ES2541501B1 - METRO-ORGANIC POLYMER SYSTEM FOR MICRO- / NANOMETRIC SCALE COORDINATION, PROCEDURE FOR OBTAINING AND APPLICATIONS - Google Patents

Abstract

Metaloorganic polymeric system for coordination on a micro- / nanometric scale procedure for obtaining and applications. # The object of the present invention is a metalloorganic polymeric system for coordination of particles of high stability and having functional groups on the surface capable of acting as points of anchoring of different species that have properties such as luminescence, chemical, catalytic activity and / or biological activity. Also 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.

Description

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

DESCRIPTION

Metalloorganic polymeric coordination system on a micro- / nanometric scale, procedure for obtaining and applications.

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.

The object of the present invention is a metalloorganic polymeric system for coordination of particles of great stability and that have functional groups on the surface that can act as anchor points of different species that have properties such as luminescence, chemical activity, catalytic activity and / or activity. Biological Also objects of the present invention are a method for the micro- and nanometric level synthesis of the metalloorganic polymer system, as well as the applications thereof.

STATE OF THE TECHNIQUE

The applications of nanoparticles at the technological level have experienced an 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 has been as transport systems for enzymes, proteins or vitamins. Already in the 80s, the application within the field of bioimaging began to be developed 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 systems, immunoassays, genetic therapy and vectorization of nanoparticles for the detection and specific actuation on tumor cells has been implemented. On an industrial level (electronic, aeronautical, military), applications based on nanoparticles such as lubricants, magnetic sensors, composite additives for the improvement of physical-chemical properties, for the development of super-hydrophobic, adhesive surfaces, etc. have been described.

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 advanced technology. 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 detection and actuation on cancer cells.The appropriate experimental design allows to obtain suitable sizes for their application at the biomedical level and favor the intracellular transport of different biomolecules avoiding their elimination by the endothelial reticulum system or the accumulation in tissues.

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

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

However, the coating of the nanoparticles with a stabilizer layer usually 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 corresponds 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 practically 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).

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-guest interactions, which allows a systematization when modifying encapsulation and controlled liberation capacities 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, to 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 through different techniques (solvothermal reactions, emulsion techniques 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. an exponential increase in the publication of studies with these systems in the last 5 years and have obtained ultados very

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

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 nanometric size are obtained when the polymer was precipitated by the addition of a non-polar solvent (pentane, ether, toluene, hexane and benzene). Another reference for the synthesis of metalloorganic polymers, using a similar methodology, was published that 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. Galan-Mascaras, M. Monrabal-Capilla, J. Garcla-Martlnez, P. Pardo-Ibanez, Adv. Mater. (2007), 19, 1359-1361.

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, many 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 the tautomerla of Valencia [I. Imaz, D. Maspoch, C. Rodrlguez-Blanco, J.- M. Perez-Falcon, J. Campo, D. Ruiz-Molina, Angew. Chem. Int. Ed. 2008, 47, 1857-1860].

However, despite the latest advances, a methodology developed to achieve the functionalization of the surface of these systems directly, systematically and with a reduced cost has not been described to date. 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 form joints that are sensitive to certain external stimuli such as light, temperature or change in pH.

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 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 limitations do not exist. In fact the use of functional ligands can provide value

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

added to the systems since the correct choice of the connecting ligands and the functional ligands can have an impact on the modification of the stability, porosity or the number of functional groups on the surface that can serve as an anchor point for different molecules or biomolecules.

BRIEF DESCRIPTION OF THE INVENTION

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

The object of the present invention is a metalloorganic polymeric coordination system on a micro- / nanometric scale useful for encapsulating and covalently binding different substances on its surface comprising:

(a) a salt or complex of a metal ion of the transition series or 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;

(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.

• 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 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.

• 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 derived functional group of nitrogen, less 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. Non-covalent secondary interactions developed by the free functional groups in the organic chelate ligand modulate the thermal stability of the nanoparticles, being

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

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 group -NH2.

In all the previous embodiments, the metalorganic polymer system has a size between 40 nm and 10 pm and is functionalized on its outer surface 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.

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 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.

• 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.

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, of the organic ligand that acts as a connector of the metal centers and of the chelate ligand with affinity for the metal center that leaves a free functional group, to a single solution of reaction, which is in agitation;

(b) precipitation of the formed metalloorganic polymer system;

(c) separation of metalorganic polymer systems

The addition step can be carried out by adding the salt or metal ion complex to a solution containing the two types of ligands maintaining a 1: 1: 2 molar ratio corresponding to the metal ion mixture: linker ligand: functionalized ligand starting the formation of the metalorganic polymer system or by adding the two types of organic ligands into the solution containing the salt or complex of a metal ion.

