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    • 专利摘要:
    The present invention relates to a nanoparticulate material comprising or consisting of a resorbable nanoparticle that is functionalized with at least one compound. Furthermore, the present invention relates to a process for obtaining a nanoparticulate material, a product comprising the nanoparticulate material and uses thereof.
    公开号:ES2894878A2
    申请号:ES202130331
    申请日:2021-04-14
    公开日:2022-02-16
    发明作者:Dols Pau Turon；Christine Weis；Beltran Vanesa Sanz；Llanso Carlos Enrique Aleman；Costa Juan Torras；Ibanez Juan Francisco Julian；La Torre Carolina De；Badosa Manel Esteller
    申请人:Fundacio Inst De Recerca Contra La Leucemia Josep Carreras；Fundacio Institut De Investig En Ciencies de la Salut Germans Trias I Pujol；Universitat Politecnica de Catalunya UPC；Institucio Catalana de Recerca i Estudis Avancats ICREA；B Braun Surgical SA；
    IPC主号:
    专利说明:

    [0001] Nanoparticulate material, procedure for obtaining the nanoparticulate material, product comprising the nanoparticulate material and uses thereof
    [0005] The present invention relates to a nanoparticulate material, a process for obtaining the nanoparticulate material, a product, in particular a pharmaceutical composition, a medical kit or a medical device, comprising the nanoparticulate material, and various uses of the nanoparticulate material.
    [0009] New strategies for the treatment of current infections by pathogens of viral, bacterial or viral origin, for example a viral infection, such as the last outbreak caused by SARS-CoV-2, require: a) innovative strategies to inactivate the pathogen in media physiological, and b) new techniques to disinfect contaminated air and surfaces, particularly medical devices intended to protect health professionals. The first is required to minimize the rate of infection and to reduce or mitigate the effects of infection by the pathogen and its consequences such as pneumonia in the case of SARS-CoV-2 and, in the most critical cases, the death of the patient. The second aims to guarantee the reduction or deactivation of the pathogen in contaminated media, capable of reducing the pathogen already spread in aerosols or that remain on surfaces in order to obtain greater protection for patients and health professionals who need protective medical devices ( i.e. masks or gloves) and the prolongation of their use and recyclability
    [0011] The classical procedures to obtain an effective pharmacological treatment to combat pathogens, in particular viruses, are tedious and relatively slow compared to the immediacy of the outbreak. For example, it is necessary to develop new strategies to accelerate the treatment of SARS-CoV-2 infection.
    [0013] Nanotechnology can be a successful strategy against various pathogens. Nanotechnology involves the use of particulate materials that have at least one dimension less than 100 nanometers in length. In recent years, the field of technology has developed a growing number of applications in different areas, those focused on medicine being of particular interest. This field of research is still poorly explored and the development of safe and effective nanodevices for disinfection and therapy remains a major challenge.
    [0014] On the other hand, nanotechnology presents some problems due to its potentially harmful side effects, related to toxicity and biocompatibility. Regarding the therapeutic fields of use, the removal of nanomaterials from the body after treatment represents an important aspect. Studies on the toxicity, cytotoxicity and biodistribution of nanomaterials have been carried out showing that many types of nanoparticles are biocompatible and are neither toxic nor cytotoxic, but it has been confirmed that nanoparticles accumulate in certain tissues and organs. The development of a strategy for the purification of these accumulated nanoparticles from the body is still an incompletely explored field and remains a major challenge.
    [0016] The functionalization of nanoparticles to capture viruses is a new research field. Some studies have focused on this indication. It is worth mentioning that the impact of gold nanoparticles on viruses has been described, indicating that non-toxic nanoparticles could ultimately lead to irreversible viral deformation and subsequent deactivation. (V. Cagno, P. Andreozzi, M. D'Alicarnasso6, PJ Silva, M. Mueller, M. Galloux, R. Le Go-c7, ST Jones, M. Vallino, J. Hodek, J. Weber, S. Sen, E.-R. Janecek, A. Bekdemir, B. Sanavio, C. Martinelli, M. Donalisio, M.-A. R Welti, J.-F. Eleouet, Y. Han, L. Kaiser, L. Vukovic, C. Tapparel, P. Král, S. Krol, D. Lembo, F. Stellacci, Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism, Nature Materials, 2017, 17, 195-204).
