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    • 专利摘要:
    Metalloorganic polymeric system of coordination at micro-/nanometric scale obtaining procedure and applications. The object of the present invention is a metalloorganic polymeric system for coordinating highly stable particles and having functional groups on the surface capable of acting as anchoring points of different species that possess properties such as luminescence, chemical activity, catalytic activity and/or activity. Biological also objects of the present invention are a method for the synthesis at the micro- and nanometric level of the metallo-organic polymer system, as well as the applications thereof. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2541501A1
    申请号:ES201331869
    申请日:2013-12-19
    公开日:2015-07-20
    发明作者:Daniel Ruiz Molina；Fernando NOVIO VÁZQUEZ；Julia LORENZO RIVERA
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；Universitat Autonoma de Barcelona UAB；
    IPC主号:
    专利说明:

    DESCRIPTION

    Polymeric polymeric system of coordination at micro- / nanometric scale, procedure for obtaining and applications.
     5
    SECTOR AND OBJECT OF THE INVENTION

    The present invention is part of the scientific-technical area of Nanotechnology, Biotechnology, Medicine, Materials Science and Chemistry within the manufacturing, encapsulation and functionalization of multifunctional metal-organic systems. 10

    The object of the present invention is a metalloorganic polymer system for coordination of particles of great stability and that have functional groups on the surface capable of acting as anchor points of different species that have properties such as luminescence, chemical activity, catalytic and / or activity biological Likewise, 15 objects of the present invention are a process for the synthesis at the micro- and nanometric level of the metalloorganic polymer system, as well as the applications thereof.

    STATE OF THE TECHNIQUE
     twenty
    The applications of nanoparticles at the technological level have experienced exponential growth in the last decade. The remarkable advantages that they present with respect to materials at the micro- or macroscopic level have allowed the development of systems with very beneficial properties for use in different scientific and industrial areas. At the level of biomedicine, one of the first applications of nanoparticles had been as transport systems for enzymes, proteins or vitamins. Already in the 80s, the application began to develop within the field of bioimaging as contrast agents in magnetic resonance imaging (MRI), nanocontainers for the transport of active substances and controlled drug release. In recent years, a whole technological development focused on the biocompatibility of these 30 systems, immunoassays, gene therapy and vectorization of nanoparticles for the detection and specific action on tumor cells has been implemented. On an industrial level (electronics, aeronautics, military), applications based on nanoparticles have been described as lubricants, magnetic sensors, additives in composites for the improvement of physical-chemical properties, for the development of super-hydrophobic surfaces, adhesives, etc. 35

    At the biomedical level, a classification of the types of nanoparticles can be made according to the material that integrates them. Thus, one can speak of particles based on purely organic systems, such as lipid vesicles or organic polymers (polystyrene, polyamide, polyethylene glycol derivatives, etc.) inorganic systems, such as metal nanoparticles (gold, iron, silver, etc.) or mesoporous silica ; and hybrid systems (gel-nanoparticles, peptides-nanoparticles. However nanoparticles constituted by coordination polymers represent a new synthetic and application challenge, as a consequence of an emerging emerging technology. The nanosystems developed with this technology have shown interesting magnetic properties, electronic, optical and catalytic associated with the careful selection of ligands and metals they contain.The possible applications range from use as contrast agents in bioimaging to the detection and action on cancer cells.The appropriate experimental design allows to obtain suitable sizes for its application at the biomedical level and favor the intracellular transport of different biomolecules avoiding its elimination by the endothelial reticulum system 50 or the accumulation in tissues.

    The limitations of the use of nanoparticles at a technological level are related to their stability, the possibility of incorporating different functionalities on the surface and their biocompatibility. Most of the time synthetic procedures provide nanoparticles with low stability, low functionalization capacity and low biocompatibility. In order to improve these benefits, the coating of the nanoparticles with materials that confer a better stability and allow a subsequent functionalization is normally used. Thus, silicon-containing coatings [WO2006 / 055447], different organic polymers (dextran [US4452773], proteins [US2010 / 0029902], synthetic polymers [WO2009 / 135937, and low molecular weight compounds with affinity 10 for the surface of the surface have been used nanoparticles [WO 03/016217] or ambylic organic chains of lipid origin [Hasan, W et al. NANO LETTERS (2012), 12, 287-292].

    However, the coating of the nanoparticles with a stabilizing layer normally causes difficulties and is very limited by the affinity between the surface of the nanoparticle and the new material. Electrostatic interactions are usually very sensitive to the environment (pH conditions, presence of ions, electrical potentials, etc.) and the reaction conditions to generate covalent bonds can alter the starting system. In addition, adding a new material on the surface can significantly modify the properties of the initial nanoparticle (porosity, optical properties, catalytic, magnetic properties, etc.). Therefore, the ideal situation would correspond to a synthetic system of high stability and that directly presents a surface with functionalizable groups.

    In recent years, coordination polymers have been presented as a novel class of materials with easily modifiable properties and adaptable to a particular application. The virtually unlimited possibilities of combining a multitude of organic ligands and / or metal ions allow the design of materials with stabilities, dimensions, morphologies and functionalities on demand. One of the most widely studied families of coordination polymers is that of the "metal-organic frameworks" (MOFs). 30

    These compounds allow great control over the release of certain active species or drugs by modification of the pore size or surface area of these materials, which implies an increase in their loading capacities. The fact that they are crystalline materials facilitates the structural analysis and the study of host-35 guest interactions, which allows a systematization when modifying encapsulation and controlled release capabilities of a certain substance.

    Another family of compounds that has attracted special attention is that which concerns amorphous particles of coordination polymers (CPPs). It should be noted that, up to 40 date, the synthesis of different systems based on the conjugation of metal ions with organic ligands to generate micro- / nanometric materials with applications such as gas absorption, catalysis, ion exchangers, sensors has been described. , magnetism, optics and drug delivery. The preparation of these materials at the nanoscale can be carried out by means of different techniques (solvothermal reactions, emulsion techniques 45 or forced precipitation) that involve very rapid rainfall, which affects the formation of amorphous systems. CPPs have emerged as an alternative to metal-organic frameworks (MOF) as a result of their inherent advantages such as easy control of their morphology and size, stability, scalability, load capacity and reduced cost. As a consequence, there has been an exponential increase in the publication 50 of studies with these systems in the last 5 years and very good results have been obtained
    promising at the level of its biomedical application [F. Boyfriend et al. Cood. Chem. Rev. (2013), 257, 2839-2847].

