Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice.

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.

Synthesis of Copper Oxide-Based Nanoformulations of Etoricoxib and Montelukast and Their Evaluation through Analgesic, Anti-Inflammatory, Anti-Pyretic, and Acute Toxicity Activities.

Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.

Surface modified multifaceted nanocarriers for oral non-conventional cancer therapy; synthesis and evaluation.

Inflammatory cells orchestrate tumor niche for the proliferating neoplastic cells, leading to neoangiogenesis, lymphangiogenesis, tumor growth and metastasis. Emergence of severe side effects, multiple drug resistance and associated high cost has rendered conventional chemotherapy less effectual. The aim was to develop a multipurpose, less toxic, more potent and cheaper, oral non-conventional anticancer therapeutic. Cyclooxygenase associated with tumor niche inflammation and proliferative neoplastic cells were targeted synergistically, through anti-inflammatory and anti-proliferative effects of model drug, diclofenac sodium and fluorescent silver nanoparticles (AgNPs), respectively. Drug entrapped AgNPs were surface modified with PVA (for controlling particle size, preferred cellular uptake, evading opsonization and improved dispersion). XRD, FTIR, DSC, TGA, LIBS, particle size and surface plasmon resonance analysis confirmed the efficient drug encapsulation and PVA coating with 62% loading efficiency. In-vitro, the formulation exhibited 1st order release kinetics with sustained and maximal release at slightly acidic conditions (pH 4.5) enabling the potential for passive tumor targeting. Also, nanoparticles showed efficient protein denaturation inhibition potential, hemo-compatibility (<0.8%) and potent anti-cancer activity (P < 0.05) against breast cancer cell line (MCF-7). In-vivo, developed nanoparticles improved pharmacokinetics (2.8 fold increased AUC, 6.9 h t1/2, Cmax = 1.6 ±â€¯0.03 µg/ml, Kel = 0.1) and pharmacodynamics manifested by potent anti-inflammatory, analgesic and anti-pyretic effects (P < 0.05) at 20 fold lower doses. LD50 determination revealed a wide therapeutic window. The study showed promise of synthesized nanomaterials as cheaper, less toxic, hemo-compatible, oral and more potent anti-inflammatory and non-conventional fluorescent anti-cancer agents, vanquishing tumor niche inflammation and repressing proliferation of malignant cells.

Macrophage targeting with the novel carbopol-based miltefosine-loaded transfersomal gel for the treatment of cutaneous leishmaniasis: in vitro and in vivo analyses.

OBJECTIVE: The purpose of this study was to develop novel carbopol-based miltefosine-loaded transfersomal gel (HePCTG) for the treatment of cutaneous leishmaniasis (CL) via efficient targeting of leishmania infected macrophages. METHODS: Miltefosine-loaded transfersomes (HePCT) were prepared by ethanol injection method followed by their incorporation into carbopol gel to form HePCTG. The prepared HePCT were assessed for physicochemical properties including mean particle size, polydispersity index, zeta potential, entrapment efficiency, morphology, and deformability. Similarly, HePCTG was evaluated for physiochemical and rheological attributes. The in vitro release, skin permeation, skin irritation, anti-leishmanial activity, and in vivo efficacy in BALB/c mice against infected macrophages were also performed for HePCT. RESULTS: The optimized HePCT displayed a particle size of 168 nm with entrapment efficiency of 92%. HePCTG showed suitable viscosity, pH, and sustained release of the incorporated drug. Furthermore, HePCT and HePCTG demonstrated higher skin permeation than drug solution. The results of macrophage uptake study indicated improved drug intake by passive diffusion. The lower half maximal inhibitory concentration value, selectivity index and higher 50% cytotoxic concentration  value of HePCT compared to that of HePC solution demonstrated the improved anti-leishmanial efficacy and non-toxicity of the formulation. This was further confirmed by the notable reduction in parasite load and lesion size observed in in vivo anti-leishmanial study. CONCLUSION: It can be stated that the formulated HePCTG can effectively be used for the treatment of CL.

Hemostatic strategies for uncontrolled bleeding: A comprehensive update.

