Polymer-coated superparamagnetic iron oxide nanoparticles as T2 contrast agent for MRI and their uptake in liver

Aim: To study the efficiency of multifunctional polymer-based superparamagnetic iron oxide nanoparticles (bioferrofluids) as a T2 magnetic resonance contrast agent and their uptake and toxicity in liver. Materials & methods: Mice were intravenously injected with bioferrofluids and Endorem\uae. The magnetic resonance efficiency, uptake and in vivo toxicity were investigated by means of magnetic resonance imaging (MRI) and histological techniques. Results: Bioferrofluids are a good T2 contrast agent with a higher r2/r1 ratio than Endorem. Bioferrofluids have a shorter blood circulation time and persist in liver for longer time period compared with Endorem. Both bioferrofluids and Endorem do not generate any noticeable histological lesions in liver over a period of 60 days post-injection. Conclusion: Our bioferrofluids are powerful diagnostic tool without any observed toxicity over a period of 60 days post-injection

Procedimiento para el recubrimiento y funcionalización de nanopartículas mediante reacción de Michael

[EN] The present invention relates to a method for coating nanoparticles to achieve stable dispersions of said particles in a liquid medium and the surface functionalization thereof with groups that have physical activity such as luminescence, chemical activity such as catalytic capacity and/or biological activity such as a capacity for selectively binding with a biological entity.[ES] La presente invención describe un procedimiento para el recubrimiento de nano partículas para conseguir dispersiones estables de dichas partículas en un medio líquido y de su funcionalizacion superficial con grupos que poseen actividad fIsica, como lmniniscencia, actividad química, como capacidad catalítica, y/o actividad biológica, como capacidad de unión selectiva con un ente biológico.Peer reviewedConsejo Superior de Investigaciones CientíficasA1 Solicitud de patente con informe sobre el estado de la técnic

In vitro toxicity studies of polymer coated superparamagnetic iron oxide nanoparticles

Trabajo presentado a la conferencia NanoSpain celebrada en Santander (España) del 27 de febrero al 1 de marzo de 2012.Peer reviewe

Cell compatibility of a maghemite/polymer biomedical nanoplatform

We are reporting the cytocompatibility and cellular fate of an iron oxide/polymer nanoplatform (IONP) in its most basic formulation, using both mesenchymal (vascular smooth muscle cells, VSMC), and epithelial (opossum kidney, OK) cells. The cytotoxicity and cell internalization of the nanoplatform has been evaluated in relation to time of exposure and concentration of different components. A series of samples with different iron oxide nanoparticle, sizes, hydrodynamic sizes and iron/polymer ratio have been examined. In all cases cytotoxicity is low, and it is mostly determined by the internalization rate, being higher in VSMC than in OK cells. The mean lethal dose has a very narrow threshold, and necrosis is the only cell death type. IONP uptake shows little incidence on oxidative stress, and inflammasome activation is only observed with the smaller IONP at high concentration. The internalization rate in VSMC is determined by the polymer concentration exclusively. In OK cells, internalization rate seems to increase with decreasing hydrodynamic size. Internalization occurs through clathrin-dependent endocytosis, as it is prevented by potassium depletion and chlorpromazine. IONP are directed and accumulated in lysosomes. Under IONP overload, lysosomal dysfunction would cause cell death using concentrations that are hardly achieved in vivo.Financial support from the Spanish Ministry of Science and Innovation research grants BFU2009-12763/BFI, MAT2011-259911 and Project Consolider-Ingenio in Molecular Nanoscience CSD2007-00010 are gratefully acknowledged. Thanks are due to the EU-NoE MAGMANet for partly funding the project. L.M.A.A. acknowledges financial support from the Spanish Ministry of Science and Innovation FPI research fellowship.Peer reviewe

