided into 5 groups, each of 5 rats at random: the control group, blank group, positive control group, Cipro 5PEG group, and Cipro 5PEG coupled with IgG antibody group. The cytokines levels (IL-1ß, IL-8, and TNF-α) in the serum were detected by analysis kits. Compared with the control group, treatment with Cipro 5PEG coupled with the IgG antibody could significantly inhibit cytokines, according to histological analysis. Cipro 5PEG, coupled with the IgG antibody group, reduced prostate tissue inflammation. Hence, our results show a promising approach to delivering antibiotics for the targeted therapy of CBP.

Functional candesartan loaded lipid nanoparticles for the control of diabetes-associated stroke: In vitro and in vivo studies.

Diabetes mellitus is a metabolic disease that raises the odds of developing stroke. Candesartan has been used to prevent stroke due to its inhibitory effects on blood pressure, angiogenesis, oxidative damage, and apoptosis. However, oral candesartan has very limited bioavailability and efficacy due to its weak solubility and slow release. The study aimed to develop a nasal formulation of candesartan-loaded liposomes containing ethanol and propylene glycol (CLEP) to improve candesartan's delivery, release, permeation, and efficacy as a potential diabetes-associated stroke treatment. Using design expert software, different CLEP formulations were prepared and evaluated in vitro to identify the optimum formulation, which. The selected optimum formulation composed of 3.3% phospholipid, 10% ethanol, and 15% propylene glycol significantly increased the release and permeation of candesartan relative to free candesartan by a factor of 1.52 and 1.47, respectively. The optimum formulation significantly reduced the infarction after stroke in rats; decreased flexion, spontaneous motor activity, and time spent in the target quadrant by 70%, 64.71%, and 92.31%, respectively, and enhanced grip strength by a ratio of 2.3. Therefore, nasal administration of the CLEP formulation could be a potential diabetes-associated stroke treatment.

Box Behnken optimization of cubosomes for enhancing the anticancer activity of metformin: Design, characterization, and in-vitro cell proliferation assay on MDA-MB-231 breast and LOVO colon cancer cell lines.

This study aimed to formulate and statistically optimize cubosomal formulations of metformin (MTF) to enhance its breast anticancer activity. A Box Behnken design was employed using Design-Expert® software. The formulation variables were glyceryl monooleate concentration (GMO) w/w%, Pluronic F-127 concentration (PF127) w/w% and Tween 80 concentration w/w% whereas Entrapment efficiency (EE%), Vesicles' size (VS) and Zeta potential (ZP) were set as the dependent responses. The design expert software was used to perform the process of optimization numerically. X ray diffraction (XRD), Transmission electron microscope (TEM), in-vitro release study, short-term stability study, and in in-vitro cell proliferation assay on the MDA-MB-231 breast cancer and LOVO cancer cell lines were used to validate the optimized cubosomal formulation. The optimized formulation had a composition of 4.35616 (w/w%) GMO, 5 (w/w%) PF127 and 7.444E-6 (w/w%) Tween 80 with a desirability of 0.733. The predicted values for EE%, VS and ZP were 78.0592%, 307.273 nm and - 26.8275 mV, respectively. The validation process carried out on the optimized formula revealed that there were less than a 5% variance from the predicted responses. The XRD thermograms showed that MTF was encapsulated inside the cubosomal vesicles. TEM images of the optimized MTF cubosomal formulation showed spherical non-aggregated nanovesicles. Moreover, it revealed a sustained release profile of MTF in comparison to the MTF solution. Stability studies indicated that optimum cubosomal formulation was stable for thirty days. Cytotoxicity of the optimized cubosomal formulation was enhanced on the MDA-MB-231 breast and LOVO cancer cell lines compared to MTF solution even at lower concentrations. However, it showed superior cytotoxic effect on breast cancer cell line. So, cubosomes could be considered a promising carrier of MTF to treat breast and colon cancers.

Formulation and Therapeutic Evaluation of Isoxsuprine-Loaded Nanoparticles against Diabetes-Associated Stroke.

Ischemic stroke is the second-leading cause of death. Hyperglycemia, which is characteristic of diabetes mellitus, contributes to the development of endothelial dysfunction and increases the risk of stroke. Isoxsuprine is an efficient beta-adrenergic agonist that improves blood flow to the ischemic aria and stops the infarct core from growing. However, low bioavailability, a short biological half-life, and first-pass hepatic metabolism reduce the therapeutic efficacy of oral isoxsuprine. Therefore, the authors focused on developing isoxsuprine-loaded liposomes containing ethanol and propylene glycol (ILEP) formulation as nasal drops for the treatment of ischemic stroke in diabetic patients. Different ILEP formulations were optimized using Design Expert software, and the selected formulation was examined in vivo for its anti-stroke effect using a rat model of diabetes and stroke. The optimized ILEP, composed of 15% propylene glycol, 0.16% cholesterol, 10% ethanol, and 3.29% phospholipid, improved the sustainability, permeation, and targeting of isoxsuprine. Furthermore, the in vivo studies verified the improved neurological behavior and decreased dead shrunken neurons and vascular congestion of the rats treated with the optimized ILEP formulation, demonstrating its anti-stroke activity. In conclusion, our study found that treatment with an optimized ILEP formulation prevented the initiation and severity of stroke, especially in diabetic patients.

