A pH-sensitive silica nanoparticles for colon-specific delivery and controlled release of catechin: Optimization of loading efficiency and in vitro release kinetics.

Catechin is a naturally occurring flavonoid of the flavan-3-ol subclass with numerous biological functions; however, these benefits are diminished due to several factors, including low water solubility and degradation in the stomach's harsh environment. So, this study aimed to develop an intelligent catechin colon-targeting delivery system with a high loading capacity. This was done by coating surface-decorated mesoporous silica nanoparticles with a pH-responsive enteric polymer called Eudragit®-S100. The pristine wormlike mesoporous silica nanoparticles (< 100 nm) with high surface area and large total pore volume were effectively synthesized and modified with the NH2 group using the post-grafting strategy. Various parameters, including solvent polarity, catechin-carrier mass ratio, and adsorption time, were studied to improve the loading of catechin into the aminated silica nanoparticles. Next, the negatively charged Eudragit®-S100 was electrostatically coated onto the positively charged aminated nanocarriers to shield the loaded catechin from the acidic environment of the stomach (pH 1.9) and to facilitate site-specific delivery in the acidic environment of the colon (pH 7.4). The prepared nanomaterials were evaluated using several methods, including The Brauner-Emmett-Teller, surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope, Powder X-Ray Diffraction, Fourier Transform Infrared Spectroscopy, Energy-Dispersive X-ray Spectroscopy, and Differential Scanning Calorimetry. In vitro dissolution studies revealed that Eudragit®-S100-coated aminated nanomaterials prevented the burst release of the loaded catechin in the acidic environment, with approximately 90% of the catechin only being released at colonic pH (pH > 7) with a supercase II transport mechanism. As a result, silica nanoparticles coated with Eudragit®-S100 would provide an innovative and promising approach in targeted nanomedicine for the oral delivery of catechin and related medicines for treating diseases related to the colon, such as colorectal cancer and irritable bowel syndrome.

Intranasal Nanotransferosomal Gel for Quercetin Brain Targeting: II. Antidepressant Effect in an Experimental Animal Model.

Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER's antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for intranasal administration was formulated and optimized. The therapeutic effectiveness of the optimized formulation was assessed in a depressed rat model by conducting a behavioral analysis. Behavioral study criteria such as immobility, swimming, climbing, sucrose intake, number of crossed lines, rearing, active interaction, and latency to feed were all considerably enhanced by intranasal treatment with the QER-TFS in situ gel in contrast to other formulations. A nasal histopathological study indicated that the QER-TFS thermosensitive gel was safe for the nasal mucosa. An immunohistochemical analysis showed that the animals treated with the QER-TFS thermosensitive gel had the lowest levels of c-fos protein expression, and brain histopathological changes in the depressed rats were alleviated. According to pharmacodynamic, immunohistochemical, and histopathological experiments, the intranasal administration of the QER-TFS thermosensitive gel substantially alleviated depressive symptoms in rats. However, extensive preclinical investigations in higher animal models are needed to anticipate its effectiveness in humans.

Intranasal Nanotransferosomal Gel for Quercetin Brain Targeting: I. Optimization, Characterization, Brain Localization, and Cytotoxic Studies.

Numerous neurological disorders have a pathophysiology that involves an increase in free radical production in the brain. Quercetin (QER) is a nutraceutical compound that shields the brain against oxidative stress-induced neurodegeneration. Nonetheless, its low oral bioavailability diminishes brain delivery. Therefore, the current study aimed to formulate QER-loaded transferosomal nanovesicles (QER-TFS) in situ gel for QER brain delivery via the intranasal route. This study explored the impacts of lipid amount, edge activator (EA) amount, and EA type on vesicle diameter, entrapment, and cumulative amount permeated through nasal mucosa (24 h). The optimum formulation was then integrated into a thermosensitive gel after its physical and morphological characteristics were assessed. Assessments of the optimized QER-TFS showed nanometric vesicles (171.4 ± 3.4 nm) with spherical shapes and adequate entrapment efficiency (78.2 ± 2.8%). The results of short-term stability and high zeta potential value (-32.6 ± 1.4 mV) of QER-TFS confirmed their high stability. Compared with the QER solution, the optimized QER-TFS in situ gel formulation exhibited sustained release behavior and augmented nasal mucosa permeability. CT scanning of rat brains demonstrated the buildup of gold nanoparticles (GNPs) in the brains of all treatment groups, with a greater level of GNPs noted in the rats given the transferosomal gel. Additionally, in vitro studies on PCS-200-014 cells revealed minimal cytotoxicity of QER-TFS in situ gel. Based on these results, the developed transferosomal nanovesicles may be a suitable nanocarrier for QER brain targeting through the intranasal route.