    [0018] It is essential to establish the basis for virus inactivation and to perform toxicological risk assessment prior to authorization of any application involving nanoparticles. Current nanoparticles used in biomedicine include the use of metallic ions, such as gold, silver and zinc, however, these nanoparticles trigger significant problems related to their toxicity due to the risks associated with heavy metal elements and their accumulation in the body.
    [0020] Therefore, there is a need for new therapeutic strategies to fight against pathogens, such as viruses, or even against a proliferative disease, such as cancer.
    [0024] In view of the foregoing, the objective underlying the present invention is, therefore, to have a solution based on nanotechnology that is applicable to non-medical fields of use and medical fields of use, preferably medical fields of use, in particular to prevent and/or treat diseases and/or disorders, which at least partially avoid the aforementioned disadvantages in the context of conventional nanotechnology.
    [0026] This objective is achieved by means of a nanoparticulate material according to claim 1, a method for obtaining a nanoparticulate material according to claim 20, and a product, in particular a pharmaceutical composition, a medical kit or a medical device, according to claim 21. The embodiments preferred of the present invention are defined in the dependent claims. The subject matter and wording, respectively, of all claims are hereby incorporated into the description by explicit reference.
    [0028] According to a first aspect, the present invention relates to a nanoparticulate material comprising a resorbable nanoparticle that is functionalized with at least one compound or that consists of a resorbable nanoparticle that is functionalized with at least one compound. In other words, according to a first aspect, the present invention relates to a nanoparticulate material comprising or consisting of a resorbable functionalized nanoparticle, wherein the resorbable nanoparticle is functionalized with at least one compound.
    [0030] Within the scope of the present invention, the nanoparticulate material may also be called "resorbable functionalized nanoparticle", in particular "selective resorbable functionalized nanoparticle".
    [0032] The term "functionalized" in the context of the resorbable nanoparticle, as used according to the present invention, means to endow or equip the resorbable nanoparticle with at least one functionality, which resorbable nanoparticle normally, that is to say in a non-functionalized condition, does not possess. , by reaction of the resorbable nanoparticle with at least one compound that gives rise to a bond, in particular a covalent and/or non-covalent bond, of the at least one compound or a residue thereof to the resorbable nanoparticle or a surface thereof . Preferably, the functionality may be or comprise at least one functional group. More preferably, the at least one functional group has an affinity, in particular with respect to binding, in particular binding strength and/or selectivity, to the resorbable nanoparticle and/or the surface thereof. In particular, the functionality may be in the form of a chelating group comprising at least one functional group. For example, the at least one functional group can be selected from the group consisting of carboxyl group, hydroxyl group, amine group, phosphate group, phosphonate group, bisphosphonate group, sulfonate group, and combinations of at least two of the aforementioned functional groups.
    [0033] The term "nanoparticle", as used according to the present invention, refers to a particle or particulate material having at least one dimension, in particular a diameter, preferably an average diameter, and/or a length, preferably an average length. , and/or a width, in particular an average width, and/or a height, in particular an average height, of <500nm, in particular from 0.1nm to <500nm, in particular from 0.1nm to <250nm, preferably from 0.1nm to <100nm, more preferably from 1nm to <100nm, in particular from 1nm to 100nm or from 1nm to <100nm, preferably from 10nm to 50nm, in particular including any whole numbers and/or decimals included in the ranges mentioned above. The at least one dimension, in particular the diameter, preferably average diameter, and/or length, preferably average length, and/or width, in particular average width, and/or height, in particular average height, can be determined in particular by a Transmission Electron Microscope (TEM).
