The Idiosyncratic Efficacy of Spironolactone-Loaded PLGA Nanoparticles Against Murine Intestinal Schistosomiasis.

Background: Schistosomiasis is a chronic debilitating parasitic disease accompanied with severe mortality rates. Although praziquantel (PZQ) acts as the sole drug for the management of this disease, it has many limitations that restrict the use of this treatment approach. Repurposing of spironolactone (SPL) and nanomedicine represents a promising approach to improve anti-schistosomal therapy. We have developed SPL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to enhance the solubility, efficacy, and drug delivery and hence decrease the frequency of administration, which is of great clinical value. Methods: The physico-chemical assessment was performed starting with particle size analysis and confirmed using TEM, FT-IR, DSC, and XRD. The antischistosomal effect of the SPL-loaded PLGA NPs against Schistosoma mansoni (S. mansoni)-induced infection in mice was also estimated. Results: Our results manifested that the optimized prepared NPs had particle size of 238.00 ± 7.21 nm, and the zeta potential was -19.66 ± 0.98 nm, effective encapsulation 90.43±8.81%. Other physico-chemical features emphasized that nanoparticles were completely encapsulated inside the polymer matrix. The in vitro dissolution studies revealed that SPL-loaded PLGA NPs showed sustained biphasic release pattern and followed Korsmeyer-Peppas kinetics corresponding to Fickian diffusion (n<0.45). The used regimen was efficient against S. mansoni infection and induced significant reduction in spleen, liver indices, and total worm count (ρ<0.05). Besides, when targeting the adult stages, it induced decline in the hepatic egg load and the small intestinal egg load by 57.75% and 54.17%, respectively, when compared to the control group. SPL-loaded PLGA NPs caused extensive damage to adult worms on tegument and suckers, leading to the death of the parasites in less time, plus marked improvement in liver pathology. Conclusion: Collectively, these findings provided proof-of-evidence that the developed SPL-loaded PLGA NPs could be potentially used as a promising candidate for new antischistosomal drug development.

Fabrication and characterization of electrospun nanofibers using biocompatible polymers for the sustained release of venlafaxine.

Recently, drug-controlled release nanotechnology has gained special attention in biomedicine. This work focuses on developing novel electrospun polymeric nanofibers (NFs) for buccal delivery of VEN to avoid the hepatic metabolism and enzymatic degradation in the GIT and develop an effective control of drug release. The optimized NFs were obtained by blending polylactic acid (PLA), and poly (ɛ-caprolactone) (PCL) fixed at a ratio of 1:1. It was characterized for morphology, drug-loading, FTIR, XRD, DSC, and in vitro drug release. Ex vivo permeability of the blend NFs was assessed using chicken pouch mucosa compared to VEN suspension, followed by histopathological examination. Further, the cytotoxic effect in three different cell lines using WST-1 assay. SEM morphologies refer to defect-free uniform NFs of PLA, PCL, and PLA/PCL mats. These fibers had a diameter ranging from 200 to 500 nm. The physico-thermal characterization of NFs depicted that the drug was successfully loaded and in an amorphous state in the PLA/PCL NFs. In vitro release of NFs substantiated a bi-phasic profile with an initial burst release of about 30% in the initial 0.5 h and a prolonged cumulative release pattern that reached 80% over 96 h following a non-Fickian diffusion mechanism. Ex vivo permeation emphasizes the major enhancement of the sustained drug release and the noticeable decrease in the permeability of the drug from NFs. Cytotoxicity data found that IC50 of VEN alone was 217.55 µg/mL, then VEN-NFs recorded an IC50 value of 250.62 µg/mL, and plain NFs showed the lowest toxicity and IC50 440.48 µg/mL in oral epithelial cells (OEC). Histopathology and cell toxicity studies demonstrated the preserved mucosal architecture and the preclinical safety. The developed PLA/PCL NFs can be promising drug carriers to introduce a step-change in improved psychiatric treatment healthcare.

Long-term evaluation of early-enamel lesions treated with novel experimental tricalcium silicate paste: A 2-year randomized clinical trial.