    The first reference of nanoscopic synthesis of metalloorganic spherical particles from the polymerization of metal ions and bifunctional organic ligands is the patent and the corresponding scientific publication of Mirkin et al. in 2005 [Chemically tailorable nanoparticles realized through metal-metalloligand coordination chemistry. C. A. Mirkin, M. Oh, B.-K. Oh, WO2007053181]. In this case they were polymers formed by different metal ions from metal salts (Zn, Cu, Mn, Pb, Ni, Co, Cd, and Cr) and Schiff base ligands. The amorphous particles of nanometer size 10 were obtained when the polymer was precipitated by the addition of a non-polar solvent (pentane, ethyl ether, toluene, hexane and benzene). Another reference for synthesis of metalloorganic polymers, using a similar methodology, was published that same year by Wang et al. [X. Sun, S. Dong, E. Wang, J. Am. Chem. Soc. 2005, 127, 13102]. In this case they were polymers synthesized in water using platinum as a metal ion and p-phenylenediamine as an organic ligand. Subsequently, a new synthetic route was published for the synthesis of metalloorganic particles formed by Fe ions and triazole ligands or Gd ions and a dicarboxylic ligand synthesized with a microemulsions-based technique [E. Coronado, J. R. Galán-Mascarás, M. Monrabal-Capilla, J. García-Martínez, P. Pardo-Ibañez, Adv. Mater. (2007), 19, 1359-1361. twenty

    The first time the use of these metalloorganic particles was described as encapsulation and transport systems of active substances or species was in 2008 with the patent application of Ruiz-Molina et al. (P200801230; PCT / ES2009 / 070128). In recent years, a multitude of works based on amorphous metalloorganic polymers with fluorescent properties showing properties of selective cation exchange have been published [M. Oh, C. A. Mirkin, Angew. Chem. Int. Ed. (2006), 45, 5492-5494], hydrogen storage [Y.-M. Jeon, G. S. Armatas, J. Heo, M. G. Kanatzidis, C. A. Mirkin, Adv. Mater. (2008), 20, 2105-2110] or with very interesting magnetic behaviors such as tautomería de Valencia [I. Imaz, D. Maspoch, C. Rodríguez-Blanco, J.-30 M. Pérez-Falcón, J. Campo, D. Ruiz-Molina, Angew. Chem. Int. Ed. 2008, 47, 1857-1860].

    However, despite the latest advances, a methodology developed to achieve surface functionalization of these systems has not been described to date directly, systematically and at a reduced cost. The systematic functionalization of these materials allows to selectively modify properties such as thermal, mechanical stability, resistance to certain chemical agents, pH, or even increase their biocompatibility. The functionalization also allows to develop covalent bonds with the species of interest and to form joints that are sensitive to certain external stimuli such as light, temperature or change in pH. 40

    In the case of MOFs, significant efforts have been made to develop these systems for novel applications through the use of functionalized ligands [Seth M. Cohen Chem. Rev. (2012), 112 (2), 970-1000]. However, the use of functional ligands is very limited for the conventional solvothermal synthesis of these systems, since the presence of 45 functional groups in the ligands can induce steric impediments, solubility problems and coordination characteristics to the metal that can interfere with crystallization. and formation of three-dimensional networks.

    On the contrary, in the case of amorphous coordination polymer particles these 50 limitations do not exist. In fact the use of functional ligands can provide value
    added to the systems since the right choice of connector ligands and functional ligands can affect the modification of stability, porosity or the number of functional groups on the surface that can serve as an anchor point for different molecules or biomolecules.
     5
    BRIEF DESCRIPTION OF THE INVENTION

    By "nanoparticles" in the present invention is meant the coordination polymer particles with a size between 1 nm and 200 nm. And "microparticles" means particles larger than 200nm. 10

    The object of the present invention is a polymeric metalloorganic coordination system at micro- / nanometric scale useful for encapsulating and covalently joining different substances on its surface comprising:
     fifteen
    (a) a salt or complex of a metal ion of the transition series or of the rare earth family, selected from the list comprising zinc, copper, iron, cadmium, manganese, nickel, cobalt, gadolinium, europium, terbium , uranium, aluminum or gallium that constitute the metal centers of the metalloorganic polymer system.
    (b) at least one organic ligand that acts as a connector between metal centers; twenty
    (c) at least one functional organic chelate ligand with affinity for the metal center and having a free functional group that does not coordinate the center.
    (d) a substance of interest to be encapsulated, selected from the group comprising: a biological entity, a drug, a vaccine, a diagnostic contrast agent, a label, an organic compound, an inorganic compound, a metalorganic compound or a nanomaterial

    In successive particular embodiments of the object of the present invention:

     The metal ion comes from the compound Co (CH3OO) 2 • 4H2O. 30
     the organic ligand that acts as a linker between metal centers is an organic compound with at least one functional group, which is selected from the list comprising carboxylic acids, phosphoric groups, alcohols, thiols, amines, catechols and any nitrogen-derived functional group , particularly imidazoles, pyridine and Schiff bases, it being particularly preferred that the organic ligand that acts as a linker between metal centers is 1,4-bis (imidazol-1-ylmethyl) benzene (Bix).
     the substance of interest to be encapsulated is an entity with biological activity selected from a list comprising a bacterium, a virus, a eukaryotic cell, a protein, an antibody, sugars, DNA, RNA or a drug. 40
     the substance of interest to be encapsulated is a nanomaterial selected from a list comprising nanoparticles, nanotubes, nanowires, nanocrystals or nanodevices.
     the functional organic ligand is an organic chelate compound with at least one free functional group, where the functional group is selected from the list comprising carboxylic acids, alcohols, thiols, amines, thiocyanates, isocyanates, isothiocyanates, catechols and any functional group derived from nitrogen, minus a free functional group, where the functional group is selected from the list comprising carboxylic acids, alcohols, thiols, amines, thiocyanates, isocyanates, isothiocyanates, catechols and any nitrogen-derived functional group. The non-covalent secondary interactions developed by the free functional groups in the organic chelate ligand modulate the thermal stability of the nanoparticles, being
    These secondary interactions do not covalent hydrogen bonds, Van de Waals forces, ionic interactions or hydrophobic interactions.

    In a preferred embodiment, the organic chelate compound is a mixture in proportions, with respect to stoichiometric amounts, comprised between 75% and 25% of 3,4-dihydroxycinnamic acid provided by the free -COOH group, and between 25% and 75% dopamine (3,4-dihydroxyphenethylamine) provided by the –NH2 group.