    [0035] Therefore, the term "nanoparticle", as used according to the present invention, can mean a nanometric particle, that is, a particle having at least one dimension, in particular a diameter, preferably an average diameter, and/or a length, preferably an average length, and/or a width, in particular an average width, and/or a height, in particular an average height, of <100nm, preferably from 0.1nm to <100nm, more preferably from 1nm to <100nm, in particular from 1nm to 100nm or from 1nm to <100nm, preferably from 10nm to 50nm, and/or a submicron particle, i.e. a particle having at least one dimension , in particular a diameter, preferably an average diameter, and/or a length, preferably an average length, and/or a width, in particular an average width, and/or a height, in particular an average height, of > 100 nm to <500nm, in particular from >100nm to 500nm or from >100nm to <500nm.
    [0037] Accordingly, the term "resorbable nanoparticle", as used in accordance with the present invention, may also be referred to as "resorbable nanoparticle and/or resorbable submicron particle". Furthermore, the term "nanoparticulate material", as used according to the present invention, can also be referred to as "nanometric material and/or submicron material".
    [0039] Preferably, the term "nanoparticle", as used according to the present invention, means a nanometric particle, that is, a particle having at least one dimension, in particular a diameter, preferably an average diameter, and/or a length, preferably an average length, and/or a width, in particular an average width, and/or a height, in particular an average height, of <100nm, preferably from 0.1nm to <100nm, more preferably from 1nm to <100nm, in particular from 1nm to 100nm or from 1nm to <100nm nm, preferably 10 nm to 50 nm (a so-called nanoparticle in the strict sense of the word).
    [0041] The term "a resorbable nanoparticle" as used in accordance with the present invention may mean only one resorbable nanoparticle or a plurality of resorbable nanoparticles. In the latter case, the resorbable nanoparticles may be the same or different.
    [0043] The term "a resorbable nanoparticle" as used in accordance with the present invention may mean only one resorbable nanoparticle or a plurality of resorbable nanoparticles. In the latter case, the resorbable nanometric particles may be the same or different.
    [0045] The term "a submicron resorbable particle", as used in accordance with the present invention, may mean only one submicron resorbable particle or a plurality of submicron resorbable particles. In the latter case, the resorbable submicron particles may be the same or different.
    [0047] The term "selective resorbable functionalized nanoparticle", as used according to the present invention, means a nanoparticle that is functionalized with at least one compound, in particular at least one ligand, that is capable of selectively binding a pathogen and/or a proliferative cell, in particular, a tumor cell.
    [0049] In general, the use of nanoparticles is advantageous in that they offer unique properties due to their low particle size (such as their physical behavior when interacting with or irradiated with light), a high surface area to volume ratio that can allow higher solubility compared to larger particles, tunable surface functionalization that facilitates customization of ligands depending on the application, and specificity in interaction with other entities, such as viruses, prokaryotic cells, and eukaryotic cells. In addition, nanoparticles may have intrinsic physical properties that can be advantageously applied as therapy on their own (ie, plasmonic and magnetic nanoparticles for optical and magnetic hyperthermia, respectively).
    [0050] Furthermore, the resorbable nanoparticle is preferably an inorganic nanoparticle, ie a nanoparticle, comprising or consisting of an inorganic material. As mentioned below, the inorganic material is especially preferably a metal and/or a metal salt, such as a metal oxide and/or metal hydroxide. In general, inorganic nanoparticles have unique chemical, electrical, and optical effects and catalytic activities, which are not found in metals in general. This facilitates a variety of fields of use, in particular with respect to therapy, diagnostics, drug delivery systems, biomedicine, photoelectrochemical devices, sensors, and the like.
    [0052] In an embodiment of the present invention, the resorbable nanoparticle comprises or includes at least one metal, in particular at least one elemental metal. Preferably, the at least one metal, in particular at least one elemental metal, is selected from the group consisting of magnesium, iron and zinc.
