Thermoelectric properties of armchair phosphorene nanoribbons in the presence of vacancy-induced impurity band.

Armchair phosphorene nanoribbons (APNRs) are known to be semiconductors with an indirect bandgap. Here, we propose to introduce new states in the gap of APNRs by creating a periodic structure of vacancies (antidots). Based on the tight-binding model, we show that a periodic array of vacancies or nanopores leads to the formation of an impurity band inside the gap region. We first present an analytical expression for the dispersion relation of an impurity band induced by hybridization of bound states associated with each single vacancy defect. Then, we increase the size of vacancy defects to include a bunch of atoms and theoretically investigate the effect of nanopores size and their spacing on electronic band structure, carrier transmission function, and thermoelectric properties. Our analysis of the power generation rate and thermoelectric efficiency of these structures reveals that an ANPR can be used as a superb thermoelectric power generation module.

Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel.

Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of -7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.

Synthesis, biological evaluation and preclinical study of a novel 99mTc-peptide: A targeting probe of amyloid-ß plaques as a possible diagnostic agent for Alzheimer's disease.

With respect to the main role of amyloid-ß (Aß) plaques as one of the pathological hallmarks in the brain of Alzheimer's patients, the development of new imaging probes for targeted detection of Aß plaques has attracted considerable interests. In this study, a novel cyclopentadienyl tricarbonyl Technetium-99 m (99mTc) agent with peptide scaffold, 99mTc-Cp-GABA-D-(FPLIAIMA)-NH2, for binding to the Aß plaques was designed and successfully synthesized using the Fmoc solid-phase peptide synthesis method. This radiopeptide revealed a good affinity for Aß42 aggregations (Kd = 20 µM) in binding affinity study and this result was confirmed by binding to Aß plaques in brain sections of human Alzheimer's disease (AD) and rat models using in vitro autoradiography, fluorescent staining, and planar scintigraphy. Biodistribution studies of radiopeptide in AD and normal rats demonstrated a moderate initial brain uptake about 0.38 and 0.35% (ID/g) 2 min post-injection, respectively. Whereas, AD rats showed a notable retention time in the brain (0.23% ID/g at 30 min) in comparison with fast clearance in normal rat brains. Normal rats following treatment with cyclosporine A as a p-glycoprotein inhibitor showed a significant increase in the radiopeptide brain accumulation compared to non-treated ones. There was a good correlation between data gathered from single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Therefore, these findings showed that this novel radiopeptide could be a potential SPECT imaging agent for early detection of Aß plaques in the brain of patients with AD.

Design, preparation and biological evaluation of a 177Lu-labeled somatostatin receptor antagonist for targeted therapy of neuroendocrine tumors.

Somatostatin receptor-targeted radionuclide therapy has become an effective treatment in patients with neuroendocrine tumors. Recently, investigations on the development of antagonistic peptides are increasing with possible superior biological properties as opposed to the agonists. Herein, we have reported the development of a new somatostatin receptor peptide ligand labeled with 177Lu to achieve a therapeutic ligand for tumor treatment. The interactions of selected and drown ligands using Avogadro software were docked on somatostatin receptor by Dink algorithm. The best docked peptide-chelator conjugate (DOTA-p-Cl-Phe-Cyclo(d-Cys-l-BzThi-d-Aph-Lys-Thr-Cys)-d-Tyr-NH2) (DOTA-Peptide 2) was synthesized using the Fmoc solid-phase method. DOTA-Peptide 2 was radiolabeled with the 177Lu Trichloride (177LuCl3) solution at 95 °C for 30 min and radiochemical purity (RCP) of 177Lu-DOTA-Peptide 2 solution was monitored by radio-HPLC and radio-TLC procedures. The new radiolabeled peptide was evaluated for stability, receptor binding, internalization, biodistribution and single-photon emission computed tomography (SPECT) imaging using C6 glioma cells and C6 tumor-bearing rats. DOTA-Peptide 2 was obtained with 98% purity and efficiently labeled with 177Lu (RCP > 99%). 177Lu-DOTA-Peptide 2 showed a high value of stability in acetate buffer (91.4% at 312 h) and human plasma (>97% at 24 h). Radioconjugate exhibited low internalization (<5%) and high affinity for somatostatin receptors (Kd = 12.06 nM, Bmax = 0.20 pmol/106 cells) using saturation binding assay. Effective tumor uptake of 7.3% ID/g (percentage of injected dose per gram of tumor) at 4 h post-injection and fast clearance of radiopeptide from blood and other organs led to a high tumor-to-normal organ ratios. SPECT/CT imaging clearly showed the activity localization in tumor. The favorable antagonistic properties of 177Lu-DOTA-Peptide 2 on the somatostatin receptors can make it a suitable candidate for peptide receptor radionuclide therapy (PRRT). In the future study, the therapeutic application of this radiopeptide will be evaluated.

