Fabrication of a magnetic nanocarrier for doxorubicin delivery based on hyperbranched polyglycerol and carboxymethyl cellulose: An investigation on the effect of borax cross-linker on pH-sensitivity.

A new core-shell pH-responsive nanocarrier was prepared based on magnetic nanoparticle (MNP) core. Magnetic nanoparticles were first modified with hyperbranched polyglycerol as the first shell. Then the magnetic core was decorated with doxorubicin anticancer drug (DOX) and covered with PEGylated carboxymethylcellulose as the second shell. Borax was used to partially cross-link organic shells in order to evaluate drug loading content and pH-sensitivity. The structure of nanocarrier, organic shell loadings, magnetic responsibility, morphology, size, dispersibility, and drug loading content were investigated by IR, NMR, TG, VSM, XRD, DLS, HR-TEM and UV-Vis analyses. In vitro release investigations demonstrated that the use of borax as cross-linker between organic shells make the nanocarrier highly sensitive to pH so that more that 70% of DOX is released in acidic pH. A reverse pH-sensitivity was observed for the nanocarrier without borax cross-linker. The MTT assay determined that the nanocarrier exhibited excellent biocompatibility toward normal cells (HEK-293) and high toxicity against cancerous cells (HeLa). The nanocarrier also showed high hemocompatibility. Cellular uptake revealed high ability of nanocarrier toward HeLa cells comparable with free DOX. The results also suggested that low concentration of nanocarrier has a great potential for use as contrast agent in magnetic resonance imaging (MRI).

pH-triggered intracellular release of doxorubicin by a poly(glycidyl methacrylate)-based double-shell magnetic nanocarrier.

Two core-double-shell pH-sensitive nanocarriers were fabricated using Fe3O4 as magnetic core, poly(glycidyl methacrylate-PEG) and salep dialdehyde as the first and the second shell, and doxorubicin as the hydrophobic anticancer drug. Two nanocarriers were different in the drug loading steps. The interaction between the first and the second shell assumed to be pH-sensitive via acetal cross linkages. The structure of nanocarriers, organic shell loading, magnetic responsibility, morphology, size, dispersibility, and drug loading content were investigated by IR, NMR, TG, VSM, XRD, DLS, HRTEM and UV-Vis analyses. The long-term drug release profiles of both nanocarriers showed that the drug loading before cross-linking between the first and second shell led to a more pH-sensitive nanocarrier exhibiting higher control on DOX release. Cellular toxicity assay (MTT) showed that DOX-free nanocarrier is biocompatible having cell viability greater than 80% for HEK-293 and MCF-7 cell lines. Besides, high cytotoxic effect observed for drug-loaded nanocarrier on MCF-7 cancer cells. Cellular uptake analysis showed that the nanocarrier is able to transport DOX into the cytoplasm and perinuclear regions of MCF-7 cells. In vitro hemolysis and coagulation assays demonstrated high blood compatibility of nanocarrier. The results also suggested that low concentration of nanocarrier have a great potential as a contrast agent in magnetic resonance imaging (MRI).

Magnetic nanoparticles double wrapped into cross-linked salep/PEGylated carboxymethyl cellulose; a biocompatible nanocarrier for pH-triggered release of doxorubicin.

A magnetic nanocarrier was synthesized in which Fe3O4 nanoparticles were encapsulated into double layers of polysaccharide shells. The first shell, which was composed of cross-linked salep polysaccharide, contained multiple nitrogen atoms in its structure and provided numerous sites for multiple functionalization. A fluorescence dye and doxorubicin, as widely used chemotherapy agent, were easily attached to the first shell and then a second shell of PEGylated carboxymethyl cellulose enveloped the drug loaded carrier to enhance its biocompatibility and regulates the drug release behavior. The results of drug loading and release behavior showed that the resulting nanocarrier can carry large amounts of drug molecules and a remarkable pH-sensitive release was observed in vitro. The hemolysis and coagulation assays proved the biocompatibility of nanocarrier toward red blood cells and the MTT experiments confirmed that the drug loaded nanocarrier is highly toxic for MCF-7 cancer cells while the unloaded nanocarrier was almost nontoxic. Further flow cytometry experiments and confocal microscopy demonstrated that the double layered magnetic nanocarrier can penetrate into the cells and efficiently release the drug molecules into the cell nucleus. Moreover, the results of MRI experiments performed on the nanocarrier showed that it can be serve as a negative MRI contrast agent.