    In all the above embodiments, the metalorganic polymer system has a size between 40 nm and 10 µm and is functionalized on its outer surface 10 with another species or substance, which is selected from a list comprising an antibody, a bacterium, a virus, a cell, a protein, a sugar, DNA, a drug, a drug, an organic compound, a fluorescent compound, an inorganic compound, a metalloorganic compound or a nanomaterial.
     fifteen
    The functionalization of the metalloorganic polymer system can be performed:

     by coupling reactions between a carboxylic group and an amino group by using carbodiimides to form an amide bond (EDC / NHS).
     by an acylation reaction of amines between an acid chloride group and an amine 20 to generate an amide bond.
     by reaction between a sulfonyl chloride and an amine to form a sulfonamide bond.
     by reaction between an isocyanate and alcohols to generate a urethane bond coupling. 25
     by reaction between an isocyanate and amines to generate a urea bond coupling.
     by reaction between an isocyanate and thiols to generate a thiocarbamate link coupling.
     30
    Another object of the present invention is a method of obtaining the metalloorganic system comprising the following steps:

    (a) a step of adding the salt or complex of a metal ion, the organic ligand that acts as a connector of the metal centers and the chelate ligand with affinity for the metal center that leaves a free functional group, to a single solution reaction, which is under agitation;
    (b) precipitation of the formed metalloorganic polymer system;
    (c) separation of metalorganic polymer systems
     40
    The addition step can be carried out by adding the metal ion salt or complex to a solution containing both types of ligands while maintaining a 1: 1: 2 molar ratio corresponding to the metal ion mixture: linker ligand: functionalized ligand the formation of the metallurgical polymer system being initiated or by the addition of the two types of organic ligands into the solution containing the salt or complex of a metal ion.

    The stirring can be mechanical, magnetic or by ultrasound at room temperature. In some cases, the material formed after the addition step has low solubility in the reaction medium. In the case where the material formed after the addition step shows a high solubility in the reaction medium, precipitation is induced.
    by adding a solvent that is selected from non-polar solvents such as pentane, ethyl ether, toluene, hexane and benzene, or water, separating the metalloorganic systems obtained by centrifugation and washing with a solvent that does not solubilize the material, but dissolves the impurities or residues of starting reagents that can impurify the material, the metalorganic material being stored as solid or in a colloidal suspension.

    The various uses of the metalloorganic polymer system are also objects of the invention:
     for the release and / or protection and / or storage and / or variation of the properties 10 of the encapsulated substances of interest.
     for the elaboration of catalysts, sensors, contrast agents, biomarkers, magnetic semiconductors or devices for magnetic recording.
     for the preparation of a pharmaceutical, diagnostic or therapeutic drug or composition. fifteen

    The pharmaceutical, diagnostic or therapeutic composition comprising the metallurgical polymer system is also object of the present invention.

    Technical problem solving: 20

    1. It allows the in situ functionalization of the nanoparticles (one pot). Avoid having to coat the nanoparticles with a polymer functionalized after synthesis.
    2. The surface of the nanoparticle can be functionalized with one or more different functional groups in a single reaction (one pot). 25
    3. Increase in thermal stability and against pH. The systems detailed above showed a low melting temperature (around 60-70 ° C) and high sensitivity to pH change.
    4. Control of the hydrophilic of the nanosystems and therefore the possibility of properly redispersing the material in organic or aqueous media. 30
    5. Increase in biocompatibility by being able to anchor molecules and biomolecules on the surface that prevent immunological responses, for example chains derived from PEG.

    Advantages that it brings with respect to the current state of the art:
     35
    1. Possibility of anchoring virtually any molecule and / or biomolecule covalently and reversibly on the surface of the nanosystems.
    2. Ability to control surface loading based on the functional groups used, which is a key factor in the cellular internalization of these nanosystems (E. Fröhlich, International Journal of Nanomedicine 2012: 7 5577-5591). 40
    3. Thermal stability and pH sensitivity can be controlled by the appropriate choice of bifunctional linker ligands and ligands that provide free functional groups to the resulting coordination polymer. The diversity of free functional groups used, which are those that control the cohesion forces between polymer chains, allows modulating "on demand" the stability of the nanoparticles. Thus, it is possible to design particles with high stability or that degrade rapidly in a given environment.

    Possible applications:
     fifty
     Catalysis,
     Biosensors,
     Biomarkers,
     Contrast agents,
     Cancer Cell targeting,
     Encapsulation of drugs in general (anticancer, antiparasitic, 5 antimalarial, etc.),
     Smart nanocontainers (capable of responding to an external stimulus) for controlled release of drugs or other active or interesting species,
    Molecular devices
     10
    BRIEF DESCRIPTION OF THE FIGURES

    Fig. 1: a) Scheme of the formation of the polymer chains and the confinement in a nanostructure containing carboxyl groups on the surface manufactured according to example 1, b) aspect of the particles seen by scanning electron microscopy, c) aspect 15 in solid and d) dispersed in water.

    Fig. 2: a) SEM image of nanoparticles functionalized with a fluorescent dye (6-aminofluorescein; ANF). In the box you can see the image of the nanoparticles obtained by fluorescence spectroscopy. b) Normalized absorption spectrum 20 (solid line) and emission (broken line) for nanoparticles functionalized with 6-aminofluorescein.

    Fig. 3: a) FT-IR spectra of iron and cobalt particles functionalized with PEG on the surface and comparison with the free NH2-PEG ligand, b, c) SEM images of particles functionalized with PEG on the surface, d) Zeta potential measurements of the particles functionalized with PEG and the comparison with the non-functionalized nanoparticles.

    Fig. 4: a) Scheme of the coupling reaction between nanoparticles containing surface carboxyl groups and octadecylamine (ODA) by coupling agents 30 EDC / NHS, b) SEM image of nanoparticles containing ODA chains on the surface , c) Phase separation in a toluene / water mixture containing particles not functionalized and functionalized with ODA on the surface. It can be seen how it is possible to control the hydrophobicity of the nanoparticles by including hydrophobic chains. 35
    Fig. 5: Images of a) SEM, and b) Optical microscope of encapsulated camptothecin nanoparticles (CPT), c) Absorption and emission spectra of free and encapsulated CPT.

    Fig. 6: Cell viability of the MCF-7 cell line after 24 h of incubation with 40 organometallic nanoparticles of a) iron and b) cobalt, functionalized with a fluorescent molecule (aminofluorescein) on the surface; c) and d) Effect of cytotoxicity of nanoparticles containing encapsulated camptothecin and comparison with free camptothecin at 24h and 72h.
     Four. Five
    Fig. 7: Analysis of thermal stability of the particles by means of TGA / DSC and SEM of the particles obtained in example 7. Comparison between the particles containing the dhc ligand (a, b) and those containing the dtbucat ligand (c, d ).
    DETAILED DESCRIPTION OF THE INVENTION

    The present invention provides a process for obtaining nanoparticles based on functionalized coordination polymers on the surface, with high stability in solid state and dispersion in liquid medium, and with great potential for use in the field of biomedicine.