Soluble Enolase 1 of Candida albicans and Aspergillus fumigatus Stimulates Human and Mouse B Cells and Monocytes.

Because of the growing numbers of immunocompromised patients, the incidence of life-threatening fungal infections caused by Candida albicans and Aspergillus fumigatus is increasing. We have recently identified enolase 1 (Eno1) from A. fumigatus as an immune evasion protein. Eno1 is a fungal moonlighting protein that mediates adhesion and invasion of human cells and also immune evasion through complement inactivation. We now show that soluble Eno1 has immunostimulatory activity. We observed that Eno1 from both C. albicans and A. fumigatus directly binds to the surface of lymphocytes, preferentially human and mouse B cells. Functionally, Eno1 upregulated CD86 expression on B cells and induced proliferation. Although the receptor for fungal Eno1 on B lymphocytes is still unknown, the comparison of B cells from wild-type and MyD88-deficient mice showed that B cell activation by Eno1 required MyD88 signaling. With respect to infection biology, we noted that mouse B cells stimulated by Eno1 secreted IgM and IgG2b. These Igs bound C. albicans hyphae in vitro, suggesting that Eno1-induced Ab secretion might contribute to protection from invasive fungal disease in vivo. Eno1 also triggered the release of proinflammatory cytokines from monocytes, particularly IL-6, which is a potent activator of B cells. Together, our data shed new light on the role of secreted Eno1 in infections with C. albicans and A. fumigatus. Eno1 secretion by these pathogenic microbes appears to be a double-edged sword by supporting fungal pathogenicity while triggering (antifungal) immunity.

Hydrocortisone-Loaded Lipid-Polymer Hybrid Nanoparticles for Controlled Topical Delivery: Formulation Design Optimization and In Vitro and In Vivo Appraisal.

The barrier functionalities of the skin offer a major but not insuperable hindrance for fabrication of skin delivery effective systems. This work aimed to develop an optimized lipid polymer hybrid nanoparticle and assess the skin delivery effectiveness of hydrocortisone (9.872 ± 0.361 × 10-3 cm2/h) of a drug through the skin from an optimized formulation when compared with a drug solution. Meanwhile, histological examination after topical application of the optimized formulation showed a safe increase in epidermal thickness. In vivo, the optimized formulation showed promising anti-inflammatory activity in a croton oil-induced ear rosacea model. As an excellent anti-inflammatory agent, these findings propose that the use of lipomers could be a promising strategy to improve the topical effectiveness of hydrocortisone acetate (HCA) against inflammatory diseases. Collectively, these results support our view that lipid polymer hybrid nanoparticles can proficiently deliver hydrocortisone to the skin in treating skin inflammatory conditions.

Development of Olive Oil Containing Phytosomal Nanocomplex for Improving Skin Delivery of Quercetin: Formulation Design Optimization, In Vitro and Ex Vivo Appraisals.

The objective of the current work was to fabricate, optimize and assess olive oil/phytosomal nanocarriers to improve quercetin skin delivery. Olive oil/phytosomal nanocarriers, prepared by a solvent evaporation/anti-solvent precipitation technique, were optimized using a Box-Behnken design, and the optimized formulation was appraised for in vitro physicochemical characteristics and stability. The optimized formulation was assessed for skin permeation and histological alterations. The optimized formulation (with an olive oil/PC ratio of 0.166, a QC/PC ratio of 1.95 and a surfactant concentration of 1.6%), and with a particle diameter of 206.7 nm, a zeta potential of -26.3 and an encapsulation efficiency of 85.3%, was selected using a Box-Behnken design. The optimized formulation showed better stability at ambient temperature when compared to refrigerating temperature (4 °C). The optimized formulation showed significantly higher skin permeation of quercetin when compared to an olive-oil/surfactant-free formulation and the control (~1.3-fold and 1.9-fold, respectively). It also showed alteration to skin barriers without remarkable toxicity aspects. Conclusively, this study demonstrated the use of olive oil/phytosomal nanocarriers as potential carriers for quercetin-a natural bioactive agent-to improve its skin delivery.

Phenanthroindolizidine Alkaloids Secondary Metabolites Diversity in Medicinally Viable Plants of the Genus Tylophora.