    [0054] More preferably, the at least one metal, in particular at least one elemental metal, is magnesium or a magnesium alloy.
    [0056] Magnesium is after sodium, potassium and calcium the most abundant cation in the human body. It is found in bones and soft tissues, playing a key role in enzymatic and cellular processes. Magnesium has the additional advantage of slow dissolution in physiological aqueous medium that releases magnesium cations (Mg2+) that could form magnesium hydroxide (Mg(OH) 2 ). Chloride ions (Cl-) can further react with magnesium hydroxide to generate magnesium chloride (MgCh) which is highly soluble, ultimately dissolving magnesium. Therefore, the released ions are totally biocompatible, since they are Mg2+ ions, OH- ions and Cl- ions that can be efficiently integrated or eliminated from the body, provided that renal function is normal. Therefore, any toxicological risk can be avoided or at least reduced to a safe clinical level.
    [0058] An additional advantage of nanoparticles comprising or consisting of magnesium relates to their intrinsic optical properties, such as their localized surface plasmon resonance (LSPR), which can be used for selective recognition events (i.e., immunorecognition, hybridization of nucleic acids). Advantageously, the nanoparticles comprising or consisting of magnesium exhibit LSPR, in particular in the UV, visible and/or near infrared region, in particular from 750 nm to 1200 nm, in particular from 800 nm to 900 nm, preferably around 800 nm, which allows the use of the transmission window of a biological tissue, in particular the tissue of a subject, without damaging it. From Advantageously, this allows the development of photothermal therapies and biomedical applications inside the human or other mammalian body.
    [0060] Furthermore, for example, magnesium oxide-based nanoparticles display photocatalytic properties and are therefore capable of generating reactive oxygen species mediated by light irradiation that can react with fluorescence probes or participate in polymerization reactions that generate analytical signals that can also be related to selective recognition events. The presence of LSPRs that can be excited at different wavelengths together with the generation of electron-hole pairs by using different excitation wavelengths opens up the possibilities to develop multi-sensing platforms.
    [0062] An additional advantage of magnesium relates to luminescence that can be exploited in imaging, particularly medical imaging.
    [0064] In the following Table 1, procedures for the synthesis of magnesium-based nanoparticles are listed:
    [0069] Table 1: Synthesis procedures for magnesium-based nanoparticles
    [0071] In the sol-gel method, a magnesium alkoxide is hydrolyzed in an alcoholic medium to produce the hydroxide with the subsequent steps of hydrolysis, condensation, polymerization and thermal dehydration. Different parameters must be optimized, such as temperature, pH and the catalyst for gel formation (Alvarado, E., Torres-Martinez, LM, Fuentes, AF and Quintana, P., Preparation and characterization of MgO powders obtained from different magnesium salt and the mineral dolomite. Polyhedron, 2000, 19, 2345-2351; XM Xu,, Preparation and characterization of nanometer magnesia powder by electrochemical precipitation. Inorganic Chemicals Industry, 2006, 38, 32-34). This methodology is simple, cost-effective, requires a low reaction temperature and is characterized by a high yield of nanoparticles, although it has the disadvantage of a high agglomeration rate of the MgO nanoparticles. Surfactant-mediated synthesis strategies have been studied to solve this problem, such as the cetyltrimethylammonium bromide (CTAB)-assisted method that can also control the morphology and size of nanoparticles. In the hydrothermal strategy, a magnesium salt is mixed in a basic aqueous medium with a basic solution at a variable proportion of Mg2+/OH-, washing and calcining the obtained precipitate (JP Jiu, LP Li, Y. Ge, SR Zhang, F Tu, AR Hua, and L. Nie, The preparation of MgO nanoparticles protected by polymer Chinese Journal of Inorganic Chemistry, 2001, 17, 361-365 J. Zhang, Study on preparing nanometer-sized MgO by homogeneous precipitation Method , Materials, 1999,30, 193-194, YX Zhu, RJ Zeng, XJ Liu, H. Zhang, R. Pan, XL Zhou, Y. Zhang, Preparation and characterization of MgO nanopowder, Journal of Xiamen University ( Nature Science) , 2001, 