Novel nasal niosomes loaded with lacosamide and coated with chitosan: A possible pathway to target the brain to control partial-onset seizures.

This work aimed to develop and produce lacosamide-loaded niosomes coated with chitosan (LCA-CTS-NSM) using a thin-film hydration method and the Box-Behnken design. The effect of three independent factors (Span 60 amount, chitosan concentration, and cholesterol amount) on vesicle size, entrapment efficiency, zeta potential, and cumulative release (8 h) was studied. The optimal formulation of LCA-CTS-NSM was chosen from the design space and assessed for morphology, in vitro release, nasal diffusion, stability, tolerability, and in vivo biodistribution for brain targeting after intranasal delivery. The vesicle size, entrapment, surface charge, and in vitro release of the optimal formula were found to be 194.3 nm, 58.3%, +35.6 mV, and 81.3%, respectively. Besides, it exhibits sustained release behavior, enhanced nasal diffusion, and improved physical stability. Histopathological testing revealed no evidence of toxicity or structural damage to the nasal mucosa. It demonstrated significantly more brain distribution than the drug solution. Overall, the data is encouraging since it points to the potential for non-invasive intranasal administration of LCA as an alternative to oral or parenteral routes.

Numerical Optimization of Prednisolone-Tacrolimus Loaded Ultraflexible Transethosomes for Transdermal Delivery Enhancement; Box-Behnken Design, Evaluation, Optimization, and Pharmacokinetic Study.

The aim of the present study is to formulate highly permeable carriers (i.e., transethosomes) for enhancing the delivery of prednisolone combined with tacrolimus for both topical and systemic pathological conditions. A Box-Behnken experimental design was implemented in this research. Three independent variables: surfactant concentration (X1), ethanol concentration (X2), and tacrolimus concentration (X3) were adopted in the design while three responses: entrapment efficiency (Y1), vesicle size (Y2), and zeta potential (Y3) were investigated. By applying design analysis, one optimum formulation was chosen to be incorporated into topical gel formulation. The optimized transethosomal gel formula was characterized in terms of pH, drug content, and spreadability. The gel formula was challenged in terms of its anti-inflammatory effect and pharmacokinetics against oral prednisolone suspension and topical prednisolone-tacrolimus gel. The optimized transethosomal gel achieved the highest rate of rat hind paw edema reduction (98.34%) and highest pharmacokinetics parameters (Cmax 133.266 ± 6.469 µg/mL; AUC0-∞ 538.922 ± 49.052 µg·h/mL), which indicated better performance of the formulated gel.

Impact of the functional coating of silver nanoparticles on their in vivo performance and biosafety.

OBJECTIVE AND SIGNIFICANCE: Silver nanoparticles (AgNPs) have become an interesting therapeutic modality and drug delivery platform. Herein, we aimed to investigate the impact of functional coating on the in vivo performance of AgNPs as an economic and scalable method to modulate their behavior. METHODS: AgNPs were coated with chitosan (CHI) as a model biopolymer using a one-pot reduction-based method, where CHI of two molecular weight ranges were investigated. The resultant CHI-coated AgNPs (AgNPs-CHI) were characterized using UV-VIS spectroscopy, DLS, and TEM. AgNPs were administered intravenously to rats and their biodistribution and serum levels of hepato-renal function markers were monitored 24 h later compared to plain AgNO3 as a positive control. RESULTS: UV-VIS spectroscopy confirmed the successful coating of AgNPs with CHI. DLS revealed the superiority of medium molecular weight CHI over its low molecular weight counterpart. AgNPs-CHI demonstrated a semi-complete clearance from the systemic circulation, a liver-dominated tissue tropism, and limited renal exposure. On the other hand, AgNO3 was poorly cleared from the circulation, with relatively high renal exposure and a non-specific tissue tropism. AgNPs-CHI were well-tolerated by the liver and kidney without signs of toxicity or inflammation, in contrary with AgNO3 which resulted in a significant elevation of Creatinine (CRE), Urea, and Total Protein (TP), suggesting a significant nephrotoxicity and inflammation. CONCLUSIONS: Functional coating of AgNPs with CHI substantially modulated their in vivo behavior, promoting their hepatic selectivity and biotolerability, which can be invested in the development of drug delivery systems for the treatment of liver diseases.