Plants of the genus Tylophora have commonly been used in traditional medicine in various communities, especially in the tropical and subtropical regions of climatic zones. Of the nearly 300 species reported in the Tylophora genus, eight are primarily used in various forms to treat a variety of bodily disorders based on the symptoms. Certain plants from the genus have found use as anti-inflammatory, anti-tumor, anti-allergic, anti-microbial, hypoglycemic, hypolipidemic, anti-oxidant, smooth muscle relaxant, immunomodulatory, and anti-plasmodium agents, as well as free-radical scavengers. Pharmacologically, a few plant species from the genus have exhibited broad-spectrum anti-microbial and anti-cancer activity, which has been proven through experimental evaluations. Some of the plants in the genus have also helped in alcohol-induced anxiety amelioration and myocardial damage repair. The plants belonging to the genus have also shown diuretic, anti-asthmatic, and hepato-protective activities. Tylophora plants have afforded diverse structural bases for secondary metabolites, mainly belonging to phenanthroindolizidine alkaloids, which have been found to treat several diseases with promising pharmacological activity levels. This review encompasses information on various Tylophora species, their distribution, corresponding plant synonyms, and chemical diversity of the secondary metabolic phytochemicals as reported in the literature, together with their prominent biological activities.

Polymeric Nanoparticles for Delivery of Natural Bioactive Agents: Recent Advances and Challenges.

In the last few decades, several natural bioactive agents have been widely utilized in the treatment and prevention of many diseases owing to their unique and versatile therapeutic effects, including antioxidant, anti-inflammatory, anticancer, and neuroprotective action. However, their poor aqueous solubility, poor bioavailability, low GIT stability, extensive metabolism as well as short duration of action are the most shortfalls hampering their biomedical/pharmaceutical applications. Different drug delivery platforms have developed in this regard, and a captivating tool of this has been the fabrication of nanocarriers. In particular, polymeric nanoparticles were reported to offer proficient delivery of various natural bioactive agents with good entrapment potential and stability, an efficiently controlled release, improved bioavailability, and fascinating therapeutic efficacy. In addition, surface decoration and polymer functionalization have opened the door to improving the characteristics of polymeric nanoparticles and alleviating the reported toxicity. Herein, a review of the state of knowledge on polymeric nanoparticles loaded with natural bioactive agents is presented. The review focuses on frequently used polymeric materials and their corresponding methods of fabrication, the needs of such systems for natural bioactive agents, polymeric nanoparticles loaded with natural bioactive agents in the literature, and the potential role of polymer functionalization, hybrid systems, and stimuli-responsive systems in overcoming most of the system drawbacks. This exploration may offer a thorough idea of viewing the polymeric nanoparticles as a potential candidate for the delivery of natural bioactive agents as well as the challenges and the combating tools used to overcome any hurdles.

Exploring the potential of quercetin/aspirin-loaded chitosan nanoparticles coated with Eudragit L100 in the treatment of induced-colorectal cancer in rats.

Growing evidence suggests quercetin and aspirin may have anticancer properties, notably in the case of colorectal cancer. The goal of this study was to create Pluronic F127 and polyethylene glycol4000 solid dispersion-loaded chitosan nanoparticles for colonic quercetin and aspirin delivery. In 1:1 polymeric stoichiometric ratio, solubility and complex formation were verified. Solid dispersion-loaded chitosan nanoparticles with a diameter of 244.45 ± 8.5 nm, a surface charge of 34.1 ± 3.3 mV, and encapsulation effectiveness of 76.3 ± 4.3% were generated under ideal conditions. In some cases, coating with Eudragit L100 resulted in a decrease in zeta potential and an increase in particle size. The coated formulation released the actives in a pH-dependent manner, considering their physicochemical features. Surprisingly, when compared to the actives' suspension and uncoated formulation, the coated formulation had greater anti-inflammatory efficacy, with a substantial reduction of PGE2 and IL-8 production in colonic tissues (16.9 ± 7.9 ng/g tissue and 134.9 ± 10.1 pg/g tissue, respectively). It also reversed most of the dimethyl hydrazine-induced histological alterations in the colon. It also demonstrated a greater reduction in TNF expression in colonic tissues. As a result, Eudragit L100-coated QT/AS-loaded chitosan nanoparticles are suggested to provide a potential platform for colonic delivery of quercetin and aspirin.

Phthalazone tethered 1,2,3-triazole conjugates: In silico molecular docking studies, synthesis, in vitro antiproliferative, and kinase inhibitory activities.

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.