40, 1256-1258;M. Suzuki, M. Kagawa, Y. Syonoetal, Synthesis of ultrafine single-component oxide particles by the spray ICP technique, Journal of Material Science, 1992, 27, 679-684; GR Chen , SH Xu, J. Yang, The study of the preparing of nanometer MgO powder in the stearic acid gel method, Journal of Functional Materials, 2002, 35, 521-52 3). To control the morphology and size of MgO nanoparticles, magnesium precursors, reactive solvents and calcination temperature must be optimized. Starch and cellulose have been used as stabilizing agents. The microwave-assisted method has the advantage of reducing the reaction time, narrowing the size distribution and increasing the reaction yield (KM Saoud, S. Saeed, RM Al-Soubaihi and MF Bertino. American Journal Nanomaterials, 2014, 2 , 21-25). In the microemulsion method, the precursor is heated with the surfactant to obtain the oxide, and the size and morphology of the nanoparticles are controlled by the choice of surfactant, water concentration, nonpolar phase, and surfactant (J. Wu , H. Yana, X. Zhang, L. Wei, X. Liu, Bingshe Xu. Magnesium hydroxide nanoparticles synthesized in water-in-oil microemulsions. Journal of Colloid and Interface Science, 2008, 324, 167-171). Coprecipitation methods are also an alternative to prepare magnesium nanoparticles under mild conditions (ERH Walter, MA Fox, D. Parker, JAG Williams. Enhanced selectivity for Mg2+ with a phosphinate-based chelate: APDAP versus APTRA. Dalton Transactions, 2018, 47, 1879-1887).
    [0072] Furthermore, the resorbable nanoparticle may comprise at least one compound, including magnesium, in particular ionic magnesium. In particular, the resorbable nanoparticle may consist of said compound. Preferably, the at least one compound including magnesium, in particular ionic magnesium, is a metal salt, in particular, as detailed in the following embodiment.
    [0074] In a further embodiment of the present invention, the resorbable nanoparticle comprises at least one metal salt, in particular at least one metal oxide and/or at least one metal hydroxide. Preferably, the at least one metal oxide is selected from the group consisting of magnesium oxide, iron oxide, zinc oxide and mixtures of at least two of the aforementioned metal oxides, and/or the at least one metal hydroxide is selected preferably from the group consisting of magnesium hydroxide, iron hydroxide, zinc hydroxide and mixtures of at least two of the aforementioned metal hydroxides. In particular, the resorbable nanoparticle can consist of at least one metal salt, in particular at least one metal oxide and/or at least one metal hydroxide, in which the at least one metal oxide is preferably selected from the group consisting of oxide magnesium, iron oxide, zinc oxide and mixtures of at least two of the metal oxides mentioned above, and/or the at least one metal hydroxide is preferably selected from the group consisting of magnesium hydroxide, iron hydroxide, iron hydroxide zinc and mixtures of at least two of the aforementioned metal hydroxides.
    [0076] More preferably, the at least one metal oxide is magnesium oxide and/or the at least one metal hydroxide is magnesium hydroxide.
    [0078] In a further embodiment of the present invention, the resorbable nanoparticle comprises a core-shell structure, in which the core comprises the at least one metal, in particular at least one elemental metal, and/or the shell comprises the at least one metal salt, in particular at least one metal oxide and/or at least one metal hydroxide. In particular, the resorbable nanoparticle may comprise a core-shell structure, in which the core consists of at least one metal, in particular at least one elemental metal, and/or the shell consists of at least one metal salt , in particular at least one metal oxide and/or at least one metal hydroxide. The core-shell structure may have a diameter, in particular an average diameter, of from 0.1 nm to 500 nm, in particular from 1 nm to 100 nm, preferably from 10 nm to 50 nm. Furthermore, the shell of the core-shell structure may have a thickness of 0.05nm to 250nm, in particular 0.5nm to 50nm, preferably 5nm to 25nm. Especially preferably, the metal, in particular the elemental metal, is magnesium, and the metal salt is magnesium oxide and/or magnesium hydroxide. More preferably, the core may comprise or consist of elemental magnesium and the shell may comprise or consist of magnesium oxide and/or magnesium hydroxide.