    The process of the invention is based on the polymerization of a metal-organic system in a single, simple, low-cost, non-polluting and high performance solvent. The result is a material that has functional groups on the surface 10 that can act as an anchor point for different molecules and biomolecules that can add value to the system.

    The metal-organic system of this invention, not only complements the existing metal-organic systems but also allows obtaining new systems with new properties, more resistant to degradation, resistant to extreme pH and with the possibility of subsequent functionalization of the nanomaterial generating multifunctional systems or platforms. The ease and simplicity of obtaining these systems that present certain functional groups or a mixture of different functional groups in the same nanostructure opens up a whole field of use of these materials in 20 nanomedicine as elements for teragnosis (therapy + diagnosis). That is, the same system can show properties to encapsulate different active species or drugs (drugs, magnetic particles, drugs, proteins, diagnostic contrast agents, vaccines, etc.), while different molecules or biomolecules can be arranged on the surface. they contribute one or several added functionalities. Some examples may be the inclusion of fluorescent molecules (for bioimaging), antibodies (for selective localization of one type of tumor or other cell), biomarkers, detection agents of certain analytes and / or molecules or biomolecules that increase biocompatibility of the nanostructure such as polyethylene glycol derivatives, polysaccharides or certain proteins. 30

    The proposed invention focuses on the description of a new methodology for generating a multifunctional metallurgical system, with the main characteristic that a mixture of ligands with different roles is used for its synthesis. On the one hand, flexible bifunctional organic ligands are used, which act as connectors between metal centers and favor polymerization. On the other hand, ligands containing a functional group that favor its coordination to the metal center and another functional group that do not coordinate with the metal cation and be free after synthesis are included in the reaction mixture. The fact that a functional group is free once the micro- / nanoscopic material is synthesized will allow the subsequent anchoring of different molecules or biomolecules. 40 In addition, the use of free functional groups that are capable of generating non-covalent secondary interactions (hydrogen bonds; Van der Waals forces; ionic interactions and hydrophobic interactions) allow modulating the stability of the nanoparticles at will and adapting them to a specific use .
     Four. Five
    The present invention is based on the synthesis of a metalorganic system containing ligands with high affinity for a large number of metal ions and which in turn have free functional groups capable of being used as anchor points of different substances at a later stage than their synthesis. The metalorganic system of this invention that contains ligands with free functional groups not only adds a new system to existing ones but also allows the design and obtaining of new systems
    functional where the properties of the metalorganic particles (porosity, encapsulation and controlled release capacity, magnetism, electronics, fluorescence, etc.) are combined with the advantages of obtaining systems with functional groups on the surface that allows anchoring, covalently , different molecules and biomolecules with important applications at the technological or medical level. By way of example, with said invention intelligent systems can be obtained, which can respond to the application of an external stimulus, for the release of drugs, storage and protection of different organic-inorganic substances, sensors, bioimage systems, magnetic devices , etc. with applications in sectors as diverse as electronics, catalysis, environmental control or medicine. 10

    Apart from the benefits derived from the surface functionalization of these systems, the careful choice of ligands allows us to design nanoplatforms with different porosity, density, solubility, resistance to different pH or temperature. In addition, “intelligent” systems can be designed in which the application of an external stimulus 15 induces changes at the physical-chemical level that have an impact on its properties. All these properties can be controlled and systematized based on certain internal interactions between the chains of the polymers and propitiated by the free functional groups that can generate secondary interactions (van der Waals type, electrostatic, hydrogen bridges or pp type) that will impact in the physicochemical properties of the material. Likewise, the inclusion of pH, light or temperature sensitive bonds forming part of the flexible ligands used for polymerization allows us to generate systems sensitive to certain stimuli that can modify or degrade metalorganic systems. These systems could be part of suitable platforms for selective drug release, controlled by the application of an external stimulus that triggers it.

    EMBODIMENT OF THE INVENTION

    The polymeric metalorganic coordination system at micro- / nanometric scale, in 30 CPP, comprises different parts that are detailed below:

    (a) A salt or complex of a metal cation that acts as the connection node of the different ligands; belonging to the following group: manganese, iron, cobalt, nickel, copper, zinc, technetium, ruthenium, rhodium, osmium, iridium and platinum, aluminum, gallium, Indian 35 and lead. Also included are elements of the rare earth family such as gadolinium, terbium and uranium.
    (b) An organic ligand that acts as a connector of the metal centers and promotes the polymerization of the coordination system; belonging to the following group: bi- or polyfunctional systems derived from carboxylic acids, phosphoric groups, alcohols, thiols, amines, catechols and any functional group derived from nitrogen (imidazoles, pyridine and schiff bases).
    (c) A chelating ligand with high affinity for the metal center and having free functional groups that have no affinity for the metal center or said affinity is much lower than the chelating part; belonging to the following group: substituted derivatives of 1,2-benzenedithiol, 1,2-benzenediol, 1,2-benzenediamine, 2-mercaptophenol, 2-aminophenol or 2-aminobenzenethiol. The substituents of the aromatic rings may consist of a saturated or unsaturated alkyl chain terminated in one or more functional groups such as carboxylic groups, alcohols, thiols, amines, isocyanates or isothiocyanates. fifty
    (d) A substance of interest to covalently bind the free functional groups present on the surface of the microstructured micro- / nanostructured polymers by a complementary functional group for the coupling reaction. As an example we can cite the coupling reactions between a carboxylic group and an amino group by using carbodiimides to form a 5-amide bond (EDC / NHS), between an aldehyde group and an amine group to generate an imine by acid catalysis , between an acid chloride group and an amine to generate an amide bond (acylation of amines), between a sulfonyl chloride and an amine to form a sulfonamide bond, or between an isocyanate and alcohols, amines or thiols to generate bond couplings urethane, urea or thiocarbamate, respectively. 10