OBJECTIVE: The aim of the current study is to evaluate the remineralization potential of experimental tricalcium silicate (TCS) paste in comparison with more popular remineralizing agents like silver diamine fluoride potassium iodide (SDF-KI) and casein phosphopeptide amorphous calcium phosphate (CPP-ACP) on early enamel lesions. MATERIALS AND METHODS: Forty-five patients in the age range of 15-50 years had early enamel lesions on the buccal surface of molar teeth. The patients were randomly divided into three treatment groups (SDF-KI, CPP-ACP, and TCS group) with 15 patients per group. Lesions were evaluated clinically by DIAGNOdent pen immediately and after 3,6,12, and 24 months of treatment. RESULTS: The study was completed with 45 patients and 92 teeth. Twice-daily application of CPP-ACP and TCS paste showed a significant remineralization effect on early enamel lesions after 24 months (p < 0.001). Also, annual application of SDF-KI showed a significant remineralization effect after 24 months (p < 0.001). There was a significant difference between (SDF-KI and CPP-ACP) and (SDF-KI and TCS) at the different follow-up periods 3,6,12, and 24 months (p < 0.001). Meanwhile, there was no significant difference between CPP-ACP and TCS at the mentioned follow-up periods (p > 0.05). CONCLUSION: TCS showed potential remineralization for early enamel lesions. CLINICAL RELEVANCE: Experimental TCS is a promising remineralizing agent for management of early enamel lesions.

Remineralization of early enamel lesions with a novel prepared tricalcium silicate paste.

To evaluate the remineralization potential of prepared tricalcium silicate (TCS) paste compared to silver diamine fluoride-potassium iodide (SDF-KI) and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on artificial enamel lesions. Thirty permanent sound molars were collected for the study. After cleaning, root cutting, and applying acid-resistant nail varnish, leaving a 4 × 4 mm buccal window, the teeth were subjected to demineralization process. The teeth were divided into three treatment groups (n = 10). In each group, the teeth were sectioned buccolingually to obtain two halves (30 self-control and 30 experimental halves). The self-control halves were subjected to cross-sectional microhardness (CSMH), energy-dispersive X-ray spectroscopy at 50, 100, and 150 µm from the external enamel surface, and micromorphological analysis at the superficial enamel surface. The experimental halves were subjected to the same tests after 30 days of remineralization. Three-way analysis of variance (ANOVA) outcomes showed no significant difference in CSMH after treatment among the three different groups at the different levels (p > 0.05). Meanwhile, three-way ANOVA outcomes showed a significant difference in calcium/ phosphate ratio after treatment among the three different groups at the different levels. (p < 0.05). The tricalcium silicate paste used in this study showed potential remineralization in subsurface enamel lesions.

The protective impact of adapted trimebutine maleate-loaded nanostructured lipid carriers for alleviating the severity of acute colitis.

Nanoparticles for colon-drug delivery were designed and evaluated to solve many discrepancy issues such as high adverse effects of released drugs, insufficient drug amount at diseased areas, and unintentionally premature drug release to noninflamed GIT regions. Herein, the goal of this work was to convert trimebutine maleate (TMB) into nanostructured lipid carriers (NLC) in order to improve its protective effects in ulcerative colitis. NLC of TMB was prepared by the hot homogenization followed by ultra-sonication method. A full 42-factorial design was used to estimate the produced TMB-NLC. The study design included the exploration of the impact of two independent variables namely lipid mix amount and ratio (glyceryl mono stearate and capryol 90), surfactant concentration (0.5, 1, 1.5, and 2%), on the particle size, polydispersity index, and the entrapment efficiency (EE%). The protective activity of F9 was examined through macroscopical scores, histopathological changes, immunohistochemical localization of tumor necrosis factor-α (TNF-α) and examination of oxidative stress such as reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) against acetic acid-induced colitis in rats. Consistent with our expectations, the orally administered optimized formula (F9) alleviated the severity of colitis in acetic acid-induced rat model of colitis likely owing to the controlled release compared to free TMB. We aimed to develop TMB-loaded NLC for the treatment of acute colitis with the goal of providing a superior drug safety profile over long-term remission and maintenance therapy.

Chitosan-dipotassium orthophosphate lyophilizate: a novel in situ thermogel carrier system of allogeneic platelet lysate growth factors.