The agitation can be mechanical, magnetic or by ultrasound at room temperature. In some cases, the material formed after the addition stage has low solubility in the reaction medium. In the case where the material formed after the addition stage shows a high solubility in the reaction medium, precipitation is induced.

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

by adding a solvent that is selected from non-polar solvents such as pentane, 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 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 drug or pharmaceutical, diagnostic or therapeutic composition.

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

Technical problem that solves:

1. It allows the in situ functionalization of the nanoparticles (one pot). Avoid having to coat the nanoparticles with a functionalized polymer after its synthesis.

2. The surface of the nanoparticle can be functionalized with one or more different functional groups in a single reaction (one pot).

3. Increase of thermal stability and 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.

5. Increased biocompatibility by being able to anchor molecules and biomolecules on the surface that avoid immunological responses, for example PEG derived chains.

Advantages that it brings with respect to the state of the current technique:

1. Possibility of anchoring virtually any molecule and / or biomolecule covalently and reversibly on the surface of the nanosystems.

2. Ability to control the surface charge based on the functional groups used, which is a key factor in the cellular internalization of these nanosystems (E. Frohlich, International Journal of Nanomedicine 2012: 7 5577-5591).

3. Thermal stability and pH sensitivity can be controlled by the proper 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 forces of cohesion between polymer chains, allows to modulate "on demand" the stability of the nanoparticles. Thus it is possible to design particles with great stability or that rapidly degrade in a determined environment.

Possible applications:

• Catalysis,

5

10

fifteen

twenty

25

30

35

40

Four. Five

• Biosensors,

• Biomarkers,

• Contrast agents,

• Cancer Cell targeting,

• Encapsulation of drugs in general (anticancer, antiparasitic, antimalarial, etc.),

• Smart nanocontainers (capable of responding to an external stimulus) for controlled release of drugs or other active or interesting species,

• Molecular devices

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) solid aspect 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 (continuous 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) Measures of Zeta potential of the functionalized particles with PEG and the comparison with the non-functionalized nanoparticles.

Fig. 4: a) Scheme of the coupling reaction between nanoparticles containing carboxyl groups on the surface and octadecylamine (ODA) by EDC / NHS coupling agents, b) SEM image of nanoparticles containing ODA chains on the surface, c) Phase separation in a toluene / water mixture containing non-functionalized and functionalized particles with ODA on the surface. It can be seen how it is possible to control the hydrophobicity of the nanoparticles by including hydrophobic chains.

Fig. 5: Images of a) SEM, and b) Optical microscope of nanoparticle fluorescence containing encapsulated camptothecin (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 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.

Fig. 7: Thermal stability analysis of the particles by 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 ).

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

DETAILED DESCRIPTION OF THE INVENTION

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

The method of the invention is based on the polymerization of a meta-organic system in a single, simple, low-cost step, in non-polluting dissociants and with high performance. The resurrected is a material that presents functional groups on the surface that are likely to act as an aging point for different moiecuias and biomoiecuias that can provide a added value to the system.

The meta-organic system of this invention, not only complements existing metaorganic systems but allows the obtention of new systems with new properties, more resistant to degradation, resistant to extreme pH and with the possibility of a later functioning of nanomateria generating muitifunctional systems or piataformas. 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 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 on the surface different moiecuias or biomoiecuias can be arranged that They provide one or more functions added. One example may be the incision of fiuorescent moiecuias (for bioimaging), antibodies (for seiective iocaiization of a type of tumor or other type of ceiuias), biomarkers, agents for the detection of certain anaiites and / or moiecuias or biomoiecuias that increase the biocompatibility of The nanostructure such as derivatives of the poiietiiengiicoi, poiisacaridos or certain proteins.

The proposed invention focuses on the description of a new method for generating a multi-functional metaorganic system, with the main characteristic that a mixture of iigands with different tasks is used for their synthesis. On one side, two-function fiexibie organic ligands are used, which act as connectors between metal centers and favor polymerization. On the other hand, in the mix of reaction are included, iigands that contain a functional group that favor their coordination to the metaiic center and another functional group that does not coordinate the metaiic cation and is later free to the synthesis. The fact that a working group will be free once synthesized and the micro- / nanoscopic material will allow the later aging of different moiecuias or biomoiecuias. In addition, the use of free functional groups that are capable of generating non-covalent secondary interactions (hydrogen bonds; Van der Waais forces; ionic interactions and hydrophobic interactions) allow modulating the stability of nanoparticles at will and appropriate to a particular use.

The present invention is based on the synthesis of a metaorganic system containing igands with a high affinity for a large number of metabolic ions and which in turn have free functional groups that can be used as aging points of different substances at a later stage than their synthesis. The metaorganic system of this invention that contains iigands with free functional groups does not only add a new system to existing ones but allows the design and obtaining of new systems

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

functional where the properties of metalorganic particles (porosity, capacity of encapsulation and controlled liberation, magnetism, electronics, fluorescence, etc.) are combined with the advantages of obtaining systems with functional groups on the surface that allows anchoring, in a covalent way , 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.