    A particular aspect of the invention is the obtaining of the metallurgical polymer system of the invention, hereinafter the method of the invention, which comprises the following steps:
     fifteen
    (a) A step of adding the different elements (salt or metal complex, organic ligands and substance of interest) in a single reaction mixture, which is kept under stirring from the beginning, and which can be carried out by a in the following ways: i) the addition of a salt or complex of a metal ion to a solution containing the organic ligands and the substance of interest to encapsulate or vice versa. When the salt or complex of a metal ion is added into the solution containing the organic ligands, polymerization and formation of the metal-organic particle that directly has functional groups on the surface is initiated (see Example 1); ii) the addition of organic ligands into the solution containing the salt or complex of a metal ion and the substance of interest to be encapsulated or vice versa; Iii) the substance of interest is added to a solution containing the salt or complex of a metal ion and one or more organic ligands or vice versa; or iv) the addition of the salt or complex of a metal ion, organic ligands and substance of interest to a solvent where the resulting metalorganic system is insoluble or vice versa.
    (b) Preferably performed at room temperature 30
    (c) The separation of the obtained metalorganic systems is carried out by centrifugation. The subsequent redispersion can be carried out in different solvents, in which the material is insoluble, by shaking and applying ultrasound.
     35
    Another aspect of the invention is the use of the functionalized surface of the micro- / nanoparticles of the present invention for anchoring, immobilization, and storage of substances of interest, or for modifying the properties of the nanostructures, such as providing them of fluorescent properties (see Example 2), increase or decrease its hydrophobicity (see Example 3), decrease its toxicity or increase biocompatibility. Preferably, the functional groups present on the surface and capable of acting as an anchor point for different molecules and biomolecules are selected from the list comprising: amino, primary amine, secondary amine, tertiary amine, imine, hydrazine, nitro, isothiocyanate, isocyanate, alcohol, aldehyde, carboxylic group, phosphine, thiol, sulfonyl organometallic compounds, halide and any combination thereof. Four. Five

    Another aspect of the invention is the molecule or biomolecule that can be immobilized by covalent chemical bonding through a coupling reaction with the functional groups present on the surface of the micro- / nanoparticles. The molecules and biomolecules are selected from the list of substances that have an accessible functional group comprising: amino, primary amine, secondary amine, amine
    tertiary, imine, hydrazine, nitro, isothiocyanate, isocyanate, alcohol, aldehyde, carboxylic group, phosphine, thiol, sulfonyl organometallic compounds, halide and any combination thereof.

    Another particular aspect of the invention is the use of the metalorganic polymer system 5 in the elaboration of nanocontainers of active species (see Example 4), catalysts, sensors, contrast agents, biomarkers, magnetic semiconductors and devices for magnetic recording.

    Another particular aspect of the invention is a metalorganic system where the complex of a metal ion is Co (CH3OO) 2 · 4H2O, where the organic ligand that acts as a connection between metal centers is 1,4-bis (imidazol-1 -ylmethyl) benzene (Bix), the chelate ligand is a mixture in different proportions of caffeic acid (3,4-dihydroxycinnamic acid) provided by the free -COOH group and dopamine (3,4-dihydroxyphenethylamine) provided by the group –NH2. In this way nanoparticles with two different functional groups on the surface are obtained (-COOH + -NH2).

    Another particular aspect of the invention is a metalorganic system where a molecule or biomolecule of interest is immobilized by a covalent bond where the molecule belongs to the group: a drug, an organic compound, a fluorescent compound, an inorganic compound, a metalorganic compound or a nanomaterial (nanoparticles, nanotubes, nanowires and nanocrystals), and the biomolecule belongs to the group: an antibody, a bacterium, a virus, a cell, a protein, a sugar, DNA and RNA.

    The metallurgical systems described in the present invention can have different sizes in the range of 40nm-10micras with good control in size dispersion during synthesis.

    Another aspect of the invention is the process for obtaining the metallurgical system of the invention, which comprises the following steps:

    (a) a step of adding the various elements under stirring - salt or complex of a metal ion, organic ligand that acts as a connector of the metal centers and chelate ligand with affinity for the metal center that leaves a free functional group - in a only reaction solution, and which can be carried out in one of the following ways: i) by adding a salt or complex of a metal ion to a solution containing both types of ligands maintaining a 1 molar ratio: 1: 2 corresponding to the metal ion mixture: linker ligand: functionalized ligand - by adding the salt or complex of a metal ion into the solution containing the two types of organic ligands, the formation of the metalorganic particle 40 is initiated, which is generally a material with low solubility in the reaction medium; ii) the addition of the two types of organic ligands into the solution containing the salt or complex of a metal ion.
    (b) precipitation of the formed metalorganic polymer - normally the reaction product is insoluble in the reaction medium, but in the case where the formed polymer shows high solubility in the medium precipitation is induced by the addition of a solvent poor (usually non-polar solvents such as pentane, ethyl ether, toluene, hexane and benzene, or even water).
    (c) separation of the metalorganic systems obtained by centrifugation and several washes with a solvent that does not solubilize the nanostructured material, but that dissolves impurities or residues of starting reagents that can impurify the
    material (usually non-polar solvents such as pentane, ethyl ether, toluene, hexane and benzene or water).

    In general terms, the process of obtaining is carried out at room temperature and maintaining stirring during the polymerization process. Stirring may be by mechanical, magnetic or ultrasonic agitation.

    The size of the metalorganic systems can be controlled by varying the reaction conditions, for example, by modulating the concentrations of the initial solutions (of the metal and the organic ligands). The rate of addition of the different reagents can also modulate the size of the nanoparticles, but their effect is not as critical compared to the variation in the reagent concentrations. Another form of size control is related to the speed of agitation during synthesis. The characteristic particle size for a particular metalorganic system under certain reaction conditions is not extrapolated to another different metalorganic system, since it is also dependent on the nature of the metal and ligands used. In general terms, it is observed that at higher rates of addition of the metal salt on the ligands or vice versa, smaller metalorganic particles are obtained than when it is done more slowly. In the same sense, the greater the concentration of the reagents, the greater the size of the nanostructures. And an increase in the speed of agitation affects 20 in the decrease of the size of the particles.

    Thus, depending on the metalorganic system of the specific invention, a person skilled in the art and with the information provided in the present invention could easily design the appropriate reaction conditions to obtain a suitable particle size.

    Because of their enormous versatility, these metallurgical systems have a great field of application within nanomedicine, since they are systems with a large load capacity for different molecules and biomolecules [D. Maspoch, I. Imaz, D. Ruiz-Molina. Patent 30 Number: P200801230 and PCT No. PCT / ES2009 / 070128; I. Imaz, J. Hernando, D. Ruiz-Molina, D. Maspoch Angew. Chem. Int. Ed. (2009) 48, 2325-2329.]. It also allows to design systems with a suitable size for application in therapy and diagnosis as elements for bioimaging and controlled drug release [F. Boyfriend et al. Cood. Chem. Rev. ((2013), 257, 2839-2847] Within this area, the invention presented here provides 35 new systems with substantial advantages over those already described, since their functionality is increased by presenting free functional groups in its structure to anchor in a post-synthetic stage a great variety of molecules and / or biomolecules (drugs, vaccines, drugs, peptides, proteins or nucleic acid sequences) and then release them in a controlled way at specific points of the human body. The possibility of anchoring, on the surface of the particles of these inorganic polymers, different molecules (ligands, aptamers) that specifically recognize certain cells have a great interest for the selective therapeutic treatment towards tumor cells, which would minimize the side effects of current anti-cancer treatments based on chemo and radiotherapy. As an example, we can think of a system 45 stable in physiological media based on a fluorescent coordination polymer (containing zinc or metal ions of the rare earth family that emit above 500nm), with the ability to encapsulate one or more anti-cancer drugs, functionalized on the surface with molecules that endow it with biocompatibility (PEG derivatives) and functionalized at the same time with a family of molecules that specifically recognize a specific cancer cell. This system represents a
    multifunctional platform that facilitates its monitoring in vitro or inside living organisms by bioimage, which protects and isolates anticancer drugs until it reaches the right place for release and is able to recognize a certain cancer cell by the presence on the surface of a suitable target (antibodies, receptors, enzymes etc.). 5

