Publications 2012

2012

In vivo degradation of functionalized carbon nanotubes after stereotactic administration in the brain cortex

A. Nunes, C. Bussy, L. Gherardini, M. Meneghetti, M. A. Herrero, A. Bianco, M. Prato, T. Pizzorusso, K. T Al-Jamal, and K. Kostarelos

Carbon nanotubes (CNTs) are increasingly being utilized in neurological applications as components of implants, electrodes or as delivery vehicles. Any application that involves implantation or injection of CNTs into the CNS needs to address the distribution and fate of the material following interaction and residence within the neuronal tissue. Here we report a preliminary study investigating the fate and structural integrity of amino-functionalized CNTs following stereotactic administration in the brain cortex. Materials & methods: The CNTs investigated had previously shown the capacity to internalize in various cell types of the CNS. An aqueous suspension of multiwalled CNT-NH3 + was stereotactically injected into the mouse brain cortex. Their interaction with neural cells and consequent effects on the CNT structural integrity was investigated by optical, transmission electron microscopy and Raman spectroscopy of brain tissue sections for a period between 2 and 14 days post cortical administration. Results & discussion: The occurrence of severe nanotube structure deformation leading to partial degradation of the chemically functionalized-multiwalled CNT-NH3 + in vivo following internalization within microglia was revealed even at early time points. Such initial observations of CNT degradation within the brain tissue render further systematic investigations using high-resolution tools imperative.

Nanomedicine, 2012, 7, 1485-1494.

Degree of Chemical Functionalization of Carbon Nanotubes Determines Tissue Distribution and Excretion Profile.

K. T. Al-Jamal, A. Nunes, L. Methven, H. Ali-Boucetta, S. Li, F. M. Toma, M. A. Herrero, W. T. Al-Jamal, H. M. M. ten Eikelder, J. Foster, S. Mather, M. Prato, A. Bianco, K. Kostarelos

Angew. Chem., 2012, 124, 6495-6499.

Organic Functionalization of Graphene in Dispersion

M. Quintana, E. Vázquez, M. Prato

Graphene is considered a promising material for a range of new applications from flexible electronics to functional nanodevices, such as biosensors or intelligent coatings. Therefore researchers need to develop protocols for the mass production of graphene. One possible method is the exfoliation of graphite to form stable dispersions in organic solvents or even water. In addition, researchers need to find effective ways to control defects and locally induced chemical changes. We expect that traditional organic chemistry can provide solutions to many of these challenges. In this Account, we describe our efforts toward the production of stable dispersions of graphene in a variety of solvents at relatively high concentrations and summarize representative examples of the organic reactions that we have carried out using these stable dispersions.

The sonication procedures used to solubilize graphene can often damage these materials. To mitigate these effects, we developed a new methodology that uses mechanochemical activation by ball-milling to exfoliate graphite through interactions with melamine (2,4,6-triamine-1,3,5-triazine) under solid conditions. Alternatively, the addition of reducing agents during sonication leads to larger graphene layers in DMF. Interestingly, the treatment with ferrocene aldehyde, used as a radical trap, induces the formation of multiwalled carbon nanotubes. The resulting graphene sheets, stabilized by the interactions with the solvent, are suitable materials for performing organic reactions.

Relatively few organic reactions have been performed in stable dispersions of graphene, but organic functionalization of these materials offers the opportunity to tune their properties. In addition, thermal treatments can remove the appended organic moieties, restoring the intrinsic properties of pristine graphene. We describe a few examples of organic functionalization reactions of graphene, including 1,3-dipolar cycloadditions, amide condensations, nitrene additions, and radical reactions. The design of novel protocols for further organic functionalization should increase our knowledge of the fundamental chemistry of graphene and spur the further development and application of these materials.

Acc. Chem. Res. , DOI: 10.1021/ar300138e (2012).

Synthesis and Characterization of Highly Water-Soluble Dendrofulleropyrrolidine Bisadducts with DNA Binding Activity.