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 induces changes at the physical-chemical level that affect 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 (type van der Waals, electrostatic, hydrogen bridges or type pp) that will impact in the physical-chemical 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 the selective release of drugs, controlled by the application of an external stimulus that triggers it.

MODE OF EMBODIMENT OF THE INVENTION

The polymeric metalorganic coordination system at micro- / nanometric scale, hereinafter 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, indium 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 for 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 chelate 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 be constituted by a saturated or unsaturated alkyl chain terminated in one or more functional groups such as carboxylic groups, alcohols, thiols, amines, isocyanates or isothiocyanates.

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

(d) A substance of interest to covalently bind the free functional groups present on the surface of the micro- / nanostructured coordination 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 an 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 urethane bond couplings , urea or thiocarbamate, respectively.

A particular aspect of the invention is the obtaining of the metalorganic polymeric system of the invention, hereinafter the process of the invention, which comprises the following steps:

(a) A stage 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. By adding the salt or complex of a metal ion into the solution containing the organic ligands, polymerization and formation of the metal-organic particle that directly presents 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 encapsulate 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

(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.

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 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 of 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.

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. Molecules and biomolecules are selected from the list of substances that have an accessible functional group comprising: amino, primary amine, secondary amine, amine

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

tertiary, imine, hydrazine, nitro, isothiocyanate, isocyanate, alcohol, aldehldo, 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 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) 24H2O, 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 the dopamine (3,4-dihydroxyphenethylamine) provided by the -NH2 group. In this way nanoparticles with two different functional groups are obtained on the surface (-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 metalorganic systems described in the present invention can have different sizes in the range of 40nm-10micras with good control in the dispersion of sizes during the synthesis.

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

(a) a stage of adding the different elements under agitation - 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 The 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: 1 molar ratio : 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 that is usually a material begins 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 a high solubility in the medium, precipitation is induced by the addition of a poor solvent. (usually non-polar solvents such as pentane, ethanol, 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

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

material (usually non-polar solvents such as pentane, ether, toluene, hexane and benzene or water).

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

The size of 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 the 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 the decrease in the size of the particles.

In this way, depending on the metalorganic system of the specific invention, a medium 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 metalorganic systems have a large 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 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 its 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 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. to anchor, on the surface of the particles of these inorganic polymers, different molecules (ligands, aptamers) that specifically recognize certain cells have a great interest in the face of selective therapeutic treatment towards tumor cells, which would minimize the side effects of current anticancer treatments based on chemo and radiotherapy.As an example, we can think of a stable system in physiological means b roasted in 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

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

Multifunctional platform that facilitates its monitoring in vitro or inside living organisms by bioimage, which protects and isolates anticancer drugs until it reaches the precise place for its release and is able to recognize a certain cancer cell by the presence on the surface of a suitable target (antibodies, receptors, enzymes etc.).

Another particular aspect of the invention is the modification of the surface hydrophobicity by the inclusion or anchoring of hydrophobic 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) 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 using 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 concentration of metal 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 the 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 preparation of a diagnostic or therapeutic drug or pharmaceutical composition. And therefore, a pharmaceutical composition comprising the metalorganic system of the invention is part of the present invention.

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

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.

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

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

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, corresponding to the polymer in question (Figure 1).

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 the air or by vacuum systems and the nanoparticles can be stored in a solid state or redispersed in different solvents or saline solutions such as phosphate buffers.

The chemical analysis, infrared spectrometry and the images by electron microscopy (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.

Example 2: Aminofluorescein functionalization of nanoparticles of iron coordination polymers containing surface carboxyl groups.

The methodology presented here allows the functionalization of the surface 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 ethanol solution (milli-Q water / ethanol 4: 1; 5 ml) of 6-amino fluorescell (15 mg; 95% purity, Sigma-Aldrich) on a solution containing a dispersion of the nanoparticles synthesized in Example 1 (100 mg nanoparticles; milli-Q water / ethanol 4: 1; 50 ml) . After 10 minutes, the coupling agent W- (3-Dimethylaminopropyl) -W'-ethylcarbodiimide (EDC) (30mg;> 99.0% purity, Sigma-Aldrich) and W-hydroxysuccinimide (NHS) (17.25 mg; 98%) are 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 carried out with ethanol, until traces of fluorescence are detected in the solution, which indicates that there are no remains of the free fluorescent species.

Finally, the material can be dried in the air or by vacuum systems and the nanoparticles can be stored in a 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 show fluorescence both in solid state and in a colloidal solution (Figure 2).