    Another particular aspect of the invention is the modification of the surface hydrophobicity by the inclusion or anchoring of hydrophilic or hydrophobic chains on the surface of the coordination polymers. A particular case (see Example 5) is the metalorganic system of Example 1 functionalized on the surface with: a) 10 chains derived from polyethylene glycol, which is a highly hydrophilic material, and b) octadecylamine chains, which have a high hydrophobicity. By anchoring one or the other material on the surface of the organometallic polymer it is possible to control the hydrophilicity of these systems. This hydrophilic control allows the design of systems that accumulate in certain tissues or cross certain physiological barriers, providing a high potential for the use of these systems in the medical field.

    Another particular aspect of the invention is the toxicity of the systems generated. In vitro toxicity studies indicate that the toxicity referred to therapeutic doses is very low (see Example 6). The low metal concentration in relation to the weight of the polymer and the compatibility of the ligands used generate these good results that indicate the suitability of the use of these systems in the field of biomedicine as elements of therapy and diagnosis. Both in the case of polymers of the invention containing biocompatible metals (Fe, Zn) and those containing elements considered more toxic (Co), in vitro cytotoxicity tests show more than remarkable results for use within nanomedicine.

    Another particular aspect of the invention is the use of the metalorganic system, functionalized or not, in the elaboration of a diagnostic or therapeutic drug or pharmaceutical composition. And therefore, a pharmaceutical composition comprising the metalorganic system of the invention forms part of the present invention.

    Another particular aspect of the invention is the use of the metalorganic system, functionalized or not, in the preparation of catalysts, sensors, contrast agents, biomarkers, magnetic semiconductors and devices for magnetic recording. 35

    Another particular aspect of the invention is the use of different ligands that coordinate to the metal center and another functional group that does not coordinate to the metal cation. The ability of these free functional groups to generate secondary interactions (hydrogen bonds; Van der Waals forces; ionic interactions and hydrophobic interactions) determine the greater or lesser thermal and even chemical stability (see Example 7).

    Example 1: Synthesis of nanoparticles of iron coordination polymers containing surface carboxyl groups. Four. Five

    The methodology presented here allows the obtaining of nanoparticles between 50-200 nm. According to the method used, the metal-organic polymer is obtained by adding, at room temperature and under magnetic stirring, a solution (milli-Q water; 5 ml) of Fe (CH3COO) 2 (100 mg; 95% purity, Sigma -Aldrich) on a solution (ethanol; 25 ml) containing the organic ligand 1,4-bis (imidazol-1-ylmethyl) benzene (Bix; 138 mg; synthesized by
    procedure described by Dhal, (P. K. Dhal, F. H. Arnold, Macromolecules, 1992, 25, 7051) and the commercial ligand 3,4-dihydroxycinnamic acid (dhc; 205 mg; ≥98.0% purity, Sigma-Aldrich). Immediately, the precipitation of a dark violet dispersed solid is observed, which corresponds to the polymer in question (Figure 1).
     5
    The nanoparticles are separated by centrifugation (5000 rpm; 15 minutes) and redispersed in ethanol. The process is repeated several times (between 4-6 times), depending on the synthesized material, to obtain the nanoparticles as pure as possible and avoid the presence of impurities from the starting reagents. Normally the absence of turbidity or color in the solvent after centrifugation indicates a correct washing of the material. Finally, the material can be dried in air or by vacuum systems and the nanoparticles can be stored in solid state or redispersed in different solvents or saline solutions such as phosphate buffers.

    The chemical analysis, infrared spectrometry and images by electron microscopy 15 (SEM / TEM) show us a chemical composition and structure corresponding to 1D polymers confined in nanoparticles between 150-200nm in which several carboxyl groups are present on the surface of the nanoparticle, being in all cases easy to determine by an expert.
     twenty
    Example 2: Aminofluorescein functionalization of nanoparticles of iron coordination polymers containing surface carboxyl groups.

    The methodology presented here allows surface functionalization of metal-organic nanoparticles by means of a type of coupling reaction mediated by carbodiimide coupling agents (EDC). According to the method used, the functionalization of the metal-organic polymer surfaces with 6-aminofluorescein is obtained by adding, at room temperature and under magnetic stirring, an ethanolic solution (milli-Q water / 4: 1 ethanol; 5 ml) of 6-amino fluorescein (15 mg; 95% purity, Sigma-Aldrich) on a solution containing a dispersion of the nanoparticles synthesized in Example 1 30 (100 mg nanoparticles; milli-Q water / 4: 1 ethanol; 50 ml ). After 10 minutes, the coupling agent N- (3-Dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) (30mg; ≥99.0% purity, Sigma-Aldrich) and N-hydroxysuccinimide (NHS) (17.25 mg; 98%) is added purity, Sigma-Aldrich). Stirring is maintained for 6 hours and subsequently the functionalized nanoparticles are precipitated by centrifugation (5000 rpm; 15 minutes). 35 different ethanol washes are performed, until no trace of fluorescence is detected in the solution, which indicates that there are no remains of the free fluorescent species.