Design, synthesis, radiolabeling and biological evaluation of new urea-based peptides targeting prostate specific membrane antigen.

Early diagnosis of Prostate cancer (PCa) plays a vital role in successful treatment increasing the survival rate of patients. Prostate Specific Membrane Antigen (PSMA) is over-expressed in almost all types of PCa. The goal of present study is to introduce new 99mTc-labeled peptides as a PSMA inhibitor for specific detection of PCa at early stages. Based on published PSMA-targeting compounds, a set of peptides bearing the well-known Glu-Urea-Lys pharmacophore and new non-urea containing pharmacophore were designed and assessed by in silico docking studies. The selected peptides were synthesized and radiolabeled with 99mTc. The in-vitro tests (log P, stability in normal saline and fresh human plasma, and affinity toward PSMA-positive LNCaP cell line) and in-vivo characterizations of radiopeptides (biodistribution and Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging in normal and tumour-bearing mice) were performed. The peptides 1-3 containing Glu-Urea-Lys and Glu-GABA-Asp as pharmacophores were efficiently interacted with crystal structure of PSMA and showed the highest binding energies range from -8 to -11.2 kcal/mol. Regarding the saturation binding test, 99mTc-labeled peptide 1 had the highest binding affinity (Kd = 13.58 nM) to PSMA-positive cells. SPECT-CT imaging and biodistribution studies showed high kidneys and tumour uptake 1 h post-injection of radiopeptide 1 and 2 (%ID/g tumour = 3.62 ± 0.78 and 1.8 ± 0.32, respectively). 99mTc-peptide 1 (Glu-urea-Lys-Gly-Ala-Asp-Naphthylalanine-HYNIC-99mTc) exhibited the highest binding affinity, high radiochemical purity, the most stability and high specific accumulation in prostate tumour lesions. 99mTc-peptide 1 being of comparable efficacy and pharmacokinetic properties with the well-known PET tracer (68Ga-PSMA-11) seems to be applied as a promising SPECT imaging agent to early diagnose of PCa and consequently increase survival rate of patients.

Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors.

Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer's disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 µM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of ß-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Hydroxypropyl beta cyclodextrin: a water-replacement agent or a surfactant upon spray freeze-drying of IgG with enhanced stability and aerosolization.

The great potential of hydroxypropyl beta-cyclodextrin (HPßCD), as a dried-protein stabilizer, has been attributed to various mechanisms namely water-replacement, vitrification and surfactant-like effects. Highlighting the best result in our previous study (weight ratio IgG: HPßCD of 1:0.4), herein we designed to evaluate the efficacy of upper (1:2) and lower (1:0.05) ratios of HPßCD in stabilization and aerosol properties of spray freeze-dried IgG. The protective effect of HPßCD, as measured by size exclusion chromatography (SEC-HPLC) was most pronounced at C3' and C3″, IgG:trehalose:HPßCD ratios of 1:2:0.25 and 1:2:0.05 with aggregation rate constants of 0.46 ± 0.02 and 0.58 ± 0.01 (1/month), respectively. The secondary conformations were analyzed through Fourier transform infrared spectroscopy (FTIR) and all powders well-preserved with the lack of any visible fragments qualified through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PPAGE). Scanning electron microscopy (SEM) and twin stage impinger (TSI) were employed to characterize the suitability of particles for further inhalation therapy of antibodies and the highest values of fine particle fraction (FPF) were achieved by C3' and C3″, 56.43 and 48.12%. The powders produced at the current ratio 1:2:0.25 and 1:2:0.05 are superior to our previous examination with regards to manifesting lower aggregation and comparable FPF values.