Quercetin-Loaded Mesoporous Silica Nanoparticle-Based Lyophilized Tablets for Enhanced Physicochemical Features and Dissolution Rate: Formulation, Optimization, and In Vitro Evaluation.

Mesoporous silica nanoparticles (MSNPs) have been proposed as a potential approach for stabilizing the amorphous state of poorly water-soluble actives. This study aimed to improve the physiochemical characteristics of poorly water-soluble quercetin (QT) through a novel lyophilized formulation. Various parameters, including solvent polarity, QT-carrier mass ratio, and adsorption time, were studied to improve the loading of QT into MSNPs. The optimized loaded MSNPs were formulated into lyophilized tablets through a freeze-drying process using hydrophilic polyvinylpyrrolidone (PVP-K30) as a polymeric stabilizer and water-soluble sucrose as a cryoprotectant. The effect of PVP-K30 and sucrose on the particle size, disintegration time, friability, and time required to release 90% of QT were studied using 32 full factorial design. The optimized formula was characterized using different evaluating techniques; for instance, differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, drug content, moisture content, and saturation solubility. The analysis proved that QT was consistently kept in the nanosize range with a narrow size distribution. The loaded silica nanoparticles and the optimized formulation are in an amorphous state devoid of any chemical interaction with the silica matrix or the lyophilization excipients. The optimized formula also featured low friability (less than 1%), fast disintegration (< 30 s), and a pronounced enhancement in saturation solubility and dissolution rate. Briefly, we established that the lyophilized MSNPs-based tablet would be a potential strategy for improving the rate of dissolution and, ultimately, the bioavailability of the poorly water-soluble QT.

Development and assessment of phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery.

Luteolin is an excellent flavone possessing several beneficial properties such as antioxidant and anti-inflammatory effects which are interesting for skin delivery. Development of an appropriate skin delivery system could be a promising strategy to improve luteolin cutaneous performance.So, the main aim of this work was to fabricate, characterize and evaluate phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. The influence of phospholipid/oil ratio, surfactant type and chitosan coating were investigated. The prepared formulations underwent in vitro assessment and the selected formulations were evaluated ex vivo and in vivo. The mean diameters of investigated formulations varied between 174 nm and 628 nm while zeta potential varied between -25.7 ± 4.8 mV and 6.8 ± 1.7 mV. Increasing in phospholipid/oil ratios resulted in decrease in particles size with little effect on zeta potential and drug encapsulation. Cremophor EL showed the lowest particle sizes and the highest drug encapsulation. Chitosan coating shifted zeta potential towards positive values. Structural analyses showed that luteolin is incorporated into lipid core of nanocapsules. Selected formulations (LNC4 and LNC13) exhibited sustained in vitro release and antioxidant activity. LNC13 (chitosan coated) showed higher flux (0.457 ± 0.113 µg/cm2/h), permeability (45.70 ± 11.66 *10-5 cm2/h) and skin retention (121.66 ± 7.6 µg/cm2 after 24 h) when compared to LNC4 and suspension. It also showed disordered the integrity of the stratum corneum, increased epidermal thickness and relieving most of inflammatory features in animal model. In conclusion, this study proves that lipid nanocapsules could effectively deliver luteolin into skin and then can be established as a potential system in the pharmaceutical and cosmeceutical horizons.

EthoLeciplex: a new tool for effective cutaneous delivery of minoxidil.

This work designates EthoLeciplex, a vesicular system consisting of phospholipid, CTAB, ethanol and water, as an innovative vesicular system for cutaneous/transfollicular minoxidil (MX) delivery. MX-loaded EthoLeciplex was fabricated by one-step fabrication process. Formulations were designed to study the effects of drug/phospholipid ratio, CTAB/phospholipid ratio, and ethanol concentration on vesicular size, PDI, surface charge and EE%. The optimized formulation was characterized by in vitro release, drug/excipient compatibility, ex vivo skin permeability and safety. A size of 83.6 ± 7.3 to 530.3 ± 29.4 nm, PDI of 0.214 ± 0.01 to 0.542 ± 0.08 and zeta potential of +31.6 ± 4.8 to +57.4 ± 12.5 mV were observed. Encapsulation efficiency was obtained in its maximum value (91.9 ± 16.2%) at the lowest drug/phospholipid ratio, median CTAB/phospholipid and the highest ethanol concentration. The optimized formulation was consisted of 0.3 as drug/lipid ratio, 1.25 as CTAB/lipid ratio and 30% ethanol concentration and showed responses' values in agreement with the predicted results. Differential scanning calorimetry studies suggested that EthoLeciplex existed in flexible state with complete incorporation of MX into lipid bilayer. The cumulative amount of MX permeated from EthoLeciplex, conventional liposome and ethanolic solution after 12 h were 36.3 ± 1.5 µg/ml, 21 ± 2.0 µg/ml and 55 ± 4.0 µg/ml respectively. Based on the remaining amount, the amount of MX accumulated in different skin layers can be predicted in descending order as follows; EthoLeciplex > conventional liposome > MX solution. EthoLeciplex produced marked disorder in the stratum corneum integrity and swelling with no features of skin toxicity. This new cationic system is a promising carrier for cutaneous/transfollicular drug delivery.

