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Perez-Medina C.,The New School | Perez-Medina C.,Research Center En Red Of Enfermedades Respiratorias | Perez-Medina C.,Advanced Imaging Unit | Abdel-Atti D.,Sloan Kettering Cancer Center | And 8 more authors.
Nature Communications | Year: 2016

The application of nanoparticle drug formulations, such as nanoliposomal doxorubicin (Doxil), is increasingly integrated in clinical cancer care. Despite nanomedicine's remarkable potential and growth over the last three decades, its clinical benefits for cancer patients vary. Here we report a non-invasive quantitative positron emission tomography (PET) nanoreporter technology that is predictive of therapeutic outcome in individual subjects. In a breast cancer mouse model, we demonstrate that co-injecting Doxil and a Zirconium-89 nanoreporter (89 Zr-NRep) allows precise doxorubicin (DOX) quantification. Importantly, 89 Zr-NRep uptake also correlates with other types of nanoparticles' tumour accumulation. 89 Zr-NRep PET imaging reveals remarkable accumulation heterogeneity independent of tumour size. We subsequently demonstrate that mice with >25 mg kg-1 DOX accumulation in tumours had significantly better growth inhibition and enhanced survival. This non-invasive imaging tool may be developed into a robust inclusion criterion for patients amenable to nanotherapy.

Benito M.,Advanced Imaging Unit | Benito M.,CIBER ISCIII | De Molina A.,Comparative Medicine Unit | Sepulveda P.,Institute Investigacion Sanitaria La Fe | Cervera A.M.,Institute Investigacion Sanitaria La Fe
Diabetes | Year: 2015

A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1-/- mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1-/- mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1-/- mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1-/- mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity. © 2015 by the American Diabetes Association.

Popota F.D.,University of Barcelona | Popota F.D.,University Pompeu Fabra | Aguiar P.,Fundacion Ramon Dominguez | Aguiar P.,University of Southern California | And 11 more authors.
Physics in Medicine and Biology | Year: 2015

In this work a comparison between experimental and simulated data using GATE and PeneloPET Monte Carlo simulation packages is presented. All simulated setups, as well as the experimental measurements, followed exactly the guidelines of the NEMA NU 4-2008 standards using the microPET R4 scanner. The comparison was focused on spatial resolution, sensitivity, scatter fraction and counting rates performance. Both GATE and PeneloPET showed reasonable agreement for the spatial resolution when compared to experimental measurements, although they lead to slight underestimations for the points close to the edge. High accuracy was obtained between experiments and simulations of the system's sensitivity and scatter fraction for an energy window of 350-650 keV, as well as for the counting rate simulations. The latter was the most complicated test to perform since each code demands different specifications for the characterization of the system's dead time. Although simulated and experimental results were in excellent agreement for both simulation codes, PeneloPET demanded more information about the behavior of the real data acquisition system. To our knowledge, this constitutes the first validation of these Monte Carlo codes for the full NEMA NU 4-2008 standards for small animal PET imaging systems. © 2015 Institute of Physics and Engineering in Medicine.

Zahraei M.,Isfahan University of Technology | Marciello M.,CSIC - Institute of Materials Science | Lazaro-Carrillo A.,Autonomous University of Madrid | Villanueva A.,Autonomous University of Madrid | And 9 more authors.
Nanotechnology | Year: 2016

Three biocompatible polymers, polyethylene glycol (PEG), dextran and chitosan, have been used in this work to control the colloidal stability of magnetic nanoparticles (14 ± 5 nm in diameter) and to vary the aggregation state in order to study their effect on relaxometric and heating properties. Two different coating strategies have been deeply developed; one based on the formation of an amide bond between citric acid coated nanoparticles (NPs) and amine groups present on the polymer surface and the other based on the NP encapsulation. Relaxometric properties revealed that proton relaxation rates strongly depend on the coating layer hydrophilicity and the aggregation state of the particles due to the presence of magnetic interactions. Thus, while PEG coating reduces particle aggregation by increasing inter-particle spacing leading to reduction of both T1 and T2 relaxation, dextran and chitosan lead to an increase mainly in T2 values due to the aggregation of particles in bigger clusters where they are in close contact. Dextran and chitosan coated NPs have also shown a remarkable heating effect during the application of an alternating magnetic field. They have proved to be potential candidates as theranostic agents for cancer diagnosis and treatment. Finally, cytotoxicity of PEG conjugated NPs, which seem to be ideal for intravenous administration because of their small hydrodynamic size, was investigated resulting in high cell viability even at 0.2 mg Fe ml-1 after 24 h of incubation. This suspension can be used as drug/biomolecule carrier for in vivo applications. © 2016 IOP Publishing Ltd.

Salinas B.,Complutense University of Madrid | Salinas B.,Advanced Imaging Unit | Ruiz-Cabello J.,Complutense University of Madrid | Ruiz-Cabello J.,Advanced Imaging Unit | And 3 more authors.
Bioinspired, Biomimetic and Nanobiomaterials | Year: 2012

The functionalization of iron oxide superparamagnetic nanoparticles (NP) is one of the most active research fields due to the necessity of robust and, particularly, reproducible methods for the attachment of new biomolecules on the surface. Olefin metathesis offers many of these features, thanks to the new family of catalysts, especially Hoveyda-Grubbs second generation. Iron oxide NP were synthesized by the decomposition of organic precursors obtaining hydrophobic Fe3O4 NP with oleic acid as surfactant. These NP have been functionalized by the use of olefin metathesis reaction with different ligands. The metathesis was performed between the double bond in oleic acid structure and four different molecules with a terminal olefin, methyl acrylate, 6-hexenenitrile, allyltrifl uoroacetate and 3-allyloxy-1,2-propandiol, in presence of the catalyst. These new NPs were fully characterized showing the success of the functionalization, small hydrodynamic size, narrow size distribution, and stability in water. This proof of concept opens a new way for the formation of carbon-carbon bonds on the surface of NP for biomedical applications.

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