Uncontrolled bleeding remains the leading cause of morbidity and mortality across the entire macrocosm. It refers to excessive loss of blood that occurs inside of body, due to unsuccessful platelet plug formation at the injury site. It is not only limited to the battlefield, but remains the second leading cause of death amongst the civilians, as a result of traumatic injury. Startlingly, there are no effective treatments currently available, to cater the issue of internal bleeding, even though early intervention is of utmost significance in minimizing the mortality rates associated with it. The fatal issue of uncontrolled bleeding is ineffectively being dealt with the use of pressure dressings, tourniquet, and surgical procedures. This is not a practical approach in combat arenas or in emergency situations, where the traumatic injury inflicted is deep inside the body, and cannot be addressed externally, by the application of topical dressings. This review focuses on the traditional hemostatic agents that are used to augment the process of hemostasis, such as mineral zeolites, chitosan based products, biologically active agents, anti-fibrinolytics, absorbable agents, and albumin and glutaraldehyde, as well as the micro- and nano-based hemostatic agents such as synthocytes, thromboerythrocytes, thrombosomes, and the synthetic platelets.

Development of bactericidal spinel ferrite nanoparticles with effective biocompatibility for potential wound healing applications.

The current study was devised to explore the antibacterial activity and underlying mechanism of spinel ferrite nanoparticles (NPs) along with their biocompatibility and wound healing potentials. In this regard, nickel ferrite and zinc/nickel ferrite NPs were synthesized via a modified co-precipitation method and were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy Energy-dispersive X-ray spectroscopy (EDX). The biocompatibility of the synthesized NPs with human dermal fibroblast (HDF) and red blood cells (RBCs) was assessed. The biocompatible concentrations of the NPs were used to investigate the antimicrobial activity against various pathogenic Gram-negative and Gram-positive bacteria. The mode of bactericidal action was also explored. In vitro scratch assay was performed to evaluate the wound healing potential of NPs. The SEM-EDX analysis showed that the average particles size of nickel ferrite and zinc/nickel ferrite were 49 and 46 nm, respectively, with appropriate elemental composition and homogenous distribution. The XRD pattern showed all the characteristic diffraction peaks of spinel ferrite NPs, which confirmed the synthesis of the pure phase cubic spinel structure. The biocompatible concentration of nickel ferrite and zinc/nickel ferrite NPs was found to be 250 and 125 µg ml-1, respectively. Both the NPs showed inhibition against all the selected strains in the concentration range of 50 to 1000 µg ml-1. Studies on the underlying antimicrobial mechanism revealed damage to the cell membrane, protein leakage, and intracellular reactive oxygen species production. The in vitro scratch assay confirmed the migration and proliferation of fibroblast with artificial wound shrinkage. This study shows that nickel ferrite and zinc/nickel ferrite NPs could be a strong candidate for antibacterial and wound healing nano-drugs.

Anticancer therapeutics: a brief account on wide refinements.

The flustering rise in cancer incidence along with treatment anomalies has made cancer the second leading cause of death globally. The total annual economic impact of cancer is pronounced and is increasing. Besides the lack of proper curative therapy, treatment associated adverse effects, drug resistance, and tumor relapse are the instigations behind increased morbidity and mortality. Meanwhile, the survival rate has inclined impressively. In the last few decades, cancer treatment has undergone wide refinements aiming towards cancer prevention, complete tumor regression, subsiding treatment adverse effects, improving patient's life standard and avoiding tumor relapse. Chemotherapy has been successfully extended towards natural, cheaper and bioactive anti-inflammatory agents manifesting potent anticancer activity. Antibody-based cancer therapy has become well established as a vital and effective strategy for treating hematological malignancies as well as solid tumors. Individualized immunotherapy is becoming the forefront of cancer treatment enabling personalized, precise and patient's cancer mutanome specific adjustable regimen. The emergence of anti-neoangiogenesis and cancer stem cell targeting techniques have dropped cancer recurrence significantly. Advancements in hyperthermia and photodynamic therapies along with improvements in cancer vaccination have declined death rate and amplified survival rate convincingly.

Pharmaceutical and Biomedical Applications of Green Synthesized Metal and Metal Oxide Nanoparticles.

BACKGROUND: Due to the rapid growth in life threatening diseases such as cancer, diabetes, chronic wound and HIV/AIDS along with rise of side effects of the current treatments, world is now focusing to utilize new treatment options. Currently, the development of green nanotechnology field seems as a potential alternate for diseases diagnosis and treatment by preparation of various sizes and shapes of nanomaterials. OBJECTIVE: This review is to present the explored biological sources in synthesis of nanomaterials particularly metal and metal oxides nanoparticles and critical review of the applications of biosynthesized nanoparticles in pharmaceutical and biomedical fields. METHODS: In this review, the various biological sources including bacteria, fungi, algae and plants used in synthesis of nanomaterials and mechanism involved in preparation are elaborated. In addition, biosynthesized nanomaterials applied as drug delivery system for anticancer, antibiotic, antidiabetic agent and functioned as potential diagnostic, antimicrobial, anticancer and wound healing candidates are comprehensively reviewed. RESULTS: The synthesized metal and metal oxides from green protocol proved to have advantages such as being biocompatible, effective and cheap. Furthermore, the green synthesized metal and metal oxide nanoparticles showed to possess prominent physical, chemical and biological properties that can be efficiently utilized for pharmaceutical and biomedical applications. CONCLUSION: The information gathered in this review will provide a baseline for exploring more potential usage of green synthesized metal and metal oxide nanomaterials for various other applications. However, a concrete understanding of the safety of these nanomaterials is still needed to minimize the potential side effects.