A. Montellano Lopez, F. Scarel, N. Rubio Carrero, E. Vázquez, A. Mateo-Alonso, T. Da Ros, M. Prato

The synthesis, characterization and DNA binding studies of a series of polycationic fullerene adducts are reported. These cationic species, exhibiting reasonably high water solubility and a heterogeneous distribution of positive charges, can efficiently complex plasmid DNA. Electrophoresis studies show different DNA binding efficiencies for different adducts, some of which can be considered excellent candidates for DNA binding therapies

Org. Lett. 2012, 14, 4450-4453

Enhanced docetaxel-mediated cytotoxicity in human prostate cancer cells through knockdown of cofilin-1 by carbon nanohorn delivered siRNA

F. C. Pérez-Martínez, B. Carrión, M. I. Lucio , N. Rubio, M. A. Herrero, E. Vázquez, V. Ceña

We synthesized a non-viral delivery system (f-CNH3) for small interfering RNA (siRNA) by anchoring a fourth-generation polyamidoamine dendrimer (G4-PAMAM) to carbon nanohorns (CNHs). Using this new compound, we delivered a specific siRNA designed to knockdown cofilin-1, a key protein in the regulation of cellular cytoskeleton, to human prostate cancer (PCa) cells. The carbon nanohorn (CNH) derivative was able to bind siRNA and release it in the presence of an excess of the polyanion heparin. Moreover, this hybrid nanomaterial protected the siRNA from RNAse-mediated degradation. Synthetic siRNA delivered to PCa cells by f-CNH3 decreased the cofilin-1 mRNA and protein levels to about 20% of control values. Docetaxel, the drug of choice for the treatment of PCa, produced a concentration-dependent activation of caspase-3, an increase in cell death assessed by lactate dehydrogenase release to the culture medium, cell cycle arrest and inhibition of tumor cell proliferation. All of these toxic effects were potentiated when cofilin-1 was down regulated in these cells by a siRNA delivered by the nanoparticle. This suggests that knocking down certain proteins involved in cancer cell survival and/or proliferation may potentiate the cytotoxic actions of anticancer drugs and it might be a new therapeutic approach to treat tumors.

Biomaterials, 2012, 33, 8152-8159.

Carbon nanohorns functionalized with polyamidoamine dendrimers as efficient biocarrier materials for gene therapy

J. Guerra, M. A. Herrero, B. Carrión, F. C. Pérez-Martínez , M. Lucio, N. Rubio , M. Meneghetti , M. Prato , V. Ceña, E. Vázquez

Carbon nanohorns are suitable platforms for use in biological applications. Their high surface areas allow the incorporation of molecular entities, such as polyamidoamine dendrimers. In this work, we report the synthesis, structural characterization and biological data of new hybrid systems of carbon nanohorns that hold polyamidoamine dendrimers. One of these derivatives has been employed as an agent for gene delivery. The system is able to release interfering genetic material diminishing the levels of a house-keeping protein and a protein directly involved in prostate cancer development. Importantly, this hybrid material is also far less toxic than the corresponding free dendrimer. These results allow us to conclude that these nanomaterials can be exploited as useful non-viral agents for gene therapy.

Carbon, 2012, 50, 2832–2844.

Cross-coupling in flow using supported catalysts: Mild, clean, efficient and sustainable Suzuki–Miyaura coupling in a single pass.

J. M. Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortiz. A mild, clean, practical, sustainable and high yielding procedure for Suzuki–Miyaura cross-coupling in a single pass using a silica-supported palladium catalyst is described. The catalyst can be used in more than 30 reactions and for more than 8 hours of continuous processing without a decrease in reactivity due to the low leaching observed. Different halides/pseudo halides and organoboron compounds can be used without modifying the standard procedure.

Adv. Synth. Catal. 2012, 18, 3456-3460.

Flow Microwave Technology and Microreactors in Synthesis

I. R. Baxendale, C. Hornung, S. V. Ley, J. M. Muñoz, A. Wikström. A bespoke microwave reactor with a glass containment cell has been developed for performing continuous flow reactions under microwave heating. The prototype unit has been evaluated using a series of standard organic chemical transformations enabling scale-up of these chemical processes. As part of the development, a carbon-doped PTFE reactor insert was utilized to allow the heating of poorly absorbing reaction media, increasing the range of solvents and scope of reactions that can be performed in the device.

Aust. J. Chem. http://dx.doi.org/10.1071/CH12365

Sustainable and efficient methodology for CLA synthesis and identification

M. Moreno ,  M. V. Gómez ,  C. Cebrián ,  P. Prieto,  A. de la Hoz, A. Moreno. Microwave-assisted organic synthesis and continuous-flow techniques have been successfully employed for the preparation of conjugated linoleic acids (CLA), compounds with high health beneficial effects. A good production rate of CLA was obtained. A sustainable methodology for the differentiation of both positional and geometrical CLA isomers (diene), based on the analysis by NMR spectroscopy of the resulting Diels–Alder cycloadducts with an appropriate dienophile, was developed.