    Finally, the material can be dried in air or by vacuum systems and the nanoparticles can be stored in solid state or redispersed in different solvents or saline solutions such as phosphate buffers. The characterization by chemical analysis, absorbance measurements, infrared spectroscopy, optical microscopy and fluorescence corroborate the coupling of the fluorescent molecule on the surface of the nanoparticle by covalent bond (amide). The particles have fluorescence both in solid state and in a colloidal solution (Figure 2). Four. Five

    Example 3: Coupling of PEG derivatives in the metalorganic system of the invention

    The methodology presented here allows the surface functionalization of the 50 metal-organic nanoparticles with hydrophilic chains derived from PEG that provide the
    nanoparticles of greater hydrophilicity, biocompatibility and low toxicity. Starting from the nanoparticles synthesized in Example 1, covalent bonding of a functionalized PEG polymer at one end with an amine group results in the generation of a peptide bond mediated by the coupling agents (EDC / NHS) in the same way as In the previous example. The external surface functionalization of said 5 systems is carried out by adding, at room temperature and under stirring, a solution (50mM phosphate buffer, pH7.4; 5 ml) containing 30 mg of O- (2-aminoethyl) polyethylene glycol 3,000 on a solution containing a dispersion of the nanoparticles synthesized in Example 1 (100 mg nanoparticles; 50mM phosphate buffer, pH7.4; 25 ml). After 10 minutes, the coupling agent N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide 10 (EDC) (60mg; ≥99.0% purity, Sigma-Aldrich) and N-hydroxysuccinimide (NHS) (34.5 mg; 98 % purity, Sigma-Aldrich). Stirring is maintained for 6 hours and subsequently the functionalized nanoparticles are precipitated by centrifugation (5000 rpm; 15 minutes). Different washes are performed with ethanol (a minimum of four times). Finally, separate, clean and dry systems under vacuum can be stored in solid state or redispersed in different solvents.

    The characterization by chemical analysis, absorbance measurements, infrared spectroscopy and optical microscopy corroborates the coupling of the PEG chains on the surface of the nanoparticle by covalent amide bonding (Figure 3). The particles 20 show a marked improvement in their colloidal stability in aqueous solutions.

    Example 4: Coupling of hydrophobic chains in the metallurgical system of the invention
     25
    Octadecylamine is used as a hydrophobic chain, a hydrocarbon chain with an amino function at one of its ends that constitutes the point of attachment to the carboxylic groups of the nanoparticles synthesized in Example 1.

    Formation of the imino covalent bond occurs by the procedure described in Examples 2 and 3 by the EDC / NHS coupling agents in ethanolic medium. At room temperature and with stirring, an ethanolic octadecylamine (ODA) solution (25 mg ODA; ethanol / miliQ water 4: 1.5 ml) is added onto a solution containing a dispersion of the nanoparticles synthesized in Example 1 (100 mg nanoparticles; ethanol / water miliQ 4: 1, 25 ml). After 10 minutes, the coupling agent N-35 (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) (60mg; ≥99.0% purity, Sigma-Aldrich) and N-hydroxysuccinimide (NHS) (34.5 mg; 98%) is added purity, Sigma-Aldrich). Stirring is maintained for 6 hours and subsequently the functionalized nanoparticles are precipitated by centrifugation (5000 rpm; 15 minutes). Different washes are performed with ethanol (a minimum of four times). Finally, separate, clean and dry systems under vacuum 40 can be preserved in a solid state (Figure 4).

    Example 5: Encapsulation of drugs with metal-organic systems of the invention

    The same procedure is used as to obtain the nanoparticles described in Example 1. In addition, a concentration of a drug (eg camptothecin-CPT) is included in a concentration ([CPT] = 3.0 x 10-3 M) in the ethanolic solution of the ligands. The resulting nanoparticles were purified by centrifugation and washed several times with ethanol. This process is repeated until fluorescent species are not detected in solution by fluorimetric measurements. SEM and EM images reveal formation 50
    of nanoparticles with an average size of 112 ± 19 nm and an encapsulation efficiency of 15% by weight of the nanoparticle (Figure 5).

    Example 6: Toxicity studies
     5
    To evaluate the toxicity effect of free metal-organic nanoparticles and containing an antitumor drug, different in vitro tests were performed to evaluate the IC50 index. For this calculation, MCF-7 cells were incubated with different concentrations of nanoparticles containing a surface fluorescent marker such as those obtained in example 2. The quantification of the nanoparticles that are capable of being introduced into the cells was performed by spectrofluorometric measurements and observed an internalization greater than 30%. The toxicity of metal-organic nanoparticles is surprisingly low. In addition, there was a notable increase (more than 6 times) in the tumor activity of the encapsulated drug with respect to the free drug (Figure 6).
     fifteen
    Example 7: Thermal stability studies comparing two nanoparticle systems containing different ligands with free functional groups that generate different secondary interactions.

    The thermal stability of the system synthesized in Example 1 was compared with another analogue, in which the commercial ligand 3,4-hydroxycinnamic acid (dhc) was replaced by equimolar amounts of the commercial ligand 3,4-di (tert-butyl) catechol (dtbucat). The synthesis, isolation and characterization of the material is analogous. The size of the particles containing dtbucat is in the same range as those containing dhc.
     25
    Electron microscopy (SEM) and thermogravimetry (TGA / DSC) monitoring shows that the particles synthesized in Example 1 begin to melt at 105 ° C and decompose above 220 ° C, due to the thermal stability conferred by the numerous hydrogen bonds generated by the carboxylic groups within the particle. The replacement of the dhc ligands with dtbucat induces a rather notable decrease in the melting point that drops to about 60 ° C. (Figure 7).
    权利要求:
    Claims (30)
    [1]

    1.- Metalloorganic polymeric system of coordination on a micro- / nanometric scale useful for encapsulating and covalently joining different substances on its surface comprising:
    (a) a salt or complex of a metal ion of the transition series or of the family of the 5 rare earths, selected from the list comprising zinc, copper, iron, cadmium, manganese, nickel, cobalt, gadolinium, europium, terbium, uranium, aluminum or gallium that constitute the metal centers of the metalloorganic polymer system.
    (b) at least one organic ligand that acts as a connector between metal centers;
    (c) at least one functional organic chelate ligand with affinity for the metal center and which has a free functional group that does not coordinate the center.
    (d) a substance of interest to encapsulate, selected from the group comprising: a biological entity, a drug, a vaccine, a diagnostic contrast agent, a label, an organic compound, an inorganic compound, a metalorganic compound or a nanomaterial . fifteen

    [2]
    2. Metalloorganic polymer system according to claim 1, characterized in that the metal ion comes from the compound Co (CH3OO) 2 · 4H2O.