The clinical success of platelet-rich plasma (PRP) is constrained by its limited mechanical strength, rapid disintegration by lytic enzymes, and the consequent short-term release of bioactive growth factors (GFs). Recently, attempts to formulate PRP and other hemoderivatives, such as platelet lysate (PL) have been underway. The current study aimed to formulate allogeneic freeze-dried human platelet lysate (HPL) onto lyophilized chitosan - dipotassium hydrogen orthophosphate (CS/DHO) thermo-sensitive scaffolds. A systemic approach was employed to optimize freeze-drying (FD) procedures targeting predefined critical quality attributes (CQAs). Thermal behavior, vibrational spectroscopy, morphological and moisture content analyses were used to detect possible protein destabilization during formulation and suboptimal cake properties. The effect of CS/DHO concentrations on thermo-responsiveness and release kinetics were investigated. Finally, six-months stability and cytotoxicity studies were carried out. An optimized lyophilizate was attainable with residual moisture of less than 5% and thermoresponsive to 33 °C in less than 3 min. HPL proteins were sustainedly released over five days in a pH-sensitive manner. The stability study indicated plausible physical and biochemical stability. Cell viability testing supported the cytocompatibility of the system. Finally, the lyophilizate variant of CS/DHO thermogel overcomes limited storage stability previously posed as a challenge in freshly prepared thermogels. The developed system overcomes the drawbacks of currently used PRP treatment and provides a novel GF-rich scaffold for wound repair.

Crucial Role of PLGA Nanoparticles in Mitigating the Amiodarone-Induced Pulmonary Toxicity.

BACKGROUND: Amiodarone (AMD) is a widely used anti-arrhythmic drug, but its administration could be associated with varying degrees of pulmonary toxicity. In attempting to circumvent this issue, AMD-loaded polymeric nanoparticles (AMD-loaded NPs) had been designed. MATERIALS AND METHODS: AMD was loaded in NPs by the nanoprecipitation method using two stabilizers: bovine serum albumin and Kolliphor® P 188. The physicochemical properties of the AMD-loaded NPs were determined. Among the prepared NPs, two ones were selected for further investigation of spectral and thermal analysis as well as morphological properties. Additionally, in vitro release patterns were studied and kinetically analyzed at different pH values. In vitro cytotoxicity of an optimized formula (NP4) was quantified using A549 and Hep-2 cell lines. In vivo assessment of the pulmonary toxicity on Sprague Dawley rats via histopathological and immunohistochemical evaluations was applied. RESULTS: The developed NPs achieved a size not more than 190 nm with an encapsulation efficiency of more than 88%. Satisfactory values of loading capacity and yield were also attained. The spectral and thermal analysis demonstrated homogeneous entrapment of AMD inside the polymeric matrix of NPs. Morphology revealed uniform, core-shell structured, and sphere-shaped particles with a smooth surface. Furthermore, the AMD-loaded NPs exhibited a pH-dependent and diffusion-controlled release over a significant period without an initial burst effect. NP4 demonstrated a superior cytoprotective efficiency by diminishing cell death and significantly increasing the IC50 by more than threefold above the pure AMD. Also, NP4 ameliorated AMD-induced pulmonary damage in rats. Significant downregulation of inflammatory mediators and free radicle production were noticed in the NP4-treated rats. CONCLUSION: The AMD-loaded NPs could ameliorate the pulmonary injury induced by the pure drug moieties. Cytoprotective, anti-fibrotic, anti-inflammatory, and antioxidant properties were presented by the optimized NPs (NP4). Future studies may be built on these findings for diminishing AMD-induced off-target toxicities.

Novel electro self-assembled DNA nanospheres as a drug delivery system for atenolol.