Improving the in-vivo biological activity of fingolimod loaded PHBV nanoparticles by using hydrophobically modified alginate.

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.

Anticancer properties of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives; kinase inhibitors.

Structure activity correlation revealed that the quinoxaline ring is a satisfactory backbone for anticancer activity and a specific functional group at position 1 and 2 can improve the activity. In this basis, besides quinoxaline, imidazoles as potential anticancer agents were used as a supplementary agents for cancer treatment. In this paper, a new series of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives were synthesized in a simple and efficient step. The products are fully characterized by 1H NMR, 13C NMR, FT-IR, HRMS, and CHN elemental analysis. Several starting materials with different functionalities have been used for the synthesis of the final products with high isolated yields. The biological activities of the synthesized compounds were evaluated in kinase inhibition and cytotoxic activity in several cancerous cell lines. All compounds (6) were evaluated for inhibition of the cell proliferation using 4 cancerous cell lines. Five of the more active compounds were studied for determination of IC50%. Compounds 6(32-34) showed good activity on some of cancerous cell lines. The results showed that compound 6-32 has the highest biological activity (IC50% 9.77 for K562 cell line). An IC50% value of 15.84 µM was observed for 6-34. Furthermore 6-34 exhibited inhibition of ABL1 and c-Src kinases with an IC50% value of 5.25 µM and 3.94 µM respectively. Docking simulation was performed to position active synthesized compounds 6-32, 6-33, and 6-34 over the ABL1 active site in two different wild-type (DFG-in and DFG-out motif conformer) and T315I mutant to determine the probable binding orientation, conformation and mode of interaction. According to docking study, the docked location in wild type forms is similar and can be found near the P-loop region while in the case of T315I mutant form, the compounds have a distinct docked location which is close to the αC helix and activation loop. Also, it concluded the role of R1 substituent on phenyl ring produced higher interaction energy. Additionally, the detailed inter-molecular energy and types of non-bonding interaction of these compounds over the wild-type and mutant form of ABL1.

Simultaneous Determination of Nine Sunscreen Agents by HPLC and Chemometric Analysis.

A worldwide outbreak of skin cancer, related to ultraviolet (UV) radiations, was reported. Therefore, primary prevention programs were initiated. Application of sunscreens is one of the most efficient ways of protection; however, their efficiency and safety have remained a challenging issue. So, it seems necessary to consider the potential side effects for limiting the use and amount of sunscreens. In this study, an high performance liquid chromatography (HPLC) system equipped with a UV-visible detector has been used. For separation, an Agilent C18 column was used (Agilent Technologies, Santa Clara, CA). This method was applied for quantitative determination of nine UV filters in commercial sunscreen products which were widely used in Iran. Fifty samples of Iranian and imported sunscreen products were analyzed. The detection limit was determined to be 0.439-1.481 µg/ml, and the quantization limit was determined to be 1.330-4.490 µg/ml. Also, in this study, chemometric methods were used to investigate the differences between Iranian and other countries' sunscreen brands. It was observed that despite the amount of UV filters in Iranian sunscreens, which was in the allowed range, there were some differences between Iranian and other countries' sunscreens. The proposed HPLC method allows efficient and simultaneous analysis of UV filters and is suitable as a quality control assay for commercial sunscreen products.

Design, synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 value = 0.073 µM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aß peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Novel cinnamic acid-tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study.

A novel series of cinnamic acid-tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid-tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 µM. This compound showed a 14-fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 µM) and inhibited BChE through a mixed-type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against ß-secretase, which exhibited low activity (inhibition percentage: 38%).

Effects of coating layer and release medium on release profile from coated capsules with Eudragit FS 30D: an in vitro and in vivo study.

The aim of the present research was to evaluate the impact of coating layers on release profile from enteric coated dosage forms. Capsules were coated with Eudragit FS 30D using dipping method. The drug profile was evaluated in both phosphate buffer and Hank's solutions. Utilization X-ray imaging, gastrointestinal transmission of enteric coated capsules was traced in rats. According to the results, no release of the drug was found at pH 1.2, and the extent of release drug in pH 6.8 medium was decreased by adding the coating layers. The results indicated single-layer coated capsules in phosphate buffer were significantly higher than that in Hank's solution. However, no significant difference was observed from capsules with three coating layers in two different dissolution media. X-ray imaging showed that enteric coated capsules were intact in the stomach and in the small intestine, while disintegrated in the colon.