    [0080] In a further embodiment of the present invention, the resorbable nanoparticle has an average diameter, in particular determined by a Transmission Electron Microscope (TEM), from 0.1 nm to 500 nm, in particular from 1 nm to 100 nm, preferably from 10nm to 50nm, in particular including any whole numbers and/or decimals included in the ranges mentioned above.
    [0082] In addition, the resorbable nanoparticle a specific surface area (SSA), in particular determined by the Brunauer-Emmett-Teller (N2-BET) adsorption method, methylene blue (MB) staining, ethylene glycol monoethyl ether (EGME) adsorption complex-ion adsorption electrokinetic analysis or protein retention (PR) method or according to ISO 9277, from 5 m2/g to 800 m2/g, in particular from 25 m2/g to 400 m2/g, preferably from 50 m2/g to 80 m2/g.
    [0084] In principle, the resorbable nanoparticle can have a polyhedral shape or a non-polyhedral shape.
    [0086] In a further embodiment of the present invention, the resorbable nanoparticle has a shape selected from the group consisting of a cube shape, a cuboid shape, a prism shape, a tetrahedral shape, a cylindrical shape, a triangular shape, a pyramidal shape , a cone shape, an egg shape, a spherical shape, a star shape, a rod shape, and combinations of at least two of the aforementioned shapes.
    [0088] In a further embodiment of the present invention, the at least one compound or a moiety thereof is bound, in particular covalently bound (conjugated) and/or non-covalently bound, in particular by van der Waals forces and/or or hydrogen bonds and/or coordination bonds and/or ionic interactions, to the resorbable nanoparticle or a surface of the resorbable nanoparticle, preferably forming a coating or layer, more preferably an outer coating or an outer layer, of or on the resorbable nanoparticle or on the surface of the resorbable nanoparticle. The coating or layer may have a thickness of 0.1nm to 100nm, in particular 1nm to 100nm, preferably 5nm to 50nm.
    [0089] In a further embodiment of the present invention, the at least one compound or a moiety thereof is directly or indirectly bound to the surface of the resorbable nanoparticle.
    [0091] In a further embodiment of the present invention, the at least one compound is selected from the group consisting of an antioxidant agent, a blocking agent, an antibody, such as a monoclonal antibody, a protein, a nucleic acid, a lipid, a antigen, an agent capable of binding to a pathogen, and combinations of at least two of the aforementioned compounds.
    [0093] The term "antioxidant agent", as used according to the present invention, refers to a compound that is capable of preventing the resorbable nanoparticle from being oxidized.
    [0095] Preferably, the antioxidant agent is an unsaturated fatty acid, in particular selected from the group consisting of oleic acid, elaidic acid, palmitoleic acid, linoleic acid, linolelayic acid, gamma-linolenic acid, alpha-linolenic acid and mixtures of at least two of them. the unsaturated fatty acids mentioned above. Oleic acid is especially preferred.
    [0097] The term "capping agent", as used according to the present invention, refers to a compound capable of preventing the growth of the resorbable nanoparticle, in particular by agglomeration, or of retarding the growth of the nanoparticle. resorbable nanoparticle, in particular by agglomeration. According to the present invention, the blocking agent may also be called "blocking ligand".
