Chitosan-loaded piperlongumine nanoparticles and kaempferol enhance the anti-cancer action of doxorubicin in targeting of Ehrlich solid adenocarcinoma: in vivo and in silico modeling study.

Doxorubicin is a chemotherapeutic drug that generates free radical-induced toxicities. Natural agents are used to potentiate or ameliorate the toxicity of chemotherapy. None of the studies investigating whether antioxidants or prooxidants should be used with chemotherapy have addressed their efficacy in the same study. Therefore, the aim of this study was to investigate the potential synergy between doxorubicin and two natural rarely in vivo studied anticancer agents; the antioxidant "Kaempferol" and prooxidant "Piperlongumine" in Ehrlich tumor mice model. 77 albino mice were divided into 11 groups; Ehrlich ascites carcinoma cells were injected intramuscularly to develop solid tumors. After 14 days, intratumoral injections of single or combinations of free or Chitosan nanoparticles loaded with doxorubicin, Piperlongumine, and Kaempferol were performed. Tumor Characterization of nanoparticles was measured, tumors were histopathologically examined and evaluation of expression for cancer-related genes by real-time PCR. In silico molecular docking was performed to uncover potential novel targets for Piperlongumine and Kaempferol. Despite receiving half of the overall dose compared to the free drugs, the combined doxorubicin/ piperlongumine-chitosan nanoparticles treatment was the most efficient in reducing tumor volume; down-regulating Cyclin D1, and BCL2; as well as the Beclin-1, and Cyclophilin A genes modulating growth, apoptosis, autophagy, and metastasis, respectively; up-regulating the Glutathione peroxidase expression as a defense mechanism protecting from oxidative damage. When combined with doxorubicin, Kaempferol and Piperlongumine were effective against Ehrlich solid tumors. However, the combination with the Piperlongumine-loaded chitosan nanoparticles significantly enhanced its anticancer effect compared to the Kaempferol or the same free compounds.

Electrospun polyvinyl alcohol/Withania somnifera extract nanofibers incorporating tadalafil-loaded nanoparticles for diabetic ulcers.

Background: Impaired inflammation and vascularization are common reasons for delayed diabetic wound healing. Nanoparticles (NPs)-in-nanofibers composites can manage diabetic wounds. A multifunctional scaffold was developed based on tadalafil (TDF)-loaded NPs incorporated into polyvinyl alcohol/Withania somnifera extract nanofibers. Materials & methods: TDF-loaded NPs were prepared and fully characterized in terms of their physicochemical properties. Extract of ashwagandha was prepared and a blend composed of TDF-loaded NPs, herbal extract and polyvinyl alcohol was used to prepare the whole composite. Results: The whole composite exhibited improved wound closure in a diabetic rat model in terms of reduced inflammation and enhanced angiogenesis. Conclusion: Results suggest that this multifunctional composite could serve as a promising diabetic wound dressing.

Methotrexate conjugated gold nanoparticles improve rheumatoid vascular dysfunction in rat adjuvant-induced arthritis: gold revival.

Endothelial vasomotor dysfunction and accelerated atherosclerosis encompass the features of rheumatoid vascular dysfunction (RVD), increasing cardiovascular morbidity and mortality among rheumatoid arthritis (RA) patients. Methotrexate, among DMARDs, effectively reduces cardiovascular events, but its non-selectivity together with its pharmacokinetic variability often limit drug adherence and contribute to its potential toxicity. Thus, methotrexate was conjugated to gold nanoparticles (MTX/AuNPs) and its effect on RVD in rats' adjuvant-induced arthritis was evaluated. A comparative study between MTX/AuNPs, free MTX, and AuNPs treatments on joint inflammation, vascular reactivity and architecture, smooth muscle phenotype, systemic inflammation, and atherogenic profile was done. Since MTX/AuNPs effect was superior, it appears that conjugation of MTX to AuNPs demonstrated a synergistic action. MTX immunomodulatory action combined with AuNPs anti-atherogenic potential yielded prompt control of whole features of RVD. These findings highlight the usefulness of nanoparticles-targeted drug-delivery system in refining rheumatoid-induced vascular dysfunction treatment and reviving gold use in RA.

