Magnetic polymeric core-shell as a carrier for gradual release in-vitro test drug delivery.

At first functionalized graphene oxide was selected as a basic substrate obtained through process of functionalization of graphene oxide with diethylenetriamine as substrates. Then magnetic nanoparticle sediments were formed and coated on the functionalized graphene oxide as the core center. The core nanoparticle was added to a gel containing poly (lactic-co-glycolic acid), polyethylene glycol, and polyvinylpyrrolidone and nilotinib drug for forming a shell on the core. After separation and freeze-drying, single core-shell particles were obtained. The second shell was coated by dispersing first core-shell in a new gel containing polylactic acid, polyvinyl alcohol, polyethylene glycol, and nilotinib. The third layer was laminated on core-dual shell particle by entering in sodium alginate, polyethylene glycol, poly (lactic-co-glycolic acid), polylactic acid and nilotinib gel according to the same method used above. In order to determine the gradual release, the core-single, dual and triple shell nanoparticles dispersed in phosphate buffer saline at the several pHs (3, 5.4, 7.4) and as well as monitoring the released concentration of nilotinib by UV-Vis spectrophotometer technique. Core-triple shell particle had gradual release at three different rates over the long time. Finally, the average release rate for 400 mg of drug, in single layer, double-layer and three layers were reported to be equal to 15.8, 10.4 and 6.6 mg/h at intervals of 24, 37 and 60 h, respectively. The release rate of the drug reduced by increasing the pH value. All products were characterized using several techniques.

[18F]FDG-Labeled CGPRPPC Peptide Serving as a Small Thrombotic Lesions Probe, Including a Comparison with [99mTc]-Labeled Form.

Purpose: Fibrin is a perfect target for specific imaging of all types of thrombotic lesions. Cyclic peptides were introduced as the best scaffolds out of the different types of probes for thrombi detection. This study was conducted to label previously synthesized peptide-targeting fibrin with [18F]FDG and its in vitro and in vivo assessments. Materials and Methods: CGPRPPC peptide functionalized with 6-hydrazinonicotinamide and Eei-NHS was synthesized and cyclized using air oxidation method. The cyclic sequences were labeled with [18F]FDG at 85°C within 30 min. The stability studies were performed in human plasma. Fibrin-binding and platelet aggregation tests were performed in vitro. Biodistribution and scintigraphy imaging in normal mice and carotid thrombotic rat model were considered as in vivo studies. Results: Radiolabeled peptides show a good stability in human plasma and also high-affinity binding for human fibrin. Platelet aggregation test confirmed specific binding of radiopeptides to fibrin. A key problem with the authors' previous research was inability to detect small-vessel thrombi. The results of positron emission tomography/computed tomography scanning show high specific uptake of [18F]FDG-labeled CGPRPPC in small-sized thrombosis. Conclusion: The experiment revealed that radiolabeling of cyclic peptide (CGPRPPC) with [18F]FDG enables us to detect small thrombotic lesions in small animal models with high resolution.

Docking Studies, Synthesis, and In-vitro Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase.

Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineat cholinergic synapsesand terminates the cholinergic effects. Some chemical agents like organophosphorus compounds (OPCs) including nerve agents and pesticides react with acetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and result in accumulation of acetylcholineand show toxic effects andcholinergic symptoms. The process of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agent to dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15 novel nitrone based onoximes as reactivators were performed by using AutoDock program. Then, more effective reactivatorsoximes in terms of binding energy and orientation within the active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited by paraoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our results used to design new derivatives of Oxim with better efficacy than 2-PAM and obidoxime. Syntheses of some selected bis-pyridiniumoximes based on the nitrones are underway.

Preparation of Mesalamine Nanoparticles Using a Novel Polyurethane- Chitosan Graft Copolymer.