Hemostasis disorders caused by polymer coated iron oxide nanoparticles

[Background]: Superparamagnetic iron oxide nanoparticles (SPIONs) are inorganic nanomaterials gaining strong clinical interest due to their increasing number of biological and medical applications. The stabilization of SPIONs in a biocompatible stable suspension (bioferrofluid) is generally achieved by an adequate polymeric coating. As many applications using these materials are intended for clinical use through intravenous injection, it is of outmost importance to evaluate heir hemostatic behaviour. [Objectives]: The aim of this work is to evaluate the hemocompatibility of selected polymer coated bioferrofluids and of their separated components by observing the effects of the bioferrofluid on: the coagulation process-by measuring the prothrombin time (PT) and activated partial thromboplastin time (aPTT)-, the complete blood count (CBC)-Erythrocytes, Leucocytes, Platelets, Hemoglobin and hematocrit-and the hemolysis. [Methods]: A SPIONs/bioferrofluid model consisting of a magnetic core of iron oxide nanoparticles embedded within poly(4-vinyl pyridine) (P4VP) and all coated with polyethylene glycol (PEG) has been selected. [Results and Conclusions]: By increasing the concentration of the bioferrofluids an inhibitory effect on the intrinsic pathway of blood coagulation is observed, as indicated by significant increase in aPTT in vitro while PT values stay normal. The effect of the coating components on the inhibition of blood coagulation process shows that PEG has no effect on the process while the P4VP-g-PEG copolymer coating has a strong anticoagulant effect indicating that P4VP is at the origin of such effects. The studied bioferrofluids have no effect on the CBC neither they show in vitro hemolytic effect on blood.Peer Reviewe

Polymer-coated superparamagnetic iron oxide nanoparticles as T2 contrast agent for MRI and their uptake in liver

[Aim]: To study the efficiency of multifunctional polymer-based superparamagnetic iron oxide nanoparticles (bioferrofluids) as a T2 magnetic resonance contrast agent and their uptake and toxicity in liver. [Materials & methods]: Mice were intravenously injected with bioferrofluids and Endorem®. The magnetic resonance efficiency, uptake and in vivo toxicity were investigated by means of magnetic resonance imaging (MRI) and histological techniques. [Results]: Bioferrofluids are a good T2 contrast agent with a higher r2/r1 ratio than Endorem. Bioferrofluids have a shorter blood circulation time and persist in liver for longer time period compared with Endorem. Both bioferrofluids and Endorem do not generate any noticeable histological lesions in liver over a period of 60 days post-injection. [Conclusion]: Our bioferrofluids are powerful diagnostic tool without any observed toxicity over a period of 60 days post-injection.Financial support from the Spanish Ministry of Science and Innovation research grant MAT2014-54975-R, and from the Programa Operativo FEDER Aragon 2014-2020 ‘Construyendo Europa desde Aragon’, is gratefully acknowledged. Additional support from the Diputacion General de Aragon (DGA-M4) is also acknowledged. LMA Ali acknowledges financial support from the Spanish Ministry of Science and Innovation FPI research grants. The Servicio de Experimentacion Animal (SAI), and servicio de Microscopia Electronica de Materiales of Zaragoza University. P Marzola acknowledges financial support from Fondazione Cariverona (Verona,Italy) through the project ‘Verona Nanomedicine Initiative’ and from MIUR through FIRB project RBAP114AMK – RI.NA.ME. ‘Rete Integrata per la Nanomedicina’.Peer reviewe

