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The aim of this study was the successful utilization of the positively charged nanocrystals (NCs) of Tedizolid Phosphate (TZP) (0.1% w/v) for topical ocular applications. TZP belongs to the 1, 3-oxazolidine-2-one class of antibiotics and has therapeutic potential for the treatment of many drug-resistant bacterial infections, including eye infections caused by MRSA, penicillin-resistant Streptococcus pneumonia and vancomycin-resistant Enterococcus faecium. However, its therapeutic usage is restricted due to its poor aqueous solubility and limited ocular availability. It is a prodrug and gets converted to Tedizolid (TDZ) by phosphatases in vivo. The sterilized NC1 was subjected to antimicrobial testing on Gram-positive bacteria. Ocular irritation and pharmacokinetics were performed in rabbits. Around a 1.29 to 1.53-fold increase in antibacterial activity was noted for NC1 against the B. subtilis, S. pneumonia, S. aureus and MRSA (SA-6538) as compared to the TZP-pure. The NC1-AqS was "practically non-irritating" to rabbit eyes. There was around a 1.67- and 1.43 fold increase in t1/2 (h) and Cmax (ngmL−1) while there were 1.96-, 1.91-, 2.69- and 1.41-times increases in AUC0–24h,AUC0–∞,AUMC0–∞ and MRT0–∞, respectively, which were found by NC1 as compared to TZP-AqS in the ocular pharmacokinetic study. The clearance of TDZ was faster (11.43 mLh−1) from TZP-AqS as compared to NC1 (5.88 mLh−1). Relatively, an extended half-life (t1/2; 4.45 h) of TDZ and the prolonged ocular retention (MRT0–∞; 7.13 h) of NC1 was found, while a shorter half-life (t1/2; 2.66 h) of TDZ and MRT0–∞(t1/2; 5.05 h)was noted for TZP-AqS, respectively. Cationic TZP-NC1 could offer increased transcorneal permeation, which could mimic the improved ocular bioavailability of the drug in vivo. Conclusively, NC1 of TZP was identified as a promising substitute for the ocular delivery of TZP, with better performance as compared to its conventional AqS. [ABSTRACT FROM AUTHOR]

Positively charged NCs of TZP (0.1%, w/v) for ocular use were prepared by the antisolvent precipitation method. TZP is a novel 5-Hydroxymethyl-Oxazolidinone class of antibiotic and is effective against many drug-resistant bacterial infections. Even the phosphate salt of this drug is poorly soluble, therefore the NCs were prepared for its better solubility and ocular availability. P188 was found better stabilizer than PVA for TZP-NCs. Characterization of the NCs including the particle-size, PDI, and ZP by Zeta-sizer, while morphology by SEM indicated that the preparation technique was successful to get the optimal sized (151.6 nm) TZP-NCs with good crystalline morphology. Mannitol (1%, w/v) prevented the crystal growth and provided good stabilization to NC1 during freeze-drying. FTIR spectroscopy confirmed the nano-crystallization did not alter the basic molecular structure of TZP. DSC and XRD studies indicated the reduced crystallinity of TZP-NC1, which potentiated its solubility. An increased solubility of TZP-NC1 (25.9 µgmL−1) as compared to pure TZP (18.4 µgmL−1) in STF with SLS. Addition of stearylamine (0.2%, w/v) and BKC (0.01%, w/v) have provided cationic (+29.4 mV) TZP-NCs. Redispersion of freeze-dried NCs in dextrose (5%, w/v) resulted in a clear transparent aqueous suspension of NC1 with osmolarity (298 mOsm·L−1) and viscosity (21.1 cps at 35 °C). Mannitol (cryoprotectant) during freeze-drying could also provide isotonicity to the nano-suspension at redispersion in dextrose solution. In vitro release in STF with SLS has shown relatively higher (78.8%) release of TZP from NC1 as compared to the conventional TZP-AqS (43.4%) at 12 h. TZP-NC1 was physically and chemically stable at three temperatures for 180 days. The above findings suggested that TZP-NC1 would be a promising alternative for ocular delivery of TZP with relatively improved performance. [ABSTRACT FROM AUTHOR]