BACKGROUND: Chitosan nanoparticle, a potential vehicle, is used as a hydrophilic carrier system since it can deliver drugs to specific sites and also control the drug release rate. Moreover, controlled release systems are designed to minimize systemic absorption and to achieve optimum delivery of the biologically active mesalamine to the distal small intestine and the colon. OBJECTIVE: The current study investigated the development of new nanoparticulate drug delivery systems based on polyurethane-chitosan copolymers. The copolymer shows good biodegradablity and biocompatiblity properties and thus can be considered as a potential carrier for drug delivery systems. METHOD: In this work, Polyurethane was obtained from the condensation reaction between polypropylene glycol (PPG) as prepolymerpolyol, 1, 4-butanediol (BD) as diol, dimethylol propionic acid (DMPA) as chain extender and also isophoronediisocyanate (IPDI). The synthesized polyurethane was grafted onto the prepared chitosan through a covalent binding and preparation of nanoparticles was done further through a coprecipitation process. The particle size of the prepared samples was evaluated with dynamic light scattering (DLS) technique. RESULTS: The obtained particle size of the samples was 80±0.05 nm. Characterization of the synthesized chitosan-polyurethane copolymer was performed by FT-IR spectroscopy, 13CNMR and 11HNMR spectroscopy. The morphology of the synthesized polyurethane-chitosan copolymers and the amount of the loaded drug were also examined using SEM images and UV-visible spectroscopy, respectively. Moreover, drug release behavior was examined in PBS (pH 7.4) at 37°C. It was concluded that the mesalamine release from polyurethane-chitosan was sustained and no initial burst release (burst effect) was observed and the percentage of mesalamine released from nanoparticles was 92.19±0.2% within 72 hrs. CONCLUSION: The results of the drug loaded nanoparticles showed that the drug loading process was performed successfully. As a result, polyurethane-chitosan copolymer can be a good candidate for drug delivery systems.

Synthesis and Biological Evaluation of Cyclic [99mTc]-HYNIC-CGPRPPC as a Fibrin-Binding Peptide for Molecular Imaging of Thrombosis and Its Comparison with [99mTc]-HYNIC-GPRPP.

PURPOSE: Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties. PROCEDURES: Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbit femoral thrombosis model, and scintigraphic images were obtained. RESULTS: In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c mice femoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography. CONCLUSIONS: The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.

Molecular Dynamics Simulation and Docking Studies of Selenocyanate Derivatives as Anti-Leishmanial Agents.

BACKGROUND: Selenocyanate derivatives have been recently presented as potent anti-leishmanial agents. OBJECTIVE: In this research, thirty five selenocyanate and diselenide compounds were subjected to docking studies and compared to Edelfosine and Miltefosine as reference drugs and then molecular dynamics (MD) simulation analysis. METHODS: Desired Selenocyanates were built using the HyperChem program and docking calculations were performed on the crystal structure of trypanothione reductase from Leishmania infantum. Then, MD simulation analysis was performed to explore the interaction stability of selected compound during structural motions of the interacting molecules. RESULTS: Based on the binding energy, all of the aryl rings were more potent than Edelfosine and Miltefosine as reference drug. The best compound base on hydrogen bonding, π-π interactions and orientation within the active site with high binding energy was selected for MD simulation analysis. The selected compound is known as high-affinity selective inhibitor for trypanothione reductase. CONCLUSION: These results can be used for future synthesis of new antileishmanial agents with better potency.

Reinvestigation of the Two-step Synthesis of Sevoflurane.

Improvements in the two-step synthesis of 1,1,1,3,3,3-hexafluoro-2- (fluoromehoxy)propane (Sevoflurane) that result in the product cost reduction, safety level enhancement and positive environmental impacts are described. This process consists of chloromethylation reaction of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) followed by a halogen-exchange fluorination. This is the first synthesis of Sevoflurane in Iran which was successfully scaled up. During this work, several improvements have been achieved by optimization of the reaction time, the amount of consumed starting materials and solvents and work up procedure while keeping the yield and purity intact. The reaction time of the first step (24 h) was diminished to 4 h. (19)F NMR spectroscopy was used to investigate the rate of the reaction in the first step and to evaluate the influence of different parameters mentioned on the achieved improvements.

Synthesis of 2-(1,2,4-oxadiazol-3-yl)quinazolin-4(3H)-ones from diaminoglyoxime-based nitrones.