    [3]
    3. Metalloorganic polymer system according to any one of claims 1 to 2, 20 characterized in that the organic ligand that acts as a connector between metal centers is an organic compound with at least one functional group, which is selected from the list comprising carboxylic acids , phosphoric groups, alcohols, thiols, amines, catechols and any functional group derived from nitrogen, particularly imidazoles, pyridine and Schiff bases. 25

    [4]
    4. Metalloorganic polymer system according to claim 3, characterized in that the organic ligand that acts as a connector between metal centers is 1,4-bis (imidazol-1-ylmethyl) benzene (Bix).
     30
    [5]
    5. Metalloorganic polymer system according to any one of claims 1 to 4, characterized in that the substance of interest to be encapsulated is an entity with biological activity selected from a list comprising a bacterium, a virus, a eukaryotic cell, a protein, a antibody, sugars, DNA, RNA or a drug.
     35
    [6]
    6. Metalloorganic polymeric system according to any one of claims 1 to 4, characterized in that the substance of interest to be encapsulated is a nanomaterial selected from a list comprising nanoparticles, nanotubes, nanowires, nanocrystals or nanodevices.
      40
    [7]
    7. Metalloorganic polymeric system according to any of claims 1 to 6, characterized in that the functional organic ligand is a chelate organic compound with at least one free functional group, wherein the functional group is selected from the list comprising carboxylic acids, alcohols, thiols, amines, thiocyanates, isocyanates, isothiocyanates, catechols and any functional group derived from nitrogen. Four. Five

    [8]
    8. Polymeric polymeric system according to claim 7, characterized in that the non-covalent secondary interactions developed by the free functional groups in the organic chelate ligand modulate the thermal stability of the nanoparticles.
     fifty
    [9]
    9. Polymeric polymeric system according to claim 8, characterized in that the non-covalent secondary interactions are hydrogen bridges, Van de Waals forces, ionic interactions or hydrophobic interactions.

    [10]
    10. Metalloorganic polymer system according to any of claims 7 to 9, characterized in that the organic chelate compound is a mixture in proportions, with respect to stoichiometric amounts, comprised between 75% and 25% of 3,4-dihydroxycinnamic acid which provides the group -COOH free, and between 25% and 75% dopamine (3,4-dihydroxyphenethylamine) provided by the group -NH2.
     10
    [11]
    11. Polymeric polymeric system according to any one of claims 1 to 10, characterized in that it has a size between 40 nm and 10 µm.

    [ 12]
     12. Polymeric polymeric system according to any one of claims 1 to 11, characterized in that it is functionalized on its outer surface with another species or substance.

    [13]
    13. Metalloorganic polymer system according to claim 12, characterized in that the species or substance is selected from a list comprising an antibody, a bacterium, a virus, a cell, a protein, a sugar, DNA, a drug, a drug, an organic compound, a fluorescent compound, an inorganic compound, a metalloorganic compound or a nanomaterial.

    [14]
    14. Metalloorganic polymer system according to claims 12 and 13, characterized in that the functionalization is carried out by coupling reactions between a carboxylic group and an amino group by using carbodiimides to form an amide bond (EDC / NHS).

    [15]
    15. Metalloorganic polymer system according to claims 12 and 13, characterized in that the functionalization is carried out by an acylation reaction of amines between an acid chloride group and an amine to generate an amide bond.

    [16]
    16. Metalloorganic polymer system according to claims 12 and 13, characterized in that the functionalization is carried out by reaction between a sulfonyl chloride and an amine to form a sulfonamide bond. 35

    [17]
    17. Metalloorganic polymer system according to claims 12 and 13, characterized in that the functionalization is carried out by reaction between an isocyanate and alcohols to generate a urethane bond coupling.
     40
    [18]
    18. Polymeric polymeric system according to claims 12 and 13, characterized in that the functionalization is carried out by reaction between an isocyanate and amines to generate a urea bond coupling.

    [19]
    19. Metalloorganic polymer system according to claims 12 and 13, characterized in that the functionalization is carried out by reaction between an isocyanate and thiols to generate a thiocarbamate link coupling.

    [20]
    20. Procedure for obtaining the metalloorganic polymer system as defined in claims 1 to 19, characterized in that it comprises the following steps:
    a) a step of adding the salt or complex of a metal ion, the organic ligand that acts as a connector of the metal centers and the chelate ligand affinity for the metal center that leaves a functional group free, to a single reaction solution , which is in agitation;
    b) precipitation of the formed metalloorganic polymer system; 5
    c) separation of the metalorganic polymer systems

    [21]
    21. Method according to claim 20, characterized in that the addition step is carried out by adding the metal ion salt or complex to a solution containing the two types of ligands, maintaining a corresponding 1: 1: 2 molar ratio. 10 to the metal ion mixture: linker ligand: functionalized ligand starting the formation of the metalorganic polymer system

    [22]
    22. Method according to claim 20, characterized in that the addition step is carried out by adding the two types of organic ligands into the solution containing the salt or complex of a metal ion.

    [23]
    23. Method according to any one of claims 20 to 22, characterized in that the stirring is mechanical, magnetic or by ultrasound at room temperature. twenty
    [24]
    24. Method according to any one of claims 20 to 23, characterized in that the material formed after the addition stage has
    Low solubility in the reaction medium.
     25
    [25]
    25. Method according to any one of claims 20 to 23, characterized in that in the case that the material formed after the addition stage shows a high solubility in the reaction medium, precipitation is induced by the addition of a solvent that is Select from non-polar solvents such as pentane, ethyl ether, toluene, hexane and benzene, or water. 30

    [26]
    26.- Method according to any one of claims 20 to 25, characterized in that the separation of the obtained metalloorganic systems is carried out by centrifugation and washing with a solvent that does not solubilize the material, but dissolves impurities or residues of starting reagents that they can impurify the material, the metalorganic material being stored as solid or in a colloidal suspension.

    [27]
    27.- Use of the metalloorganic polymer system as defined in any of claims 1 to 19 for the release and / or protection and / or storage and / or variation of the properties of the encapsulated substances of interest.

    [28]
    28.- Use of the metalloorganic polymer system as defined in any of claims 1 to 19 for the preparation of catalysts, sensors, contrast agents, biomarkers, magnetic semiconductors or devices for magnetic recording.

    [29]
    29.- Use of the metalorganic system as defined in any of claims 1 to 19 for the preparation of a pharmaceutical, diagnostic or therapeutic drug or composition. fifty

    [30]
    30.- Pharmaceutical, diagnostic or therapeutic composition characterized in that it comprises the metalorganic polymeric system according to claims 1 to 19.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2331781B1|2008-01-31|2010-10-27|Universidad Pablo De Olavide|METALLIC NANOPARTICLES FUNCTIONED WITH THE VIP NEUROPEPTIDE AND PREPARATION PROCEDURE.|
    ES2327596B1|2008-04-29|2010-08-10|Consejo Superior De Investigaciones Cientificas 33.33%|USEFUL METALORGANIC SYSTEM FOR THE ENCAPSULAMENT AND RELEASE OF INTEREST COMPOUNDS, PROCEDURE OF OBTAINING AND ITS APPLICATIONS.|CN107446401B|2017-04-01|2019-08-20|华南理工大学|Using dopamine as high hydrophobicity anti-bacterial attachment surface of anchor molecule and preparation method thereof|
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