Low aqueous solubility and membrane permeability of some drugs are considered major limitations for their use in clinical practice. Polymeric micelles are one of the potential nano-drug delivery systems that were found to ameliorate the low aqueous solubility of hydrophobic drugs. The main objective of this study was to develop and characterize a novel copolymer based on poly (ethylene glycol) stearate (Myrj™)-block-poly(ε-caprolactone) (Myrj-b-PCL) and evaluate its potential as a nanosystem for ocular delivery of cyclosporine A (CyA). Myrj-b-PCL copolymer with various PCL/Myrj ratios were synthesized via ring-opening bulk polymerization of ε-caprolactone using Myrj (Myrj S40 or Myrj S100), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. The co-solvent evaporation method was used to prepare CyA-loaded Myrj-b-PCL micelles. The prepared micelles were characterized for their size, polydispersity, and CMC using the dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Transmission electron microscopy (TEM) images of the prepared micelles showed spherical shapes with diameters in the nano range (<200 nm). Ex vivo corneal permeation study showed sustained release of CyA from the developed Myrj S100-b-PCL micelles. In vivo ocular irritation study (Draize test) showed that CyA-loaded Myrj S100-b-PCL88 was well tolerated in the rabbit eye. Our results point to a great potential of Myrj S100-b-PCL as an ocular drug delivery system. [ABSTRACT FROM AUTHOR]

A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release of Indomethacin (IND). PLGA-NPs were prepared by the single-emulsion solvent evaporation technique using dichloromethane (DCM)/chloroform as the organic phase with Polyvinyl-alcohol (PVA)/Polyvinylpyrrolidone (PVP) as stabilizers to encapsulate IND. The effects of different proportions of PVA/PVP with DCM/chloroform on the physiochemical properties (particle size, the polydispersity index, the zeta potential by Malvern Zetasizer and morphology by SEM) of the NPs were investigated. DSC was used to check the physical state, the possible complexation of PLGA with stabilizer(s) and the crystallinity of the encapsulated drug. Stabilizers at all concentrations produced spherical, regular-shaped, smooth-surfaced discrete NPs. Average size of 273.2–563.9 nm was obtained when PVA (stabilizer) with DCM, whereas it ranged from 317.6 to 588.1 nm with chloroform. The particle size was 273.2–563.9 nm when PVP was the stabilizer with DCM, while it was 381.4–466.6 nm with chloroform. The zeta potentials of PVA-stabilized NPs were low and negative (−0.62 mV) while they were comparatively higher and positive for PVP-stabilized NPs (+17.73 mV). Finally, drug-loaded optimal NPs were composed of PLGA (40 mg) and IND (4 mg) in 1 mL DCM/chloroform with PVA/PVP (1–3%), which resulted in sufficient encapsulation (54.94–74.86%) and drug loading (4.99–6.81%). No endothermic peak of PVA/PVP appeared in the optimized formulation, which indicated the amorphous state of IND in the core of the PLGA-NPs. The in vitro release study indicated a sustained release of IND (32.83–52.16%) from the PLGA-NPs till 72 h and primarily followed the Higuchi matrix release kinetics followed by Korsmeyer–Peppas models. The cell proliferation assay clearly established that the organic solvents used to prepare PLGA-NPs had evaporated. The PLGA-NPs did not show any particular toxicity in the HepG2 cells within the dose range of IND (250–500 µg/mL) and at an equivalent concentration of PLGA-NPs (3571.4–7142.7 µg/mL). The cytotoxicity of the hepatotoxic drug (IND) was reduced by its encapsulation into PLGA-NPs. The outcomes of this investigation could be implemented to prepare PLGA-NPs of acceptable properties for the encapsulation of low/high molecular weight drugs. It would be useful for further in vitro and in vivo applications to use this delivery system. [ABSTRACT FROM AUTHOR]