Improving Gamma Ray Shielding Behaviors of Polypropylene Using PbO Nanoparticles: An Experimental Study.

Recently, polymers have entered into many medical and industrial applications. This work aimed to intensively study polypropylene samples (PP) embedded with micro and nanoparticles of PbO for their application in radiation shielding. Samples were prepared by adding 10%, 30%, and 50% by weight of PbO microparticles (mPbO) and adding 10% and 50% PbO nanoparticles (nPbO), in addition to the control sample (pure polypropylene). The morphology of the prepared samples was tested; on the other hand, the shielding efficiency of gamma rays was tested for different sources with different energies. The experimental linear attenuation coefficient (LAC) was determined using a NaI scintillation detector, the experimental results were compared with NIST-XCOM results, and a good agreement was noticed. The LAC was 0.8005 cm-1 for PP-10%nPbO and 0.6283 cm-1 for PP-10%mPbO while was 5.8793 cm-1 for PP-50%nPbO and 3.9268 cm-1 for PP-50%mPbO at 0.060 MeV. The LAC values have been converted to some specific values, such as half value layer (HVL), mean free path (MFP), tenth value layer (TVL), and radiation protection efficiency (RPE) which are useful for discussing the shielding capabilities for gamma-rays. The results of shielding parameters reveal that the PP embedded with nPbO gives better attenuation than its counterpart pp embedded with mPbO at all studied energies.

Experimental Study of Polypropylene with Additives of Bi2O3 Nanoparticles as Radiation-Shielding Materials.

This work aimed to intensively study polypropylene samples (PP) embedded with micro- and nanoparticles of Bi2O3 for their application in radiation shielding. Samples were prepared by adding 10%, 20%, 30%, 40%, and 50% of Bi2O3 microparticles (mBi2O3) by weight, and adding 10% and 50% of Bi2O3 nanoparticles (nBi2O3), in addition to the control sample (pure polypropylene). The morphology of the prepared samples was tested, and also, the shielding efficiency of gamma rays was tested for different sources with different energies. The experimental LAC were determined using a NaI scintillation detector, the experimental results were compared with NIST-XCOM results, and a good agreement was noticed. The LAC values have been used to calculate some specific parameters, such as half value layer (HVL), mean free path (MFP), tenth value layer (TVL), and radiation protection efficiency (RPE), which are useful for discussing the shielding capabilities of gamma rays. The results of the shielding parameters show that the PP embedded with nBi2O3 gives better attenuation than its counterpart, PP embedded with mBi2O3, at all studied energies.

Synthesis, characterisation and enhanced apoptotic effect of gemcitabine-loaded albumin nanoparticles coating with chitosan.

Gemcitabine was loaded in albumin nanoparticles then coated with chitosan. The diameter of GEM-ANPs/CS was 200 ± 4 nm. Gemcitabine was loaded in GEM-ANPs/CS with an efficacy of 75%. The IC50 of GEM-ANPs/CS was found to be 12.98 and 6.08 µg/ml after incubation for 48 and 72 h with MCF-7 cells, respectively. Treatment of MCF-7 cells with IC50 of GEM-ANPS, and GEM-ANPS/CS resulted in membrane damage which led to elevated LDH activity of 4 and 3.4, and increasing GSH level of 4.6 and 9.3, respectively, when compared with untreated cells. DNA fragmentation and up-regulated of caspase-3 and p53 had illustrated the apoptotic effect of MCF-7 treated with GEM-ANPS/CS. The tumour suppressor RRM1 gene expression was down-regulated in MCF-7 cells treated with GEM-ANPS/CS. The modified ANPs coated with chitosan may be used as a promising nanomatrix for gemcitabine delivery and targeting to improve its therapeutic index against MCF-7 cells.

Effect of alginate nanoparticles on the immunogenicity of excretory-secretory antigens against acute toxoplasmosis in murine model.