Chitosan encapsulated ZnO nanocomposites: Fabrication, characterization, and functionalization of bio-dental approaches.

Current report is paramount contribution via nanotechnology to the existing remedies of health diseases. The lag in application of capped metallic oxide nanoparticles in restorative dentistry exist which is covered by this promising study. The uncapped and chitosan encapsulated ZnO nanoparticles were fabricated by facile co-precipitation method, and characterized using various biophysical strategies including X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM) and Energy dispersive x-ray (EDX). ZnO nanoparticles and ZnO-Citosan nanoparticles were estimated to be <30 nm and <25 nm in size on respective basis. Significant in vitro antibacterial, antioxidant, cytotoxic and antidiabetic activity of ZnO nanoparticles has been elucidated that is enhanced by capping with chitosan polymer. 90% cytotoxicity against brine shrimps, 69.6% antidiabetic activity against α-amylase, and noteworthy antioxidation power by chitosan decorated ZnO nanoparticles has been effectively illustrated. Furthermore, the effective secondary caries remediation approach has been established by an amalgamation of ZnO nanoparticles and ZnO-Chitosan nanoparticles into dentine bonding agents. A remarkable reduction in Streptococcus mutans and Lactobacillus acidophillus strains has been observed, in-specific boosted by chitosan capped ZnO nanoparticles reinforced dental adhesive discs. Additionally, augmented mechanical properties, greater resistance to water sorption and solubility, notably high release profile, and slight variation of shear bond strength values have been obtained. In short, the prepared nanoparticles reported are detected to be auspicious theranostic agents for combating wide array of human pathogens in healthcare system.

PEG capped methotrexate silver nanoparticles for efficient anticancer activity and biocompatibility.

BACKGROUND: Nanocarriers endow tremendous benefits to the drug delivery systems depending upon the specific properties of either component. These benefits include, increase in the drug blood retention time, reduced efflux, additional toxicity and targeted delivery. Methotrexate (MTX) is clinically used for cancer treatment. Higher dosage of MTX results in hepatic and renal toxicity. In this study methotrexate silver nanoparticles (Ag-MTX) coated with polyethylene glycol (PEG) are synthesized and characterized. Their anticancer activity and biocompatibility is also evaluated. RESULTS: Ag-MTX nanoparticles are synthesized by chemical reduction method. They are characterized by Ultraviolet-Visible Spectroscopy and Fourier Transform Infrared Spectroscopy. Average size of PEG coated Ag-MTX nanoparticles (PEG-Ag-MTX nanoparticles) is 12nm. These particles exhibited improved anticancer activity against MCF-7 cell line. Hemolytic activity of these particles was significantly less than MTX. CONCLUSION: PEG-Ag-MTX nanoparticles are potential nanocarrier of methotrexate which may offer MTX based cancer treatment with reduced side effects. In-vivo investigations should be carried out to explore them in detail.

Synthesis and bioactivities of silver nanoparticles capped with 5-amino-ß-resorcylic acid hydrochloride dihydrate.

BACKGROUND: Conjugated and drug loaded silver nanoparticles are getting an increased attention for various biomedical applications. Nanoconjugates showed significant enhancement in biological activity in comparison to free drug molecules. In this perspective, we report the synthesis of bioactive silver capped with 5-Amino-ß-resorcylic acid hydrochloride dihydrate (AR). The in vitro antimicrobial (antibacterial, antifungal), enzyme inhibition (xanthine oxidase, urease, carbonic anhydrase, α-chymotrypsin, cholinesterase) and antioxidant activities of the developed nanostructures was investigated before and after conjugation to silver metal. RESULTS: The conjugation of AR to silver was confirmed through FTIR, UV-vis and TEM techniques. The amount of AR conjugated with silver was characterized through UV-vis spectroscopy and found to be 9% by weight. The stability of synthesized nanoconjugates against temperature, high salt concentration and pH was found to be good. Nanoconjugates, showed significant synergic enzyme inhibition effect against xanthine and urease enzymes in comparison to standard drugs, pure ligand and silver. CONCLUSIONS: Our synthesized nanoconjugate was found be to efficient selective xanthine and urease inhibitors in comparison to Ag and AR. On a per weight basis, our nanoconjugates required less amount of AR (about 11 times) for inhibition of these enzymes.