This study investigates the development of topically applied non-invasive chitosan-nanoparticles (CSNPs) for ocular delivery of tedizolid phosphate (TZP) for the treatment of MRSA-related ocular and orbital infections. An ionic-gelation method was used to prepare TZP-encapsulated CSNPs using tripolyphosphate-sodium (TPP) as cross-linker. Particle characterization was performed by the DLS technique (Zeta-Sizer), structural morphology was observed by SEM. The drug encapsulation and loading were determined by the indirect method. In-vitro release was conducted through dialysis bags in simulated tear fluid (pH 7) with 0.25% Tween-80. Physicochemical characterizations were performed for ocular suitability of CSNPS. An antimicrobial assay was conducted on different strains of Gram-positive bacteria. Eye-irritation from CSNPs was checked in rabbits. Transcorneal flux and apparent permeability of TZP from CSNPs was estimated through excised rabbit cornea. Ionic interaction between the anionic and cationic functional groups of TPP and CS, respectively, resulted in the formation of CSNPs at varying weight ratios of CS/TPP with magnetic stirring (700 rpm) for 4 h. The CS/TPP weight ratio of 3.11:1 with 10 mg of TZP resulted in optimal-sized CSNPs (129.13 nm) with high encapsulation (82%) and better drug loading (7%). Release profiles indicated 82% of the drug was released from the TZP aqueous suspension (TZP-AqS) within 1 h, while it took 12 h from F2 to release 78% of the drug. Sustained release of TZP from F2 was confirmed by applying different release kinetics models. Linearity in the profile (suggested by Higuchi's model) indicated the sustained release property CSNPs. F2 has shown significantly increased (p < 0.05) antibacterial activity against some Gram-positive strains including one MRSA strain (SA-6538). F2 exhibited a 2.4-fold increased transcorneal flux and apparent permeation of TZP as compared to TZP-AqS, indicating the better corneal retention. No sign or symptoms of discomfort in the rabbits' eyes were noted during the irritation test with F2 and blank CSNPs, indicating the non-irritant property of the TZP-CSNPs. Thus, the TZP-loaded CSNPs have strong potential for topical use in the treatment of ocular MRSA infections and related inflammatory conditions. [ABSTRACT FROM AUTHOR]

Magnetic particle imaging is an emerging tomographic method used for evaluation of the spatial distribution of iron‐oxide nanoparticles. In this work, the effect of the polymer coating on the response of particles was studied. Particles with covalently crosslinked coating showed improved signal and image resolution. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the ability of PLGA nanoparticles (NPs) to reduce the tacrolimus (TAC)-associated nephrotoxicity following multiple dose administration. The mean diameter of prepared NPs was in the range of 227 to 263 nm with an 8.32% drug loading (w/w). Moreover, in vitro release profile of TAC-loaded NPs showed a sustained release of the drug with only less than 30% release within 12 days. Flow cytometry as well as fluorescence microscopy results confirmed the uptake of FITC-labelled PLGA NPs by dendritic cells. The ex vivo study showed that TAC-loaded NPs caused a significant suppression of the proliferation of CD4+ and CD8+ cells, which was comparable to the control formulation (Prograf). In vivo immunosuppressive activity as well as the kidney function were assessed following drug administration to mice. The animals received TAC subcutaneously at a daily dose of 1 mg/kg for 30 days delivered as the control formulation (Prograf) or TAC-loaded NPs. The results revealed significantly lower drug-associated toxicity with an activity comparable to Prograf for TAC-loaded PLGA NPs. These findings show a potential for PLGA NPs in reducing the nephrotoxicity of TAC while preserving the immunosuppressive activity. [ABSTRACT FROM AUTHOR]

Gemfibrozil (GEM) is cholesterol-lowering agent which is being proposed as poorly water soluble drug (PWSD). Temperature based solubility values of GEM are not yet available in literature or any pharmacopoeia/monograph. Hence, the present studies were carried out to determine the solubility of PWSD GEM (as mole fraction) in various pharmaceutically used solvents such as water (H2O), methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), dimethyl sulfoxide (DMSO) and Transcutol® (THP) at the temperatures ranging from T = 298.2 K–318.2 K under atmospheric pressure P = 0.1 MPa. Equilibrium/experimental solubilities of GEM were recorded by applying a saturation shake flask methodology and regressed using 'van't Hoff and Apelblat models'. Hansen solubility parameters for GEM and various pharmaceutically used solvents were estimated using HSPiP software. The solid states of GEM (both in pure and equilibrated states) were studied by 'Differential Scanning Calorimetry' which confirmed no transformation of GEM after equilibrium. Experimental solubilities of GEM in mole fraction were observed maximum in THP (1.81 × 10−1) followed by DMSO, PEG-400, EA, 1-BuOH, 2-BuOH, IPA, EtOH, PG, MeOH, EG and H2O (3.24 × 10−6) at T = 318.2 K and similar tendencies were also recorded at T = 298.2 K, T = 303.2 K, T = 308.2 K and T = 313.2 K. 'Apparent thermodynamic analysis' on experimental solubilities furnished 'endothermic and entropy-driven dissolution' of GEM in each pharmaceutically used solvent. [ABSTRACT FROM AUTHOR]