We describe new method for preparing DNA nanospheres for a self-assembled atenolol@DNA (core/shell) drug delivery system. In this paper, we propose the electrochemical transformation of an alkaline polyelectrolyte solution of DNA into DNA nanospheres. We successfully electrosynthesized DNA nanospheres that were stable for at least 2 months at 4 °C. UV-visible spectra of the prepared nanospheres revealed a peak ranging from 372 to 392 nm depending on the DNA concentration and from 361 to 398.3 nm depending on the electrospherization time. This result, confirmed with size distribution curves worked out from transmission electron microscopy (TEM) images, showed that increasing electrospherization time (6, 12 and 24 h) induces an increase in the average size of DNA nanospheres (48, 65.5 and 117 nm, respectively). In addition, the average size of DNA nanospheres becomes larger (37.8, 48 and 76.5 nm) with increasing DNA concentration (0.05, 0.1 and 0.2 wt%, respectively). Also, the affinity of DNA chains for the surrounding solvent molecules changed from favorable to bad with concomitant extreme reduction in the zeta potential from -31 mV to -17 mV. Principally, the attractive and hydrophobic interactions tend to compact the DNA chain into a globule, as confirmed by Fourier transform infrared spectroscopy (FTIR) and TEM. To advance possible applications, we successfully electro self-assembled an atenolol@DNA drug delivery system. Our findings showed that electrospherization as a cost-benefit technique could be effectively employed for sustained drug release. This delivery system achieved a high entrapment efficiency of 68.03 ± 2.7% and a moderate drug-loading efficiency of 3.73%. The FTIR spectra verified the absence of any chemical interaction between the drug and the DNA during the electrospherization process. X-ray diffraction analysis indicated noteworthy lessening in atenolol crystallinity. The present findings could aid the effectiveness of electrospherized DNA for use in various other pharmaceutical and biomedical applications.

Appraisal of amiodarone-loaded PLGA nanoparticles for prospective safety and toxicity in a rat model.

AIMS: Amiodarone (AM) is a highly efficient drug for arrhythmias treatment, but its extra-cardiac adverse effects offset its therapeutic efficacy. Nanoparticles (NPs)-based delivery system could provide a strategy to allow sustained delivery of AM to the myocardium and reduction of adverse effects. The primary purpose was to develop AM-loaded NPs and explore their ameliorative effects versus off-target toxicities. MATERIALS AND METHODS: Polymeric NPs were prepared using poly lactic-co-glycolic acid and their physicochemical properties were characterized. Animal studies were conducted using a rat model to compare exposure to AM versus that of the AM-loaded NPs. Biochemical evaluation of liver enzymes, lipid profile, and thyroid hormones was achieved. Besides, histopathological changes in liver and lung were studied. KEY FINDINGS: Under optimal experimental conditions, the AM-loaded NPs had a size of 186.90 nm and a negative zeta potential (-14.67 mV). Biochemical evaluation of AM-treated animal group showed a significant increase in cholesterol, TG, LDL, T4, and TSH levels (ρ < 0.05). Remarkably, the AM-treated group exhibited a significant increase of liver enzymes (ρ < 0.05) coupled with an obvious change in liver architecture. The AM-loaded NPs displayed a reduction of liver damage and enzyme levels. Lung sections of the AM-treated group demonstrated thickening of interalveolar septa, mononuclear cellular infiltration with congested blood vessels, and heavy collagenous fibers deposition. Conversely, less cellular infiltration and septal thickening were observed in the animal lungs treated with the AM-loaded NPs-treated. SIGNIFICANCE: Our findings demonstrate the competence of the AM-loaded NPs to open several exciting avenues for evading the AM-induced off-target toxicities.

The impact of topical phenytoin loaded nanostructured lipid carriers in diabetic foot ulceration.