Green Chem., 2012, 14, 2584-2594

Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Loupy. Editores. Wiley (Weinheim) ISBN 3-527-33116-6 (in press).

Selectivity under the action of microwave irradiation. In Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Díaz-Ortiz, J.R. Carrillo, M.A. Herrero. Eds. A. de la Hoz, A. Loupy Wiley (Weinheim) ISBN 3-527-33116-6 (in press).

Elucidation of microwave effects: Methods, theories and predictive models. In Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Díaz-Ortiz, A. Sánchez Migallón, M.V. Gómez Almagro, P. Prieto. Eds. A. de la Hoz, A. Loupy. Wiley (Weinheim) ISBN 3-527-33116-6 (in press).

Application of Flow Chemistry to the Selective Reduction of Esters to Aldehydes.

J. M. Muñoz, J. Alcázar, A. Diaz-Ortiz; A. de la Hoz. The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity.

Eur. J. Org. Chem. 2012, 260-263.

Translocation mechanisms of chemically functionalised carbon nanotubes across plasma membranes

L. Lacerda, J. Russier, G. Pastorin, M.A. Herrero, E. Venturelli, H. Dumortier, K. Al-Jamal, M. Prato, K. Kostarelos. Understanding the mechanisms responsible for carbon nanotube (CNT) internalisation into live cells is considered critical both from a fundamental point of view and for further engineering of CNT-based delivery systems to intracellular targets. While several studies are focused on the development of such CNT-based delivery systems, attempts to systematically elucidate the cellular uptake mechanisms of CNTs are still rather limited. The aim of the present study is to evaluate the cellular internalisation of chemically functionalised multi-walled carbon nanotubes (f-MWCNTs) in the presence of different well-known cellular uptake inhibitors. Our data reveal how f-MWCNTs are able to translocate across cell membranes of both phagocytic and non-phagocytic cell lines. We have evidenced that at least 30–50% of f-MWCNTs are taken up by cells through an energy-independent mechanism. This characteristic makes nanotubes loaded with therapeutic or diagnostic cargos extremely interesting as the release of active molecules directly into the cytoplasm increase their biological activity and therapeutic efficacy.

Biomaterials 2012, 33, 3334-3343.

DFT-Studies on Cobalt Catalyzed Cyclotrimerization Reactions. Mechanism and Origin of Reaction Improvement under Microwave Irradiation.

A.M. Rodriguez, C. Cebrián, P. Prieto, J. I. García, A. de la Hoz, Á. Díaz-Ortiz.  A DFT computational mechanistic study of the [2+2+2] cyclotrimerization of a diyne with benzonitrile, catalyzed by a cobalt complex, has been carried out. Three alternative catalytic cycles have been examined together with the precatalytic step (responsible for the induction period). The favored mechanism takes place by means of an intramolecular metal-assisted [4+2] cycloaddition. The beneficial role of microwave activation has been studied. It is concluded that microwave irradiation can decrease the catalytic induction period through thermal effects and can also increase the triplet lifetime and promote the reaction, thus improving the final yield.

Chem. Eur. J. 2012, 18, 6217-6224

Preparation of amides mediated by isopropylmagnesium bromide under continuous flow conditions.

J.M. Muñoz, J. Alcázar, A. de la Hoz,  A. Díaz-Ortíz, S.-A. Alonso de Diego. A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure and a simple scale-up. This reaction represents an efficient and green alternative to the use of alkylaluminium and metal-catalyzed procedures.

Green Chem. 2012, 14, 1335-1341.

Continuous-Flow Microliter Microwave Irradiation in the Synthesis of Isoxazole Derivatives: An Optimization Procedure

A. M. Rodriguez, A. Juan, M. V. Gómez, A. Moreno, A. de la Hoz. An efficient method was developed for the synthesis of 3,4,5-trisubstituted and 3,5-disubstituted isoxazoles by using continuous-flow microwave-heated microreactors. A study on the separate effects of the temperature, continuous-flow regime, and microwave irradiation showed that the continuous-flow regime had important effects for less reactive diketones, where microwave heating enhanced the reaction, permitting the formation of 5-methyl-3-phenylisoxazole, which was not formed in the absence of microwaves.

Synthesis 2012, 44, 2527-2530

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