Toxicity studies of polymer based superparamagnetic iron oxide nanoparticles

Resumen del póster presentado a la: "13th edition of Trends in Nanotechnology International Conference" celebrada en Madrid (España) del 10 al 14 de septiembre de 2012.-- Pdf adjunto con las figuras.Superparamagnetic iron oxide nanoparticles (SPIONs) have been of great interest since the last decades due to their important contributions to nanomedicine. These inorganic nanomaterials can be useful as a diagnostic tool (e.g. magnetic resonance image contrast agent), a therapeutic tool (e.g. hyperthermia), or a theranostic tool. Stable biocompatible suspension of these nanoparticles is mandatory for efficient application, which is achieved by an adequate polymeric coating. Our model consists of iron oxide nanoparticles (ɣ-Fe2O3) embedded within a hydrophobic poly(vinylpyridine) (P4VP) polymer and coated with a hydrophilic polyethylene glycol (PEG). A fraction of coating PEG can also be functionalized for the conjugation of fluorescent dyes (dual reporter nanoparticles), antibodies and drugs Fig1. These nanoparticles are dispersed in phosphate buffer saline (PBS) at pH 7.4 to mimic physiological conditions. The resulting ferrofluids have core diameter (ferric oxide nanoparticles diameter) ranging between 4 to 15 nm, with 10% size dispersion, and hydrodynamic diameter ranging between 50 to 164 nm. Since the in vivo delivery of these nanoparticles for biomedical applications ends at the cell, studies pertaining to the toxicological effect on the cell (cytotoxicity), and nanoparticles cellular uptake and uptake kinetics are of utmost importance. Cytotoxicity studies of the ferrofluids have been carried out on two different cell lines, opossum kidney cells (OK) and vascular smooth muscle cells (VSMS). The activity of the lactate dehydrogenase in culture media was determined as a function of the dose. LC50 has been also calculated. As the nanoparticles uptake by the cell is depending on several factors, this work focused on the effect of the nanoparticle size and cell type on the cellular uptake. Sub cellular tracking studies have been carried out using fluorescent nanoparticles. Results show the localization of the nanoparticles after 24h of incubation with the cells inside the lysosomes Fig 2. By using the pharmacological inhibitor we found that the nanoparticles uptake takes place by clathrin-dependent endocytosis. These nanoparticles are developed for intravenous administration; therefore, studies pertaining to their haematological behaviour are of outmost importance and should be included in the toxicity and compatibility tests to be made in the development of these nanoparticles. We studied the effect of the nanoparticles and their polymers on the blood coagulation process. Results show that P4VPg-PEG-coated SPIONs in PBS act as non-specific circulating anticoagulant agents in vitro. While PEG component does not seem to have any effect on the coagulation process, the coating copolymer P4VP-g-PEG shows strong anticoagulant behaviour indicating that P4VP is at the origin of the effect.Peer reviewe

Multifunctional nanoplatform for biomedical applications

Resumen del trabajo presentado a la "2nd European Event in Nanoscience & Nanotechnology" celebrado en Bilbao (España) del 23 al 26 de abril de 2013.Working machinery in life is nanometric, thus, it is no wonder tliat the development of adequate nanotools would be very helpful in biomedical science. In this direction, the idea behind this work is to build a nanoplatform that can incorporate, in an easy way, multiple physical and biological functionalities. The core of the platform is an hydrophobic polymer that may be used as a matrix for the encapsulation of inorganic nanoparticles (magnetic, luminescent, radioactive, . . .). This matrix contains a Michael acceptor (or an acceptor) on its surface for functionalization. Organic bioactive molecules are attached to one end of a hydrophilic polymer (Le. PEG) terminated on a Michael acceptor (or a donor), and then they are anchored to the hydrophobic core by Michael addition. This system has the advantages of a clean synthesis (no by-products), mild conditions, and an easy and controlled multifunctionalization. The nanoplatform has been functionalized with radiochemical tracers (In111), luminescent dyes (fluorescein, rhodamine, lanthanide compounds), and magnetic nanoparticles, and therefore it can be a powerful tool in imaging. Besides, it has also been functionalized with a therapeutical drug, an antibody, and an optical thermometer made of lanthanide complexes. Health safety of tlhe system has been tested in cellular and in vivo assays. The nanoplatform is highly stable in biological fluids, shows low cell toxicity, high capacity of cell internalization, excellent hematocompatibility, and anticoagulation properties. It is shown that magnetic properties can be tuned up in the whole superparamagnetic range. Moreover, the system has shown excellent performance in magnetic resonance imaging and liyperthermia.Peer Reviewe