    [0099] Preferably, the blocking agent is selected from the group consisting of catecholates, salicylic acid, salicylates, phosphates, phosphonates, bisphosphonates, hydrophilic polymers, in particular conjugated hydrophilic polymer, and mixtures of at least two of the aforementioned blocking agents. More preferably, the blocking agent may be selected from the group consisting of dopamine, 3,4-dihydroxyhydrocinnamic acid, 2-aminoethylphosphonic acid, alendronate, alendronic acid, Furaptra (Mag-Fura-2), and combinations of at least two of the blocking agents mentioned above. Preferably, the alendronate is alendronate sodium, in particular in the form of the hydrate, preferably in the form of the trihydrate.
    [0101] The term "catecholates", as used according to the present invention, refers to compounds that carry or contain at least one catechol group or skeleton, that is, at least one 1,2-dihydroxybenzene group or skeleton and/or at least one group or skeleton of 1-hydroxy,2-alkoxybenzene and/or at least one 1-alkoxy,2-hydroxybenzene group or skeleton and/or at least one 1,2-dialkoxybenzene group or skeleton.
    [0103] The term "salicylates", as used according to the present invention, refers to salts and/or compounds of salicylic acid, in particular that carry or contain at least one group or skeleton of salicylic acid and/or at least one group or salicylic acid ester skeleton and/or at least one salicylic acid amide group or skeleton.
    [0105] The term "hydrophilic polymers" as used in accordance with the present invention refers to a polymer that is soluble or swellable in water or an aqueous solution.
    [0107] Advantageously, by using a hydrophilic polymer, in particular, as detailed below, the stability of the resorbable nanoparticle, and therefore of the nanoparticulate material of the invention, can be increased, particularly when it is dispersed, preferably in an aqueous medium.
    [0109] In particular, the hydrophilic polymer can be linear and/or multifunctional, in particular bifunctional, preferably a linear and multifunctional, in particular bifunctional, polymer. Advantageously, the hydrophilic polymer may have two terminal functional groups, namely a first terminal functional group and a second terminal functional group. The first terminal functional group is capable of binding, in particular covalently and/or non-covalently, to the resorbable nanoparticle or to the surface thereof. The first functional group may also be referred to as an "anchor group" within the scope of the present invention. Preferably, the second terminal functional group is capable of binding, in particular covalently and/or non-covalently, (directly) to a pathogen or to an agent capable of binding to a pathogen or an analyte. Furthermore, the first terminal functional group may be a functional group selected from the group consisting of carboxyl group, hydroxyl group, amine group, phosphate group, phosphonate group, sulfonate group, and mixtures of at least two of the aforementioned functional groups. Furthermore, the second terminal functional group may be a chelating group, in particular a multidentate ligand, such as a bidentate, tridentate, tetradentate or octadentate ligand group. For example, the chelating group may comprise at least one functional group selected from the group consisting of carboxyl group, hydroxyl group, amine group, phosphate group, phosphonate group, sulfonate group, and mixtures of at least two of the aforementioned functional groups. For example, the chelating group may be a phosphinate-based chelating group, such as an o-aminophenol-N,N,O-triacetate group (APTRA) or an o-aminophenol-N,N-diacetate-O-methylene- methylphosphinate (APDAP).
    [0110] Specifically, the hydrophilic polymer may comprise a polymer block or unit selected from the group consisting of polyethylene glycol block or unit, polyaspartic acid block or unit, polyglutamic acid block or unit, hydrophilic protein block or unit. , such as albumin block or unit, in particular serum albumin block or unit, for example bovine serum albumin (BSA) block or unit, and mixtures of at least two of the aforementioned polymer blocks or units.
    [0112] Preferably, the hydrophilic polymer may be a polymer selected from the group consisting of polyethylene glycol conjugated with a catecholate, polyethylene glycol conjugated with a salicylate, polyethylene glycol conjugated with a phosphate, polyethylene glycol conjugated with a phosphonate, polyethylene glycol conjugated with a bisphosphonate, polyglutamic acid conjugated with a catecholate, polyglutamic acid conjugated with a salicylate, polyglutamic acid conjugated with a phosphate, polyglutamic acid conjugated with a phosphonate, polyglutamic acid conjugated with a bisphosphonate, polyaspartic acid conjugated with a catecholate, polyaspartic acid conjugated with a salicylate, polyaspartic acid conjugated with a phosphate , polyaspartic acid conjugated with a phosphonate, polyaspartic acid conjugated with a bisphosphonate and mixtures of at least two of the hydrophilic polymers mentioned above.