Various 2-[5-(aryl)-1,2,4-oxadiazol-3-yl]quinazolin-4(3H)-ones have been synthesized from the reaction of diaminoglyoxime-based nitrones with methyl 2-aminobenzoate or 2-aminobenzamide in the presence of acetic acid at 100 °C. The reaction was extended as a one-pot three-component approach starting from diaminoglyoxime, aldehyde and methyl 2-aminobenzoate.

Diaminoglyoxime as a versatile reagent in the synthesis of bis(1,2,4-oxadiazoles), 1,2,4-oxadiazolyl-quinazolines and 1,2,4-oxadiazolyl-benzothiazinones.

The synthesis of bis(1,2,4-oxadiazoles), 1,2,4-oxadiazolyl-quinazolines, and 1,2,4-oxadiazolyl-benzothiazinones has been investigated by the reaction of diaminoglyoxime with various ketones and methyl 2-aminobenzoate, 2-amino-5-chlorophenyl)(phenyl)methanone, and 2-mercapto benzoic acid in acetic acid either a catalyst or solvent at 100 °C.

A convenient Simple Method for Synthesis of Meta-iodobenzylguanidine (MIBG).

Radioiodinated meta-iodobenzylguanidine (MIBG) is one of the important radiopharmaceuticals in Nuclear Medicine. [(123/131)I] MIBG is used for imaging of Adrenal medulla, studying heart sympathetic nerves, treatment of pheochromacytoma and neuroblastoma. For clinical application, radioiodinated MIBG is prepared through isotopic exchange method, which includes replacement of radioactive iodine in a nucleophilic substitution reaction with cold iodine ((127)I). The unlabelled MIBG hemisulfate is synthesized by the procedure described by Wieland et al. (1980). The availability of a more practical and cost-effective procedure for MIBG preparation encouraged us to study the MIBG synthesis methods. In this study the preparation of MIBG through different methods were evaluated and a new method, which is one step, simple and cost-effective is introduced. The method has ability to be scaled up for production of unlabelled MIBG.

An Eu(III) sensor based on N,N-diethyl-N-(4-hydroxy-6-methylpyridin-2-yl)guanidine.

A highly selective poly(vinyl chloride)-based membrane sensor produced by using N,N-diethyl-N-(4-hydroxy-6-methylpyridin-2-yl)guanidine (GD) as active material is described. The electrode displays Nernstian behavior over the concentration range 7.0 x 10(-5) - 1.0 x 10(-1) M. The detection limit of the electrode is 5.0 x 10(-5) M. The best performance was obtained with the membrane containing 30% PVC, 55% benzyl acetate, 5% GD and 10% oleic acid. The response of the sensor is pH-independent in the range of 3.0 - 7.0. The sensor possesses satisfactory reproducibility, fast response time (< 20 s), and specially excellent discriminating ability for Eu(III) ion with respect to the alkali, alkaline earth, transition and heavy metal ions. The membrane sensor was used as an indicator electrode in potentiometric titration of Eu(III) ion with EDTA. It was also applied in determination of fluoride ions in mouth wash preparations.

Sub-micro level monitoring of beryllium ions with a novel beryllium sensor based on 2,6-diphenyl-4-benzo-9-crown-3-pyridine.

The 2,6-diphenyl-4-benzo-9-crown-3-pyridine (DPCP) was used as an excellent ionophore in construction of a coated graphite poly(vinyl chloride) (PVC)-based membrane sensor. The best performance was obtained with a membrane composition of 30% poly(vinyl chloride), 60% o-nitrophenyloctyl ether (NPOE), 5% 2,6-diphenyl-4-benzo-9-crown-3-pyridine and 5% sodium tetraphenyl borate (TBP). This sensor shows very good selectivity and sensitivity towards beryllium ion over a wide variety of cations, including alkali, alkaline earth, transition and heavy metal ions. The sensor revealed a great enhancement in selectivity coefficients and sensitivity for beryllium, in comparison with the previously reported beryllium electrodes. The electrode exhibits a Nernstian behavior (with slope of 29.6mV per decade) over a very wide concentration range (1.0x10(-7) to 1.0x10(-1)) with a detection limit of 4.0x10(-8)M (360pgml(-1)). It shows relatively fast response time, in whole concentration range (<10s), and can be used for at least 12 weeks in the pH range of 4.5-8.0. The proposed sensor was successfully used to determination of beryllium in mineral ore.