Background: The choice of lipid excipients and their origin are crucial determinant factors in the design of self-nanoemulsifying drug delivery system (SNEDDS). Aim: To investigate the aspects of alternative excipients which can influence the development of efficient SNEDDS and determine the fate of fenofibrate in aqueous media. Methods: SNEDDS of two groups (a and b) were developed using Cremercoor MCT/Capmul MCM and Kollisolv MCT/Imwitor 742 blended oils and water soluble surfactants (to improve lipid polarity) for the model anti-cholesterol drug fenofibrate. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEDDS. Further SNEDDS optimizations were done on the basis of maximum drug loading by equilibrium solubility studies and maximum solubilized drug upon aqueous dispersion by dynamic dispersion studies. In vitro lipolysis was examined under simulated Fed and Fasted conditions. Intestinal permeability study of the optimal SNEDDS formulation was compared with the raw fenofibrate dispersion using non- everted "intestinal sac technique." Results: Initial characterization and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 (group b) containing formulations generated highly efficient SNEDDS as they are stable and produced lower nanodroplets with higher drug loading (group b) as compared to mixed glycerides of Cremercoor MCT/Capmul MCM (group a). In vitro dispersion and digestion studies confirmed that SNEDDS of group b (polar mixed glycerides) can retain high amount of drug (99% drug in solution for more than 24 h time) in dispersion media and have high recovery after digestion. The results from the permeability assessment confirmed that fenofibrate had 4.3-fold increase with F3b SNEDDS compared with the control. Conclusion: SNEDDS formulations containing alternative excipients (Kollisolv MCT/Imwitor 742 blend) could be a potential oral pharmaceutical product in taking anti-hyperlipidaemic agent fenofibrate to the systemic circulation as solubilized form. [ABSTRACT FROM AUTHOR]

Background: New approaches for the prevention of colon cancer perseveres an essential necessity. Though, resistance to existing chemo-preventive drugs is moderately predominant in colon carcinogenesis. Taxifolin (dihydroquercetin) is a flavononol, have shown virile biological activities against few cancers. The current study was designed to investigate and equate antitumor activity of Taxifolin (TAX) in colorectal cancer cell lines and in HCT116 xenograft model in a comprehensive approach.Methods: Two human colorectal cancer cell lines HCT116 and HT29, were used. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide (MMT) protocol was performed to elucidate the impact of TAX and β- catenin inhibitor (FH535) on the viability of HCT116 and HT29 cell lines. Apoptosis /cell cycle assay was performed. Data interpretation was done with a FACScan (Becton Dickinson, NJ). About 1 × 104 cells per sample were harvested. Histograms of DNA were analyzed with ModiFitLT software (verity Software House, ME, USA). Western blotting and RT-PCR were performed for protein and gene expression respectively in in vitro and in vivo.Results: We found that TAX induced cytotoxicity in colorectal cells in a dose-dependent manner and time dependent approach. Further, our data validated that administration of TAX to human colorectal cancer HCT116 and HT29 cells resulted in cell growth arrest, variation in molecules controlling cell cycle operative in the G2 phase of the cell cycle and apoptosis in a concentration dependent approach. Further our results concluded that TAX administration decreases expression of β-catenin gene, AKT gene and Survivin gene and protein expression in in vitro and in vivo.Conclusion: Our findings proposed that targeting β-catenin gene may encourage the alterations of cell cycle and cell cycle regulators. Wnt/β-catenin signaling pathway possibly takes part in the genesis and progression of colorectal cancer cells through regulating cell cycle and the expression of cell cycle regulators. [ABSTRACT FROM AUTHOR]

Supramolecular self-assembly of histidine-capped-dialkoxy-anthracene (HDA) results in the formation of light-responsive nanostructures. Single-crystal X-ray diffraction analysis of HDA shows two types of hydrogen bonding. The first hydrogen bond is established between the imidazole moieties while the second involves the oxygen atom of one amide group and the hydrogen atom of a second amide group. When protonated in acidic aqueous media, HDA successfully complexes siRNA yielding spherical nanostructures. This biocompatible platform controllably delivers siRNA with high efficacy upon visible-light irradiation leading up to 90% of gene silencing in live cells. [ABSTRACT FROM AUTHOR]