New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling.

In this study new sulphamethoxazole derivatives (S1-S4, S6-S12, and S14-S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. All new derivatives (S1-S22) were assayed against human carbonic anhydrase (hCAs IX and XII) for their inhibitory activities. hCAs IX and XII were chosen due to the fact that CAIX expression is recognized as a hypoxia marker with a poor prognosis in breast cancer. When compared to Dorzolamide HCl as a standard reference, derivatives S2, S3, S8, S9, and S15 had the most effective inhibition with low IC50 values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds S8, S9 and S15 showed the least inhibitory effect compared to the reference standard, acetazolamide, indicating that their effect in normal cells is the lowest. Cell viability tests for the selected compounds were carried out on MCF7 (normoxia and hypoxia) and on the normal breast cell line (MCF10a) with Staurosporine as a standard. The results showed that compound S15 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound S15 triggered cell cycle arrest and apoptosis in G1/S of MCF7 cancer cells. Finally, molecular docking was performed to point out the possible explanation for the vital structural features and key-interactions exerted by our ligands with hCAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative S15 could be the potential lead for emerging selective cytotoxic compounds directing h CAs IX and XII.

Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats.

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (-) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity.

Impact of highly phospholipid-containing lipid nanocarriers on oral bioavailability and pharmacodynamics performance of genistein.

Oxidative stress is a leading cause of different diseases. Genistein is a valuable bioflavonoid possessing antioxidant and anti-inflammatory activity but unfortunately, it suffers from low aqueous solubility, extremely poor bioavailability and first pass effect when used in its pure state. The aim of this work was to formulate and characterize genistein-loaded highly phospholipid-containing lipid nanocarriers to improve oral bioavailability and pharmacodynamic performance. Lipid nanocarriers were prepared by the emulsification/sonication technique. The influence of phospholipid percentage (1%-10%) on physicochemical properties, drug release and stability was investigated. The particle size, zeta potential and EE% were in ranges from 211.9 ± 21.6 to 342.3 ± 7.9 nm, -11.6 ± 1.7 to -19.4 ± 3.1 mV and 78.5 ± 4.7% to 92.2 ± 1.9%, respectively. Drug release was less predominant in the case of SLN formulations when compared to corresponding NLC formulations. High phospholipid percentage produced less stable formulations in terms of particle size growth, gelation and heterogeneous particle distributions. DSC, FT-IR and XRD tools revealed that genistein has existed in an amorphous form in NLC4. The bioavailability of NLC4 was approximately 2.6-fold greater than that of conventional suspension. Additionally, lipid peroxidation in liver homogenate and histopathological alterations in liver and kidney sections were particularly improved, providing a promising strategy for oral administration of genistein.

Arabinoxylan-Carboxymethylcellulose Composite Films for Antibiotic Delivery to Infected Wounds.

Modern dressings should provide for local delivery of antibiotics and protect the wound from bacterial infection, dehydration and environmental factors to achieve optimal healing. The local delivery of antibiotics can reduce adverse effects and resistance challenges. In this study, we fabricated film dressings composed of arabinoxylan (AX) from Plantago ovata seed husks and carboxymethylcellulose (CMC) by a solvent cast method for the delivery of the antibiotic amikacin (AMK). To determine the suitability of the prepared AX-CMC composite films as wound dressings and drug delivery materials, their physical, chemical, mechanical, morphological, thermal, pharmaceutical, antimicrobial, cytocompatible, and drug delivery properties were investigated. The results demonstrated that the dressings were suitable for delivering the drug at the wound site in a sustained manner and keeping the environment moist for rapid healing. The AMK-loaded AX-CMC films exhibited controlled release of AMK, excellent antibacterial activity, and cytocompatibility. Thus, the AX-CMC composite films appear to be promising bioactive dressing materials for the prevention of wound infections.

Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells.

Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.