OBJECTIVE: The aim of this study is to develop, and characterize nanostructured lipid carriers (NLCs) of phenytoin (PHT) in order to improve its entrapment efficiency and sustained release to improve the healing process. METHODS: Twenty-seven patients with neuropathic diabetic foot ulceration (DFU) were enrolled in this study. Patients were comparable regarding size, grading of ulcer and control of diabetes with no major deformity. All patients were managed by weekly sharp debridement if indicated and offloaded with cast shoes. They were equally divided into three groups: PHT-NLC-hydrogel (0.5%w/v), phenytoin hydrogel (0.5%w/v) and blank hydrogel groups. Changes in wound area were monitored over 2 months. RESULTS: Baseline wound area of PHT-NLC, PHT and blank hydrogels were 5.50 ± 3.66, 3.94 ± 1.86 and 5.36 ± 2.14 cm2, respectively. Ulcers treated with PHT-NLC hydrogel showed smaller wound area compared to control groups (ρ < 0.05). The overall reduction in ulcer size were 95.82 ± 2.22% for PHT-NLC-hydrogel in comparison to 47.10 ± 4.23% and -34.91 ± 28.33% for PHT and blank-hydrogel (ρ < 0.001), respectively. CONCLUSION: PHT-NLC hydrogel speeds up the healing process of the DFU without adverse effects when compared to the positive and negative control hydrogels. Moreover, the study can open a window for topical application of NLCs loaded with PHT in the treatment of numerous dermatological disorders that resist conventional treatment. KEY MESSAGE: The delivery of drug molecules and their localization into the skin is the main purpose of the topical dosage forms. In this manuscript, the impact of topical phenytoin loaded nanostructured lipid carrier in improving wound healing in patients with neuropathic diabetic foot ulceration was investigated. Phenytoin loaded nanostructured lipid carrier dressing was found to be more effective than phenytoin hydrogel at the same concentration in healing of neuropathic diabetic foot ulcer.

Topical phenytoin nanostructured lipid carriers: design and development.

Phenytoin (PHT) is an antiepileptic drug that was reported to exhibit high wound healing activity. Nevertheless, its limited solubility, bioavailability, and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop, characterize nanostructured lipid carriers (NLCs), and evaluate their potential in topical delivery of PHT to improve the drug entrapment efficiency and sustained release. The NLCs were prepared by hot homogenization followed by ultra sonication method using 23 factorial design. NLC formulations were characterized regarding their particle size (PS), zeta potential (ZP), entrapment efficiency percent (%EE), surface morphology, physicochemical stability, and in vitro release studies. The optimized NLC (F7) was further incorporated in 1%w/v carbopol gel and then characterized for appearance, pH, viscosity, stability, and in vitro drug release. The prepared NLCs were spherical in shape and possessed an average PS of 121.4-258.2 nm, ZP of (-15.4)-(-32.2) mV, and 55.24-88.80 %EE. Solid-state characterization revealed that the drug is dispersed in an amorphous state with hydrogen bond interaction between the drug and the NLC components. NLC formulations were found to be stable at 25 °C for six months. The stored F7-hydrogel showed insignificant changes in viscosity and drug content (p>.05) up to six months at 25 °C that pave a way for industrial fabrication of efficient PHT products. In vitro release studies showed a sustained release from NLC up to 48 h at pH 7.4 following non-Fickian Higuchi kinetics model. These promising findings encourage the potential use of phenytoin loaded lipid nanoparticles for future topical application.

Nanoemulsifying drug delivery system to improve the bioavailability of piroxicam.

OBJECTIVE: The aim of this study is to develop and characterize self-nanoemulsifying drug delivery system (SNEDDS) of piroxicam in liquid and solid forms to improve its dissolution, absorption and therapeutic efficacy. MATERIALS AND METHODS: The generation of liquid SNEDDS (L-SNEDDS) was composed of soybean or coconut oil/Tween 80/Transcutol HP (12/80/8%w/w) and it was selected as the optimized formulation based on the solubility study and pseudo-ternary phase diagram. Optimized L-SNEDDS and liquid supersaturatable SNEDDS (L-sSNEDDS) preparations were then adsorbed onto adsorbents and formulated as directly compressed tablets. RESULTS AND DISCUSSION: The improved drug dissolution rate in the solid supersaturatable preparation (S-sSNEDDS) may be due to the formation of a nanoemulsion and the presence of drug in an amorphous state with hydrogen bond interaction between the drug and SNEDDS components. In vivo pharmacokinetic studies on eight healthy human volunteers showed a significant improvement in the oral bioavailability of piroxicam from S-sSNEDDS (F12) compared with both the pure drug (PP) and its commercial product (Feldene®) (commercial dosage form (CD)). The relative bioavailability of S-sSNEDDS (F12) relative to PP or CD was about 151.01 and 98.96%, respectively. CONCLUSION: The obtained results ratify that S-sSNEDDS is a promising drug delivery system to enhance the oral bioavailability of piroxicam.