The successful ophthalmic delivery system is reliant on the diminution in the precorneal loss of drugs by increasing the corneal contact time and increasing the transcorneal permeability, which may enhance the bioavailability of drug to the eyes. The objective of this investigation was to develop and evaluate the potential of microemulsions of gatifloxacin with respect to the conventional eye drops of gatifloxacin. Oil-in-water microemulsions were prepared with different concentrations of oil, surfactant and co-surfactant using aqueous titration method. All formulations showed circular shape droplets, displayed an average droplet size ranged between 51 and 74 nm and absolute zeta potential values ranged from 15 to 24 mV, with optimum physicochemical characteristics suitable for eye. The optimized microemulsion possessed good stability, showed greater adherence to corneal surface and good permeation of gatifloxacin in the anterior chamber of the eye, resulting in a twofold increase in gatifloxacin concentration than the conventional dosage form. Hence, the optimized microemulsions showed increased intraocular penetration and enhance ocular bioavailability of gatifloxacin. [ABSTRACT FROM AUTHOR]

This study aims to improve gatifloxacin bioavailability to the eye using solid-lipid nanoparticles (SLN). Cationic SLNs were prepared by o/w-microemulsion method using stearylamine. The generated formulations were optimized by three-factor, three-level Box-Behnken statistical design. The independent variables were the lipidmix concentration ( X1), poloxamers-188 ( X2), and sodium-taurocholate ( X3), while the dependent variables were drug release ( Y1), encapsulation efficiency (EE) ( Y2), and particle size ( Y3) with applied constraints of maximizing drug release and EE and minimizing particle size. Response surface plots were drawn, statistical validity of the polynomials was established, optimized formulations were selected by feasibility and grid search, and the optimization process was validated. Particle size, polydispersity index, and zeta-potentials were measured by photon correlation spectroscopy. Particle's morphology was evaluated by transmission electron microscopy. Differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WXRD) studies were performed to characterize state of drug and lipid modification. SLN size was (250-305 nm) and zeta-potential (29-36 mV) after 3-month storage. Entrapment efficiencies were 46.58 and 78.55%, and loading efficiencies were 29.60 and 20.70 for SLN-C and SLN-D, respectively. DSC and WXRD analyses showed low-crystalline SLN and amorphous drug dispersion in SLN. In vitro release data were fitted to release kinetics equations, where the release pattern was found to follow Korsmeyer-Peppas model. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. [ABSTRACT FROM AUTHOR]

This study describes corneal permeation of gatifloxacin from solid lipid nanoparticle (SLN) through the cornea and its effect on corneal hydration level. The aqueous humor levels of gatifloxacin after single topical instillation in Gate® Eyedrops and positively charged SLN-C were determined. A 3.37-fold increase in the relative bioavailability was observed with the SLN-C (AUC0→∞ 2.192 μg mL−1 h) (AUC, area under the curve) as compared to Gate® Eyedrops (AUC0→∞ 0.651 μg mL−1 h). The t1/2 of drug in SLN-C exhibited a 2.34-fold higher than Gate® Eyedrops seem to be significantly increased ( p > 0.05), Cmax of gatifloxacin from SLN-C showed 1.09-fold higher concentration as compared to Gate® Eyedrops. The results suggested that SLNs could enhance ocular bioavailability of gatifloxacin and prolong its residence time in the eyes. Moreover, no signs of ocular irritation were seen with the SLN formulations, indicating their relative safety compared to the marketed drops. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is among the major mechanisms leading to failure in chemotherapy of cancer patients. The ATP-binding cassette proteins are major contributors to MDR, involved in the active efflux of xenobiotics out of cancer cells. Among them, P-glycoprotein (P-gp) is the most dominant protein involved in the efflux of drugs. For more than 30 years, scientists have searched for the ideal P-gp inhibitor to modulate drug resistance activity of P-gp. This inhibitor should be tissue and cell specific with side effects on other tissues, must not provoke immune responses from the host, should provide sustained inhibition, and must be synthesized readily with low cost. Chemical P-gp inhibitors tested to date, have shown nonspecific toxic effects limiting their clinical applications. Sequence-specific P-gp gene silencing by RNA interference (RNAi) may provide a more effective approach for downregulation of specific protein targets due to high specificity, limited toxicity and immunogenicity, and relative ease in synthesis. RNAi can be implemented by delivery of synthetic small interfering RNAs (siRNAs) or by gene expression of short hairpin RNAs using gene expressing vectors. Specific delivery systems and expression vectors have been designed for this purpose and many researchers have explored their effectiveness for P-gp downregulation. In this report, we review the efficiency of various methods for siRNA delivery and transfection for P-gp downregulation in cancer cells for MDR reversal. Novel ideas and observations by different research groups were discussed for future improvement in this essential field. © 2011 Wiley Periodicals, Inc. Med Res Rev [ABSTRACT FROM AUTHOR]