A mechanistic study of the effect of transferrin conjugation on cytotoxicity of targeted liposomes.

This study was performed to prepare 5-fluorouracil (5FU) containing targeted liposomes for the safety and efficacy enhancement. Liposomes were prepared using thin layer method and transferrin (Tf) was employed as the targeting ligand. Morphology of 5FU-loaded liposomes was assessed by transmission electron microscopy (TEM). The in vitro cytotoxicity was investigated via MTT assay on HT-29, CT26 and fibroblast cells. Mitochondrial membrane and cell death evaluations were also investigated. Resulted showed that the encapsulation efficiency (EE%) and particle size of the liposomes were 40.12% and 130 nm, respectively. TEM image implied that liposomes were spherical in shape. In cancer cells, targeted liposomes triggered the mitochondrial apoptotic pathway by lower production of reactive oxygen species (ROS) (63.58 vs 84.95 fluorescence intensity), reduced mitochondrial membrane potential and releasing of cytochrome c (68.66 vs 51.13 ng/mL). The results of this study indicated that Tf-targeted 5FU liposomes can be employed as promising nanocarrier for the delivery of drugs to cancer cells.

Synthesis, docking study and neuroprotective effects of some novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety.

Novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety were synthesized and evaluated against acetylcholinestrase (AChE) and butylcholinestrase (BuChE). Among the synthesized compounds, N-(3-cyano-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl)-2-(4-phenylpiperazin-1-yl)acetamide (6c) exhibited the highest acetylcholinestrase inhibitory (AChEI) activity (IC50=1.12µM) and most of them showed moderate butylcholinestrase inhibitory activity (BChEI). Kinetic study of compound 6c confirmed mixed type of inhibition towards AChE which was in covenant with the results obtained from docking study. Also, it was evaluated against ß-secretase which demonstrated low activity (inhibition percentage: 18%). It should be noted that compounds 6c, 7b, 6g, and 7d showed significant neuroprotective effects against H2O2-induced PC12 oxidative stress.

Targeted DNA delivery to cancer cells using a biotinylated chitosan carrier.

A novel biotinylated chitosan-graft-polyethyleneimine (Bio-Chi-g-PEI) copolymer was synthesized and evaluated as a nonviral gene delivery carrier for improvement of the transfection efficiency, endosomal escape, and targeted gene delivery of a plasmid encoding green fluorescent protein N1 (pEGFP-N1) into two different biotin-overexpressing cell lines including HeLa and OVCAR-3 cells. The structure of the obtained copolymers was confirmed by 1 H nuclear magnetic resonance (1 H NMR) and Fourier transform infrared spectroscopy. Physicochemical properties of the Bio-Chi-g-PEI/plasmid DNA (pDNA) complexes such as complex stability, size, zeta potential, and their morphology were investigated at various weight ratios of copolymer to pDNA. Bio-Chi-g-PEI copolymers could effectively condense pDNA into small particles with average diameters less than 164 nm and the zeta potential of +34.8 mV at the N/P ratio of 40/1. As revealed by flow cytometry, Bio-Chi-g-PEI/pDNA complexes had lower cytotoxicity than that of PEI 25 kDa/pDNA complexes in both cell lines. In vitro experiments revealed that the Bio-Chi-gPEI/pDNA complexes not only had much lower cytotoxicity, but also displayed higher transfection efficiency than that of PEI 25kDa/pDNA complexes. High percentage of cancer cells was successfully transfected by Bio-Chi-g-PEI/pDNA and properly expressed GFP protein. This study indicates that this copolymer complex can be a promising gene delivery carrier.

Ion-pair switchable-hydrophilicity solvent-based homogeneous liquid-liquid microextraction for the determination of paraquat in environmental and biological samples before high-performance liquid chromatography.