Efficacy of alginate nanoparticles (Alg-NPs) as vaccine delivery for the excretory-secretory antigens (ESAs) against the virulent strain of Toxoplasma gondii was evaluated. Swiss albino mice were intraperitoneally immunized with three doses of either in vivo and in vitro-prepared ESA vaccines, 20 µg each, at 2-week intervals, then were challenged with 2500 tachyzoites of the RH HXGPRT (-) Toxoplasma gondii strain, four weeks later. Mice mortality, tachyzoite number in both peritoneal fluid and impression smear, and viability, ultrastructural tachyzoite changes, measuring immunological markers, and histopathological changes of both liver and spleen were studied, in comparison to alum adjuvanted ESAs and infected control subgroups. The in vivo-prepared Alg-NPs loaded ESAs vaccinated subgroups induced significant reduction in mice mortality, tachyzoite count in both peritoneal fluid and impression smears and viability. Scanning electron microscopy revealed tachyzoites deformities with multiple irregularities, while transmission electron microscopy showed tachyzoites distortion, disrupted plasma membranes, loss of nuclear integrities, and absence of dense granules with extensive vacuolations. A statistically significant increase in the level of both IFN-γ and anti-Toxoplasma IgG was noted. Histopathological results recorded amelioration of the pathological changes induced by Toxoplasma infection in both liver and spleen, with scanty parasites. Therefore, Alg-NPs proved its effectiveness in enhancing the ESAs antigencity, and recommended to test its potentiality as drugs carrier for anti-Toxoplasma agents to enhance their therapeutic efficacy.

Schistosomiasis mansoni: A new therapeutic target for ubiquinol, a natural inhibitor of neutral magnesium-dependent sphingomyelinase in murine model.

Constituting the host-parasite interface and playing a censorious role in host immune response modulation and parasite survival, tegument represents a crucial target for many antischistosomal drugs. Sphingomyelin forms a stable outer leaflet of tegumental membrane-lipid bilayer. Neutral magnesium -dependent sphingomyelinase (Mg2+-nSMase) is a key enzyme in sphingomyelin breakdown was identified in schistosomes. We investigated the in vivo efficacy of ubiquinol, a natural inhibitor of Mg2+-nSMase, in free and niosomes-encapsulated forms, through five-day and 15-day regimens on the early and late Schistosoma mansoni parasitic stages, respectively, compared to PZQ. Oral administration of 300 mg/kg/day ubiquinol-encapsulated niosomes (U-N) showed significant deterioration of the parasitic growth and development in the term of reduction of lung schistosomula burden (39.12%), adult worm burden (50.81%), hepatic and intestinal tissue-egg counts (80.89% and 75.54%, respectively). PZQ and free ubiquinol regimens reported reductions in lung schistosomula counts (45.36% and 22.90%, respectively) and total worm burdens of 86.28% and 24.58%, respectively. U-N therapy revealed worms de-pairing and remarkable diminution in female worms' perimeters and fecundity. Scanning electron microscope revealed disruption of tegumental ridges with excessive longitudinal corrugation. Transmission electron microscope showed testicular and ovarian parenchymal degeneration, signs of immaturity and cell apoptosis. Indirect immunofluorescence assay approved parasite's tegumental changes. Remarkable reduction of granulomas size with amelioration of hepatic pathology and fibrosis were assumed to be attributed to the anti-inflammatory and anti-oxidant properties of ubiquinol. These findings with the drug safety profile suggest that U-N could be a promising candidate for a new antischistosomal drug development.

Paclitaxel Nanoparticles Induce Apoptosis and Regulate TXR1, CYP3A4 and CYP2C8 in Breast Cancer and Hepatoma Cells.