One scenario by which tumors escape immune recognition is the constitutive activation of signal transducer and activator of transcription 3 (STAT3). This transcription factor mediates the production of tumor-derived factors that negatively influence target immune cells, such as dendritic cells, and polarize them toward immune-tolerance also through the induction of STAT3 activation. In the current study, the effect of p-STAT3-positive murine colon carcinoma cell line (CT26) on bone marrow-derived DCs was examined. The results showed a remarkable increase in p-STAT3 in dendritic cells (DCs) only after CT26-CM incubation. The induction of p-STAT3 in CT26-CM exposed DCs was attributed at least in part to the high levels of interleukin-6 secreted by CT26 in culture. This was also accompanied by a significant reduction in the response to the immunostimulatory adjuvant lipopolysaccharide by lowering the expression of co-stimulatory molecules CD86 and CD40. Taken together, the results suggest an inhibitory effect of CT26 colon carcinoma on DC maturation through induction of STAT3 phosphorylation. Therefore, tumor-induced p-STAT3 in DCs can be seen as a promising target for colon cancer immunotherapy. [ABSTRACT FROM AUTHOR]

In this study, 5-fluorouracil (5-FU)-loaded pollens of Phoenix dactylifera and their coating with ERS was done and evaluated for the colon-targeted delivery of 5-FU to treat colon cancer. Sporopollenin exine microcapsules (SEMC) from the pollens of Phoenix dactylifera were extracted by the reflux method and 5-FU into SEMC was encapsulated by the vacuum-assisted loading method. 5-FU loaded SEMC was coated with Eudragit® RS-100 (ERS) by the organic solvent-evaporation technique under vacuum to avoid the discharge of 5-FU in the stomach and small intestine. Morphological and physicochemical characterization of drug-loaded SEMC (coated/uncoated) was performed by scanning electron microscopy (SEM), FTIR, XRD, and DSC. The encapsulation and drug loading were determined by the direct method, and an in vitro release study was performed in simulated gastric and intestinal fluids (SGF/SIF). The colon-specific delivery of 5-FU from the SEMC was assessed in terms of pharmacokinetics and gastrointestinal tract distribution after oral administration in rats. The successful encapsulation and loading of 5-FU into SEMC by a vacuum-assisted loading technique and its coating with ERS by a solvent-evaporation technique were achieved. SEM images of uncoated SEMC have shown porous structures, and coating with ERS reserved their morphology with a smooth surface and discrete microstructures and the 5% w/v ERS acetone solution. ERS-coated SEMC sustained the release of 5-FU until 24 h in SIF, while it was up to 12 h only from uncoated SEMC. The maximum plasma concentration (Cmax) of 5-FU from uncoated SEMC was 102.82 μg/mL after 1 h, indicating a rapid release of 5-FU in the upper gastrointestinal tract. This concentration decreased quickly with a half-life of 4 h, AUC0-t was 264.1 μg/mL.h, and MRT0-inf was 5.2 h. The Cmax of 5-FU from ERS-coated SEMC was 19.47 μg/mL at 16 h. The Cmax of 5-FU in small intestines was 406.2 μg/g at 1 h from uncoated SEMC and 1271.5 μg/g at 12 h from coated SEMC. Conclusively, a 249.9-fold higher relative bioavailability of 5-FU was achieved with the ERS-coated SEMC in colon tissues than that from uncoated SEMC. [ABSTRACT FROM AUTHOR]