Enhanced biocidal activity of Au nanoparticles synthesized in one pot using 2, 4-dihydroxybenzene carbodithioic acid as a reducing and stabilizing agent.

BACKGROUND: The conjugation of gold nanoparticles with biocides such as natural products, oligosaccharides, DNA, proteins has attracted great attention of scientists recently. Gold NPs covered with biologically important molecules showed significant enhancement in biological activity in comparison with the activity of the free biocides. However, these reports are not very systematic and do not allow to draw definitive conclusions. We therefore embarked in a systematic study related to the synthesis and characterization of biocidal activities of Au nanoparticles conjugated to a wide variety of synthetic and natural biomolecules. In this specific report, we investigated the activity of a synthetic biocide, 2-4, Dihydroxybenzene carbodithioic acid (DHT). RESULTS: Au nanoparticles (NP) with a mean size of about 20 nm were synthesized and functionalized in one pot with the help of biocide 2,4-Dihydroxybenzene carbodithioic acid (DHT) to reduce HAuCl4 in aqueous solution. Conjugation of DHT with gold was confirmed by FT-IR and the amount of DHT conjugated to the Au nanoparticles was found to be 7% by weight by measuring the concentration of DHT in the supernatant after centrifugation of the Au NPs. To ascertain the potential for in vivo applications, the stability of the suspensions was investigated as a function of pH, temperature and salt concentration. Antibacterial, antifungal, insecticidal and cytotoxic activities of the Au-DHT conjugates were compared with those of pure DHT and of commercially available biocides. In all cases, the biocidal activity of the Au-DHT conjugates was comparable to that of commercial products and of DHT. CONCLUSIONS: Since the DHT concentration in the Au-DHT conjugates was only about 7%, our results indicate that conjugation to the Au NPs boosts the biocidal activity of DHT by about 14 times. The suspensions were found to be stable for several days at temperatures of up to 100°C, salt concentrations up to 4 mol/L and a pH range of 2-13.

Methyl 2,4-dihy-droxy-5-(4-nitro-benzamido)-benzoate.

In the title compound, C(15)H(12)N(2)O(7), the dihedral angle between the aromatic rings is 4.58 (13)° and the nitro group is rotated from its attached ring by 18.07 (17)°. Intra-molecular N-H⋯O and O-H⋯O hydrogen bonds generate S(5) and S(6) rings, respectively. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, generating [001] C(7) chains. The chains are linked by C-H⋯O inter-actions, forming a three-dimensional network, which incorporates R(2) (2)(7) and R(2) (2)(10) loops.

Methyl 2,4-dihy-droxy-5-(2-methyl-propanamido)-benzoate.

In the title compound, C(12)H(15)NO(5), the dihedral angle between the benzene ring and the C atoms of the terminal isopropyl group is 83.48 (16)°. Intra-molecular N-H⋯O and O-H⋯O hydrogen bonds generate S(5) and S(6) rings, respectively. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, generating C(7) chains propagating in [001]. Weak aromatic π-π stacking [centroid-centroid separation = 3.604 (3) Å] is also observed.

5-Carb-oxy-2,4-dihy-droxy-anilinium chloride dihydrate.

In the title compound, C(7)H(8)NO(4) (+)·Cl(-)·2H(2)O, the organic mol-ecule is almost planar with an r.m.s. deviation of 0.0164 Šfor all non-H atoms. An S(6) ring motif is formed due to an intra-molecular O-H⋯O hydrogen bond. In the crystal, the mol-ecules are linked into a three-dimensional network by N-H⋯Cl, N-H⋯O, O-H⋯Cl and O-H⋯O hydrogen bonds.

5-Carb-oxy-2,4-dihy-droxy-anilinium chloride.

In the title salt, C(7)H(8)NO(4) (+)·Cl(-), the organic group is planar with an r.m.s. deviation of 0.0265 Å. An S(6) ring motif is formed due to an intra-molecular O-H⋯O hydrogen bond. The compound consists of dimers due to inter-molecular O-H⋯O hydrogen bonds with an R(2) (2)(8) ring motif. The dimers are inter-linked through strong N-H⋯Cl and O-H⋯Cl hydrogen bonds, resulting in a three-dimensional polymeric network.