BACKGROUND AND OBJECTIVE: Although the anticancer potentials of water-insoluble drugs are improved by nanoformulation, other intervening factors may contribute in the drug efficacy. This work was designated to explore the effect of paclitaxel-loaded Poly(Lactic-co-Glycolic Acid) (PLGA) nanoparticles on the viability of cancer cells, the expression of Taxol Resistance gene I (TXR1) and paclitaxel metabolizing genes. METHODS: Paclitaxel loaded PLGA Nanoparticles (PTX-NPs) were prepared, physically characterized and used in the treatment of breast adenocarcinoma cells (MCF-7) and hepatoma cells (HepG2). Cells viability and apoptosis were investigated. In parallel, RNA was isolated, reverse transcribed and used to monitor the expression levels of TXR1, CYP 3A4 and CYP2C8 genes. RESULTS: PTX-NPs were characterized by transmission electron microscopy to be of a nano-size sphere-like shape. FTIR analysis revealed good coupling between PTX and PLGA. The encapsulation efficiency was 99% and the drug release demonstrated a progressive releasing phase followed by slower and sustained releasing phases. Although HepG2 cells demonstrated more resistance to PTX than MCF-7 cells, both cell types were more responsive to PTX-NPS compared to PTX. The IC50 values decreased from 19.3 to 6.7 in breast cancer cells and from 42.5 to 13.1µg/ml in hepatoma cells. The apoptosis was the key mechanism in both cells, where at least 44% of cells underwent apoptosis. The expression of TXR1 decreased when either cells were treated with PTX-NPs, respectively, meanwhile the expressions of CYP3A4 and CYP2C8 were increased. CONCLUSION: Taken together, this in vitro study reports the associations between the enhanced responsiveness of MCF-7 and HepG2 cells to PLGA-loaded paclitaxel nanoparticles and the accompanying decrease in the cells resistance to the PTX and its enhanced metabolism.

Smart Ultrasound-Triggered Doxorubicin-Loaded Nanoliposomes With Improved Therapeutic Response: A Comparative Study.

Doxorubicin (DOX) effectiveness in cancer treatment is hampered by its nonspecific accumulation in organs. Ultrasound (US) is a promising noninvasive targeting approach. Currently, studies focus on developing more DOX-loaded US-triggered formulations with different composition, DOX doses, and US intensities. No studies were emerged to compare and select the most effective approach to endure. The aim of this study is to prepare and comparatively address the therapeutic potential of 2 different US-tunable nanosized liposomes while minimizing DOX dose and US intensity. One of the liposomes is tailored to be responsive for US non-thermal effects (DOX-USLs) and the other is designed to be thermoresponsive (DOX-TSLs). Both systems were compared in terms of cellular uptake, cell viability and apoptosis using HeLa cells as a cancer model. The IC50 of DOX-USLs and DOX-TSLs was 2.5-5 times lower than that of free DOX. IC50 reflected the significant superior cytotoxicity of DOX-TSLs (0.1 µg/mL) over DOX-USLs (0.2 µg/mL). Cellular uptake indicated that DOX-TSLs were inside the nucleus while DOX-USLs were accumulated everywhere in the intracellular space with lower fluorescent intensity inside the nucleus. However, both showed enhanced apoptosis in terms of enhanced caspase-3 activity, reduced glutathione levels and DNA fragmentation when compared to free DOX treatment.

Effects of Silver Nanoparticles on Burn Wound Healing in a Mouse Model.

Healing of injuries caused by exposure to heat has been discussed in many studies, although a few drugs have been shown to produce satisfactory results. In this study, 100 healthy mice randomly allocated into four categories (each = 25 mice) were analyzed. A deep second-degree burn on the back of each mouse was created. The burns were dressed daily with either AgNPs or silver sulfadiazine over 28 days of treatment. Safety evaluation of the AgNP treatment was performed by measuring the deposition rate of silver in the liver, brain, and kidney of treated mice. In the murine burn model, the speed of wound healing and the antibacterial effect of AgNPs were better than those in the silver sulfadiazine group. Burn wounds treated with SSD appeared to display a greater degree of inflammation as notable by the three clinical signs of the inflammatory process such as redness and swelling which appeared to be less after wounds treated with AgNPs. Also, AgNP treatment modified leukocytic infiltration and reduced collagen degeneration in treated mice and enhanced healing processes that were confirmed by morphological and histological investigations. Beside the potential significant effects of AgNPs on reduction of some microorganism counts that routinely isolated from burn wounds included aerobic organisms as Staphylococcus aureus and Escherichia coli when compared to both SSD and control groups. The deposition kinetics of AgNPs revealed lower distribution in the liver, brain, and kidney than that in silver sulfadiazine-treated mice with respect to both SSD and control groups.