The conventional physical and chemical synthetic methods for the preparation of metal nanoparticles have disadvantages as they use expensive equipment and hazardous chemicals which limit their applications for biomedical purposes, and are not environment friendly. However, for the synthesis of biocompatible nanomaterials, plant-based techniques are eco-friendly and easy to handle. Herein a simple, single-step biosynthesis of gold nanoparticles using aqueous extracts of Nigella sativa (NSE) and Zingiber officinale (GE) as a reducing and capping agent has been demonstrated. The formation of gold nanoparticles (Au NPs) was confirmed by X-ray diffraction, UV-Vis, and EDS spectroscopies. Spectroscopic and chromatographic analysis of GE and NSE revealed the presence of bioactive phytochemical constituents, such as gingerol, thymoquinone, etc., which successfully conjugated the surface of resulting Au NPs. TEM analysis indicated the formation of smaller-sized, less-aggregated, spherical-shaped Au NPs both in the case of GE (~9 nm) and NSE (~11 nm). To study the effect of the concentration of the extracts on the quality of resulting NPs and their anticancer properties, three different samples of Au NPs were prepared from each extract by varying the concentration of extracts while keeping the amount of precursor constant. In both cases, high-quality, spherical-shaped NPs were obtained, only at a high concentration of the extract, whereas at lower concentrations, larger-sized, irregular-shaped NPs were formed. Furthermore, the as-prepared Au NPs were evaluated for the anticancer properties against two different cell lines including MDA-MB-231 (breast cancer) and HCT 116 (colorectal cancer) cell lines. GE-conjugated Au NPs obtained by using a high concentration of the extract demonstrated superior anticancer properties when compared to NSE-conjugated counterparts. [ABSTRACT FROM AUTHOR]

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1–5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS2000-b-PCL4000, TPGS3500-b-PCL7000, and TPGS5000-b-PCL15000 micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS5000-b-PCL15000. Of the abovementioned micellar formulations, TPGS5000-b-PCL15000 showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS5000-b-PCL15000 micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX. [ABSTRACT FROM AUTHOR]

Applications of chemical synthetic methods for the preparation of metal nanoparticles involve toxic reagents, which are hazardous to both humans and the environment. On the other hand, ecofriendly plant-based techniques offer rapid, non-toxic, and suitable alternatives to the traditional methods. Herein, we report an eco-friendly method for the preparation of silver nanoparticles (Ag NPs) using two different aqueous extracts of Zingiber officinale (ginger) and Nigella sativa L. seeds (black cumin). Successful preparation of Ag NPs was confirmed by X-ray diffraction, ultraviolet–visible (UV-Vis) spectroscopy, and energy dispersive spectroscopy (EDX). Transmission electron microscopy (TEM) analysis revealed that Nigella sativa L. seed extract (NSE) produced a smaller size of NPs (~8 nm), whereas the ginger extract (GE) led to the formation of slightly larger Ag NPs (~12 nm). In addition, to study the effect of concentration of the extract on the quality of resulting NPs, two different samples were prepared from each extract by increasing the concentrations of the extracts while using a fixed amount of precursor (AgNO3). In both cases, a high concentration of extract delivered less agglomerated and smaller-sized Ag NPs. Furthermore, the antibacterial properties of as-prepared Ag NPs were tested against different bacterial strains. Notably, despite the slightly better quality of Ag NPs obtained from NSE (NSE-Ag), NPs prepared by using GE (GE-Ag) demonstrated superior antibacterial properties. In case of the plant-extract-based synthesis of nanoparticles, it is widely reported that during the preparation, the residual phytomolecules remain on the surface of resulting NPs as stabilizing agents. Therefore, in this case, the high antibacterial properties of GE-Ag can be attributed to the contributing or synergetic effect of residual phytomolecules of GE extract on the surface of Ag NPs, since the aqueous extract of GE has been known to possess higher intrinsic bactericidal properties when compared to the aqueous NSE extract. [ABSTRACT FROM AUTHOR]