Delivery of Doxorubicin Using Double-Layered Core-Shell Nanocarrier Based on Magnetic Fe3O4 Core and Salep Shells.

Herein, we developed a magnetic drug delivery system based on magnetic Fe3O4 nanoparticles with double shells of modified salep polysaccharide for the delivery of doxorubicin (Dox). The drug-loaded nanocarrier was synthesized in an easy way, and large amounts of drug molecules were loaded into the nanocarrier. The drug-loaded nanocarrier showed excellent pH responsibility in vitro, and large amounts of Dox were released at lower pH (60% release), whereas the nanocarrier was stable at neutral pH. The hemolysis assay results showed that the nanocarrier has negligible hemolytic effects on human red blood cells and showed good biocompatibility. Moreover, the result of coagulation assays showed that the nanocarrier was not active in any coagulation pathways. Cytotoxicity assays of nanocarrier and drug-loaded nanocarrier toward HeLa cells demonstrated that the nanocarrier has negligible toxicity, whereas the drug-loaded nanocarrier kills more than 90% of cells during 48 h. The flow cytometry analysis also showed that the uptake of drug-loaded nanocarrier into the cancerous cells is time-dependent and higher concentrations of drug internalized into the cells at longer incubation time. On the basis of the results, we suggest that the present nanocarrier can be applicable for in vivo drug delivery as an easy-made and cheap nanocarrier.

Covalent Immobilization of Cellulase Using Magnetic Poly(ionic liquid) Support: Improvement of the Enzyme Activity and Stability.

A magnetic nanocomposite was prepared by entrapment of Fe3O4 nanoparticles into the cross-linked ionic liquid/epoxy type polymer. The resulting support was used for covalent immobilization of cellulase through the reaction with epoxy groups. The ionic surface of the support improved the adsorption of enzyme, and a large amount of enzyme (106.1 mg/g) was loaded onto the support surface. The effect of the presence of ionic monomer and covalent binding of enzyme was also investigated. The structure of support was characterized by various instruments such as FT-IR, TGA, VSM, XRD, TEM, SEM, and DLS. The activity and stability of immobilized cellulase were investigated in the prepared support. The results showed that the ionic surface and covalent binding of enzyme onto the support improved the activity, thermal stability, and reusability of cellulase compared to free cellulase.

Uncatalyzed one-pot synthesis of highly substituted pyridazines and pyrazoline-spirooxindoles via domino SN/condensation/aza-ene addition cyclization reaction sequence.

A previously unknown class of highly substituted pyridazines and pyrazoline-spirooxinoles are easily prepared by an uncatalyzed one-pot three-component approach incorporating a domino SN/condensation/aza-ene addition cyclization reaction sequence. 1,1-Dihydrazino-2-nitroethylene (DHNE) which is generated in situ from the nucleophilic substitution (SN) reaction of hydrazine and 1,1-bis(methylthio)-2-nitroethylene (BMTNE), allowed to be condensed with active 1,2-dicarbonyl compounds followed by an intramolecular aza-ene addition cyclization to obtain the titled products depending on the type of 1,2-dicarbonyl. All reactions are easily performed and proceed with high efficiency under very simple and mild conditions without any catalyst and give good yields avoiding time-consuming, costly syntheses, and tedious workup and purification of products.

Novel approach to 1,5-benzodiazepine-2-ones containing peptoid backbone via one-pot diketene-based Ugi-4CR.

An efficient and simple route for preparation of substituted 1,5-benzodiazepine-2-one containing peptoid backbone is presented. The classical Ugi reaction is considerably extended by application of o-phenylenediamine and diketene as amine and oxo component. 1,3-Dihydro-1,5-benzodiazepine-2-one is generated in situ from these two building blocks combined with isocyanide and aromatic or aliphatic carboxylic acid to assemble the multifunctionalized titled scaffold in high yields. The reaction is performed in the mixture of toluene/CH(2)Cl(2) under reflux condition without catalyst. Conformational isomerism is seen in the solution phase because of restricted free rotation around amide and C-CO bands due to steric bulk of substitutions. In single crystal state, the product is found to possess dimeric structure arising from intermolecular hydrogen bonding.