Electrospun cellulose acetate nanofiber incorporated with hydroxyapatite for removal of heavy metals.

Due to the negative impact of the heavy metal ions in water, the rejection of these toxic materials is one of the urgent requests for wastewater treatment. This work aims to facile fabrication and characterization of new organic/inorganic hybrid nanofiber membrane composites for removal of Fe (III) and Pb (II) ions using a batch technique. The manufacturing of pure cellulose acetate nanofibers (CA NFs) and its impregnated with hydroxyapatite (CA/HAp) nanocomposite fibers is explored by an electrospinning process. A production process of uniform and bead-free nanofiber is developed by adjusting various electrospinning conditions. The experiments prove that the slight changes in operating parameters may result in significant variations in the fiber morphology. The influence of various adsorption conditions and its effect on the removal efficiency is investigated. High separation efficiency of about 99.7 and 95.46% within 35 and 40 min. for adsorption Pb (II) and Fe (III) ions using hybrid nanofiber composite, respectively are obtained. The adsorption process was found to obey a pseudo-second-order and Freundlich models. The adsorption mechanism on the CA/HAp composite can be established via ion exchange and surface complexation.

Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence.

So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (VA) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to VA and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled VA-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, VA-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.

Bioadhesive Chitosan-Coated Cationic Nanoliposomes With Improved Insulin Encapsulation and Prolonged Oral Hypoglycemic Effect in Diabetic Mice.

Oral administration of insulin is hampered by the lack of carriers that can efficiently achieve high encapsulation, avoid gastric degradation, overcome mucosal barriers, and prolong the hypoglycemic effect. Chitosan (CS)-coated insulin-loaded cationic liposomes have been developed and optimized for improved oral delivery. Liposomes were prepared cationic to improve insulin encapsulation. CS was selected as a mucoadhesive coat to prolong the system's residence and absorption. The performance of CS-coated liposomes compared with uncoated liposomes was examined in vitro, ex vivo, and in vivo in streptozotocin-induced diabetic mice. Free uncoated liposomes showed high positive zeta potential of +58.8 ± 2.2 mV that reduced (+29.9 ± 1.4 mV) after insulin encapsulation, confirming the obtained high entrapment efficiency of 87.5 ± 0.6%. CS-coated liposomes showed nanosize of 439.0 ± 12.3 nm and zeta potential of +60.5 ± 1.9 mV. In vitro insulin release was limited to 18.9 ± 0.35% in simulated gastric fluid, whereas in simulated intestinal fluid, 73.33 ± 0.68% was released after 48 h from CS-coated liposomes. Ex vivo intestinal mucoadhesion showed increased tissue residence of CS-coated liposomes compared with uncoated liposomes. A striking reduction in the glucose level was observed 1 h after oral administration of CS-coated liposomes and maintained up to 8 h (p <0.01 vs. insulin solution or uncoated liposomes) within the normal value 129.29 ± 3.15 mg/dL. In conclusion, CS-coated insulin-loaded cationic liposomes improved loading efficiency with promising prolonged pharmacological effect.

The effect of chitosan nanospheres on the immunogenicity of Toxoplasma lysate vaccine in mice.

Toxoplasmosis, a zoonotic parasitic disease, is a huge challenge for which there is no effective vaccine up till now. In this study, chitosan nanospheres encapsulated with Toxoplasma lysate vaccine was evaluated for its ability to protect mice against both acute and chronic toxoplasmosis models of infection. Results showed that chitosan nanospheres were equally effective to Freund's incomplete adjuvant (FIA) in enhancing the efficacy of Toxoplasma lysate vaccine. The effectiveness was demonstrated by the delayed death of vaccinated mice following challenge either with virulent RH or avirulent Me49 strains, the significant decrease in parasite density in different organs, significant increase in the humoral and cellular immune response (IgG and IFN γ) with a marked reduction of pathological changes in the different organs. However chitosan nanospheres were superior to FIA due to their cost effective preparation and much less necrotic changes induced in the studied organs. The success of chitosan polymer as an alternative to commonly used adjuvants paves the way for the use of other newly developed polymers to be used in the field of vaccine development.