Melanoma remains the most lethal form of skin cancer and most challenging to treat despite advances in the oncology field. Our work describes the utilization of nanotechnology to target melanoma locally in an attempt to provide an advanced and efficient quality of therapy. Amino-functionalized mesoporous silica nanoparticles (MSN-NH2) were developed in situ through the utilization of anionic surfactant and different volumes of 3-aminopropyltriethoxysilane (APTES) as a co-structure directing agent (CSDA). Prepared particles were characterized for their morphology, particles size, 5-flurouracol (5-FU) and dexamethasone (DEX) loading capacity and release, skin penetration, and cytotoxicity in vitro in HT-144 melanoma cells. Results of transmission electron microscopy (TEM) and nitrogen adsorption–desorption isotherm showed that using different volumes of APTES during the functionalization process had an impact on the internal and external morphology of the particles, as well as particle size. However, changing the volume of APTES did not affect the diameter of formed mesochannels, which was about 4 nm. MSN-NH2 showed a relatively high loading capacity of 5-FU (12.6 ± 5.5) and DEX (44.72 ± 4.21) when using drug: MSN-NH2 ratios of 5:1 for both drugs. The release profile showed that around 83% of 5-FU and 21% of DEX were released over 48 h in pH 7.4. The skin permeability study revealed that enhancement ratio of 5-Fu and DEX using MSN-NH2 were 4.67 and 5.68, respectively, relative to their free drugs counterparts. In addition, the accumulation of drugs in skin layers where melanoma cells usually reside were enhanced approximately 10 times with 5-FU and 5 times with DEX when delivering drugs using MSN-NH2 compared to control. MSN-NH2 alone was nontoxic to melanoma cells when incubated for 48 h in the range of 0 to 468 µg/mL. The combination of 5-FU MSN-NH2 and DEX MSN-NH2 showed significant increase in toxicity compared to their free dug counterparts and exhibited a synergetic effect as well as the ability to circumvent DEX induced 5-FU resistance in melanoma cells. [ABSTRACT FROM AUTHOR]

Barium titanate (BaTiO3) nanoparticles (BT NPs) have shown exceptional characteristics such as high dielectric constant and suitable ferro-, piezo-, and pyro-electric properties. Thus, BT NPs have shown potential to be applied in various fields including electro-optical devices and biomedicine. However, very limited knowledge is available on the interaction of BT NPs with human cells. This work was planned to study the interaction of BT NPs with human lung carcinoma (A549) cells. Results showed that BT NPs decreased cell viability in a dose- and time-dependent manner. Depletion of mitochondrial membrane potential and induction of caspase-3 and -9 enzyme activity were also observed following BT NP exposure. BT NPs further induced oxidative stress indicated by induction of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Moreover, BT NP-induced cytotoxicity and oxidative stress were effectively abrogated by N-acetyl-cysteine (an ROS scavenger), suggesting that BT NP-induced cytotoxicity was mediated through oxidative stress. Intriguingly, the underlying mechanism of cytotoxicity of BT NPs was similar to the mode of action of ZnO NPs. At the end, we found that BT NPs did not affect the non-cancerous human lung fibroblasts (IMR-90). Altogether, BT NPs selectively induced cytotoxicity in A549 cells via oxidative stress. This work warrants further research on selective cytotoxicity mechanisms of BT NPs in different types of cancer cells and their normal counterparts. [ABSTRACT FROM AUTHOR]

We present the evaluation of a sulfoxide-based polymer (poly(propylene sulfoxide), PPSO) as a potential 'stealth' macromolecule, and at the same time as a pharmacologically active (anti-inflammatory/anti-oxidant) material. The combination of these two concepts may at first seem peculiar since the gold standard polymer in biomaterials and drug delivery, poly(ethylene glycol) (PEG), is 'stealth' due to its chemical and biological inertness, which makes it hardly biologically active. Polysulfoxides, on the contrary, may couple a substantial inertness towards biomolecules under homeostatic conditions, with the possibility to scavenge reactive oxygen species (ROS) associated to inflammation. Polysulfoxides, therefore, are rather uniquely, 'active' 'stealth' polymers. Here, we describe the synthesis of PPSO through controlled oxidation of poly(propylene sulfide) (PPS), which on its turn was obtained via anionic ring-opening polymerization. In vitro, PPSO was characterized by a low toxicity (IC50 ~7 mg/mL at 24 h on human dermal fibroblasts) and a level of complement activation (in human plasma) and macrophage uptake slightly lower than PEG of a similar size. Importantly, and differently from PEG, on LPS-activated macrophages, PPSO showed a strong and dose-dependent ROS (hydrogen peroxide and hypochlorite)-scavenging activity, which resulted in a corresponding reduction of cytokine production. [ABSTRACT FROM AUTHOR]