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

The methodology presented here allows the functionalization of the surface of the metal-organic nanoparticles with hydrophilic chains derived from the PEG that provide the

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

nanoparticles of greater hydrophilicity, biocompatibility and low toxicity. Starting from the nanoparticles synthesized in Example 1, the fixation by means of a covalent bond 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 functionalization of the external surface of these systems is carried out by adding, at room temperature and under agitation, a solution (50mM phosphate buffer, pH7.4; 5 ml) containing 30 mg of O- (2-aminoethyl) polyethylene glycol 3,000 over 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 W- (3-dimethylaminopropyl) -W'-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 can be stored in solid state or redispersed in different solvents.

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

Example 4: Coupling of hydrophobic chains in the metalorganic system of the invention

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 with the carboxylic groups of the nanoparticles synthesized in Example 1.

The formation of the covalent imino bond is produced by the procedure described in examples 2 and 3 by the EDC / NHS coupling agents in ethanol medium. At room temperature and under stirring, an ethanol solution of octadecylamine (ODA) (25 mg ODA; ethanol / water milliQ 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- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) (60mg;> 99.0% purity, Sigma-Aldrich) and N-hydroxysuccinimide (NHS) (34.5 mg; 98% purity) is added , 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 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 solution ethanol of the ligands. The resulting nanoparticles were purified by centrifugation and washed several times with ethanol. This process is repeated until no fluorescent species are detected in solution by fluorimetric measurements. SEM and EM images reveal the formation

5

10

fifteen

twenty

25

30

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

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 carried out 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).

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 the dtbucat is in the same range as those containing dhc.

Electron microscopy (SEM) and thermogravimetric (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 by dtbucat induces a fairly marked decrease in the melting point that drops to about 60 ° C. (Figure 7).

Claims (30)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 1. - Polyloorganic polymeric coordination system on a micro- / nanometric scale useful for encapsulating and covalently joining different substances on its surface, which comprises: (a) a salt or complex of a metal ion of the transition series or 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; (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 . 2. - Metalloorganic polymer system according to revindication 1, characterized in that the metal ion comes from the compound Co (CH3OO) 24H2O. 3. - Metalloorganic polymer system according to any one of claims 1 to 2, 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. 4. - Metalloorganic polymer system according to revindication 3, characterized in that the organic ligand that acts as a connector between metal centers is 1,4-bis (imidazol-1-ylmethyl) benzene (Bix). 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. 6. - Metalloorganic polymer 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. 7. - Metalloorganic polymer system according to any one of claims 1 to 6, characterized in that the functional organic ligand is an organic chelate 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. 8. - Metalorganic polymer system according to revindication 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. 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 9. - Metalorganic polymer system according to claim 8, characterized in that the non-covalent secondary interactions are hydrogen bonds, Van de Waals forces, ionic interactions or hydrophobic interactions. 10. - Metalloorganic polymer system according to any one 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-dihydroxycinmic acid which provides the free -COOH group, and between 25% and 75% dopamine (3,4-dihydroxyphenethylamine) provided by the -NH2 group. 11. - Metalorganic polymer system according to any one of claims 1 to 10, characterized in that it has a size between 40 nm and 10 pm. 12. - Metalorganic polymer 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. - 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. - 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. - 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. - 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. 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. 18. - Metalorganic polymer 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. - 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. - Method of obtaining the metalloorganic polymer system as defined in claims 1 to 19, characterized in that it comprises the following steps: 5 10 fifteen twenty 25 30 35 40 Four. Five fifty a) a step of adding the salt or complex of a metal ion, of the organic ligand that acts as a connector of the metal centers and of the chelate ligand with affinity for the metal center that leaves a free functional group, to a single reaction solution , which is in agitation; b) precipitation of the formed metalloorganic polymer system; c) separation of metalorganic polymer systems 21. - Method according to claim 20, characterized in that the step of addition is carried out by adding the salt or metal ion complex to a solution containing the two types of ligands maintaining a corresponding 1: 1: 2 molar ratio to the metal ion mixture: linker ligand: functionalized ligand starting the formation of the metalorganic polymer system 22. - Method according to claim 20, characterized in that the step of addition is carried out by adding the two types of organic ligands into the solution containing the salt or complex of a metal ion. 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. 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. - Method according to any one of claims 20 to 23 characterized in that in the case where 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. 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, storing the metalorganic material as solid or in a colloidal suspension. 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. - 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. - Use of the metalorganic system as defined in any one of claims 1 to 19 for the elaboration of a pharmaceutical, pharmaceutical or therapeutic drug or composition. 30.- Pharmaceutical, diagnostic or therapeutic composition characterized in that it comprises the metalorganic polymer system according to claims 1 to 19.