Fabrication and Assessment of Orodispersible Tablets Loaded with Cubosomes for the Improved Anticancer Activity of Simvastatin against the MDA-MB-231 Breast Cancer Cell Line.

Various factors limit the use of simvastatin as an anticancer drug. Therefore, this study aimed to analyse simvastatin (SIM)-loaded cubosome efficacy against breast cancer. SIM-loaded cubosomes were prepared using the emulsification method using different glyceryl monooleate, Pluronic F127 (PF-127), and polyvinyl alcohol (PVA) ratios. The best cubosomal formula was subjected to an in vitro cytotoxicity analysis using the human breast cancer cell line, MDA-MB-231 (MDA) (ATCC, HTB-26), and formulated as oral disintegrating tablets through direct compression. PF-127 and PVA positively affected drug loading, and the entrapment efficiency percentage of different SIM-cubosomal formulations ranged from 33.52% to 80.80%. Vesicle size ranged from 181.9 ± 0.50 to 316.6 ± 1.25 nm. PF-127 enhanced in vitro SIM release from cubosome formulations due to its solubilising action on SIM. The in vitro dissolution analysis indicated that SIM exhibited an initial dissolution of 10.4 ± 0.25% within the first 5 min, and 63.5 ± 0.29% of the loaded drug was released after 1 h. Moreover, cubosome formula F3 at 25 and 50 µg/mL doses significantly decreased MDA cell viability compared to the 12.5 µg/mL dose. The untreated SIM suspension and drug-free cubosomes at all doses had no significant influence on MDA cell viability compared to the control.

Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment.

A liposphere system for intranasal delivery of quetiapine fumarate (QTF) was created to assess the potential for enhanced drug delivery. We investigated the effects of particle size, entrapment effectiveness, poly dispersibility index, and pluronic incorporation percentage on these variables. The optimal formula was examined using a TEM, and investigations into DSC, XRD, and FTIR were made. Optimized liposphere formulation in vitro dissolution investigation with a mean diameter of 294.4 ± 18.2 nm revealed about 80% drug release in 6 h. The intranasal injection of QTF-loaded lipospheres showed a shorter Tmax compared to that of intranasal and oral suspension, per the findings of an in vivo tissue distribution investigation in Wistar mice. Lipospheres were able to achieve higher drug transport efficiency (DTE %) and direct nose-to-brain drug transfer (DTP %). A potentially effective method for delivering QTF to specific brain regions is the liposphere system.

Transethosomal Gel for the Topical Delivery of Celecoxib: Formulation and Estimation of Skin Cancer Progression.

The topical delivery of therapeutics is a promising strategy for managing skin conditions. Cyclooxygenase-2 (COX-2) inhibitors showed a possible target for chemoprevention and cancer management. Celecoxib (CXB) is a selective COX-2 inhibitor that impedes cell growth and generates apoptosis in different cell tumors. Herein, an investigation proceeded to explore the usefulness of nano lipid vesicles (transethosomes) (TES) of CXB to permit penetration of considerable quantities of the drug for curing skin cancer. The prepared nanovesicles were distinguished for drug encapsulation efficiency, vesicle size, PDI, surface charge, and morphology. In addition, FT-IR and DSC analyses were also conducted to examine the influence of vesicle components. The optimized formulation was dispersed in various hydrogel bases. Furthermore, in vitro CXB release and ex vivo permeability studies were evaluated. A cytotoxicity study proceeded using A431 and BJ1 cell lines. The expression alteration of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and DNA damage and fragmentation using qRT-PCR and comet assays were also investigated. Optimized CXB-TES formulation was spherically shaped and displayed a vesicle size of 75.9 ± 11.4 nm, a surface charge of -44.7 ± 1.52 mV, and an entrapment efficiency of 88.8 ± 7.2%. The formulated TES-based hydrogel displayed a sustained in vitro CXB release pattern for 24 h with an enhanced flux and permeation across rat skin compared with the control (free drug-loaded hydrogel). Interestingly, CXB-TES hydrogel has a lower cytotoxic effect on normal skin cells compared with TES suspension and CXB powder. Moreover, the level of expression of the CDKN2A gene was significantly (p ≤ 0.01, ANOVA/Tukey) decreased in skin tumor cell lines compared with normal skin cell lines, indicating that TES are the suitable carrier for topical delivery of CXB to the cancer cells suppressing their progression. In addition, apoptosis demonstrated by comet and DNA fragmentation assays was evident in skin cancer cells exposed to CXB-loaded TES hydrogel formulation. In conclusion, our results illustrate that CXB-TES-loaded hydrogel could be considered a promising carrier and effective chemotherapeutic agent for the management of skin carcinoma.