An approach involving ion-pair switchable-hydrophilicity solvent-based homogeneous liquid-liquid microextraction coupled to high-performance liquid chromatography has been applied for the preconcentration and separation of paraquat in a real sample. A mixture of triethylamine and water was used as the switchable-hydrophilicity solvent. The pH was regulated using carbon dioxide; hence the ratio of the ionized and non-ionized form of triethylamine could control the optimum conditions. Sodium dodecyl sulfate was utilized as an ion-pairing agent. The ion-associate complex formed between the cationic paraquat and sodium dodecyl sulfate was extracted into triethylamine. The separation of the two phases was carried out by the addition of sodium hydroxide, which changed the ionization state of triethylamine. The effects of some important parameters on the extraction recovery were investigated. Under the optimum conditions (500 µL of the extraction solvent, 1 mg sodium dodecyl sulfate, 2.0 mL of 10 mol/L sodium hydroxide, and pH 4), the limit of detection and the limit of quantification were 0.2 and 0.5 µg/L, respectively, with preconcentration factor of 74. The precision (RSD, n = 10) was  <5%. The recovery of the analyte in environmental and biological samples was in the range of 90.0-92.3%.

Synthesis of (2-mercaptoacetyl)-L-[2-14 C]tryptophan as a selective metallo-ß-lactamase inhibitor via [2-14 C]indole based on chiral pool strategy.

Metallo-beta-lactamase enzymes make bacteria resistant to a broad range of commonly used beta-lactam antibiotics. Several thiol derivatives of L-amino acids have been shown their inhibitory effects against the metallo-ß-lactamase IMP-1. In this study, (2-mercaptoacetyl)-L-tryptophan as a new inhibitor of metallo-ß-lactamases labeled with carbon-14 in the 2-position of the indole ring was prepared from [2-14 C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [14 C]carbonate as a starting material.

The effect of freeze-dried antibody concentrations on its stability in the presence of trehalose and hydroxypropyl-ß-cyclodextrin: a Box-Behnken statistical design.

The present study aimed at preparation and optimization of stable freeze-dried immunoglobulin G (IgG) applying proper amount of antibody with efficient combination of trehalose and hydroxypropyl-ß-cyclodextrin (HPßCD). Response surface methodology was employed through a three-factor, three-level Box-Behnken design. Amounts of IgG (X1), trehalose (X2) and HPßCD (X3) were independent variables. Aggregation following process (Y1), after one month at 45 °C (Y2), upon two month at 45 °C (Y3) and beta-sheet content of IgG (Y4) were determined as dependent variables. Results were fitted to quadratic models (except for beta-sheet content), describing the inherent relationship between main factors. Optimized formulation composed of 55.85 mg IgG, 52.51 mg trehalose and 16.01 mg HPßCD was prepared. The calculated responses of the optimized formulation were as follows: Y1 = 0.19%, Y2 = 0.78%, Y3 = 1.88% and Y4 = 68.60%, respectively. The thermal analysis confirmed the amorphous nature of optimum formulation and the integrity of IgG was shown to be favorably preserved. Validation of the optimization study demonstrated high degree of prognostic ability. The DOE study successfully predicted the optimum values of antibody as well as stabilizers for desirable process and storage stabilization of freeze-dried IgG.

Solid lipid nanoparticles surface modified with anti-Contactin-2 or anti-Neurofascin for brain-targeted delivery of medicines.

Multiple sclerosis (MS) is a chronic central nervous system (CNS) inflammation. Efficient drug delivery to brain is however hampered by blood-brain barrier (BBB). In order to have highly efficient and safe delivery of drugs to brain, solid lipid nanoparticles (SLNs) have indicated promising potentials as smart carriers that can pass the blood-brain barrier and deliver therapeutic biomolecules to the brain. In this study, PEGylated SLNs surface modified using anti-Contactin-2 or anti-Neurofascin, two axo-glial-glycoprotein antigens located in node of Ranvier, were prepared. These targeting moieties are considered as the main targets of autoimmune reaction in MS. The targeted SLNs were then characterized and their in vitro release profile together with their cell viability and uptake were studied. Their brain uptakes were also probed following injections in MS-induced mice. It was found that the targeted PEGylated SLNs had no significant cytotoxicity on U87MG cells although their cellular uptake was increased 4- and 8-fold when surface modified with anti-Contactin-2 or anti-Neurofascin, respectively, compared to control. Brain uptake results demonstrated higher uptake of surface-modified SLNs in the brain tissue compared with the PEGylated SLNs. The results of this report will help scientist to design more efficient nanocarriers for treatment of MS.