Crystal structure of a binuclear polymeric self-assembled lead(II) complex.

A polymeric self-assembled complex [[Pb(pydc)(pydc-H2)(H2O)2]2]n is prepared from the complexation of a novel pyridine containing self-assembling system, LH2, [pyda-H2]2+[pydc]2- (pyda = 2,6-pyridindiamine and pydc-H2 = 2,6-pyridinedicarboxilic acid) and lead(II) nitrate in 84% yield. The characterization was performed using X-ray crystallography. The crystal system is triclinic with space group P1 and two molecules per unit cell. The unit cell dimensions are a = 6.913(2) A, b = 10.687(4) A and c = 11.182(4) A with alpha = 92.805(6) degrees, beta = 101.821(6) degrees and gamma = 95.688(6) degrees. The final R value is 0.0373 for 4633 reflections measured. This compound is a nine-coordinate binuclear complex with two metal fragments linked via the central four-membered Pb2O2 ring. The crystal also contains a neutral [pydc-H2] molecule, that form hydrogen and coordination bonds that dominate the crystal packing, by forming layers of molecules.

Novel potentiometric sensor for monitoring beryllium based on naphto-9-crown-3.

A novel poly(vinyl chloride) (PVC) membrane electrode based on naphto-9-crown-3 was prepared and tested for the selective detection of beryllium ions. A suitable lipophilicity of the carrier and appropriate coordination ability were found to be essential for designing an electrode with good response characteristics. A PVC membrane with 9% naphtho-9-crown-3 carrier, 58% o-NPOE plasticizer, 3% tetraphenylborate anionic excluder and 30% poly(vinyl chloride) satisfied these requirements. The proposed sensor displayed a linear response to beryllium over a wide concentration range of 1.0 x 10(-1)-8.0 x 10(-6) M with a Nernstian slope of 29.5 mV per decade. The electrode showed very short response time (<15 s) and could be used in the pH range 3.5-9.0. The selectivity coefficient for alkali, alkaline earth, transition and heavy metal ions was smaller than 4.0 x 10(-4). The sensor was successfully used as an indicator electrode in the potentiometric titration of Be2+ with EDTA. The proposed Be(II) sensor was also used for the determination of Be2+ ions in binary mixtures.

A novel crown ether generation containing different heteroaromatic cations: synthesis, characterization, solid-phase (13)C NMR, X-ray crystal structure, and selective amino acid recognition.

The synthesis and structural characterization of a novel generation of crown ethers, 3, 5 and 6 containing pyrilium, thiopyrilium, and pyridinium subunits, respectively, are reported. The crown ether unit is potentially capable of forming host-guest complexes with inorganic and organic cations, while the heteroaromatic cationic unit is suitable to bind with anions. A variety of physicochemical methods including electrospray mass spectrometry, UV-vis spectroscopy, solution and solid-phase NMR, and X-ray crystallography were applied for structural characterization of the new crown ether derivatives. The (1)H and (13)C NMR studies indicate rapid rotation of the B9C3 unit about the C-C bond that connects the two units to each other. Single crystals for 3, 4, and 5 were successfully obtained, and their X-ray crystal structures were resolved. The perchlorate anion in 3 (orthorhombic, space group P2(1)2(1)2(1)) and 5 (orthorhombic, space group P2(1)) is far from O(+) and close to S(+). The solid-phase structure of 3 and 5 show small deviation from planarity for the four aromatic rings, whereas two of the aromatic rings in 4 are out of heteroaromatic ring. Spectrophotometric studies in methanol solution revealed that the ligand 3 can be successfully applied to selective amino acid recognition.