    [0114] More preferably, the hydrophilic polymer may be a polymer selected from the group consisting of polyethylene glycol conjugated with dopamine, polyethylene glycol conjugated with 3,4-dihydroxyhydrocinnamic acid, polyethylene glycol conjugated with 2-aminoethylphosphonic acid, polyethylene glycol conjugated with alendronate, polyethylene glycol conjugated with Furaptra (Mag -Fura-2), polyglutamic acid conjugated to dopamine, polyglutamic acid conjugated to 3,4-dihydroxyhydrocinnamic acid, polyglutamic acid conjugated to 2-aminoethylphosphonic acid, polyglutamic acid conjugated to alendronate, polyglutamic acid conjugated to Furaptra (Mag-Fura-2) , polyaspartic acid conjugated with dopamine, polyaspartic acid conjugated with 3,4-dihydroxyhydrocinnamic acid, polyaspartic acid conjugated with 2-aminoethylphosphonic acid, polyaspartic acid conjugated with alendronate, polyaspartic acid conjugated with Furaptra (Mag-Fura-2) and mixtures of at least two of the hydrophilic polymers mentioned above and.
    [0116] The term "polyethylene glycol", as used according to the present invention, can refer to a non-functionalized polyethylene glycol, that is to say a polyethylene glycol that carries or contains two terminal hydroxyl groups, or to a functionalized polyethylene glycol, that is to say a polyethylene glycol that has at least a terminal hydroxyl group, in particular only one terminal hydroxyl group or both terminal hydroxyl groups to be replaced by a different functional group, such as a carboxyl group or a carboxylate group. Preferably, the term "polyethylene glycol", as used according to the present invention, it means a carboxylated polyethylene glycol, that is to say a polyethylene glycol carrying or containing at least one terminal carboxyl or carboxylate group, in particular only one terminal carboxyl or carboxylate group or two terminal carboxyl or carboxylate groups. Furthermore, the polyethylene glycol according to the present invention may have a molecular weight of 500 Da to 50,000 Da, in particular 1,000 Da to 10,000 Da, preferably 1,500 Da to 5,000 Da, for example 3,000 Da.
    [0118] The term "agent capable of binding to a pathogen" can also be called "ligand directed at a pathogen" within the scope of the present invention, thus emphasizing that said agent and ligand, respectively, form a binding target for a pathogen, giving rise to to the formation of a bond between the targeted ligand and the pathogen.
    [0120] The antibody (mentioned in the context of the at least one compound) may be selected from the group consisting of immunoglobulin G1 (IgG1), immunoglobulin 3 (IgG3), immunoglobulin M (IgM), immunoglobulin A (IgA), monoclonal antibodies (mAbs) that recognize the receptor-binding motif (RBM) of ACE2, monoclonal antibodies (mAbs) that recognize the cryptic site CR3022 (which is the most frequent epitope recognized by cross-neutralizing antibodies (i.e., COVA1-16, H014, EY6A, and ADI-56046)), monoclonal antibodies (mAbs) that recognize the S309 binding site, and mixtures of at least two of the aforementioned antibodies. Preferably, the antibody is directed against a pathogen, such as SARS-CoV-2 or a part, in particular protein, thereof, such as spike protein, in particular spike protein S.
    [0122] The protein (mentioned in the context of the at least one compound) may be a receptor binding domain (RBD), in particular from a pathogen, such as SARS-CoV-2. For example, the protein may be the S receptor binding domain of SARS-CoV-2. Alternatively, the protein may be the ACE 2 receptor protein.
    [0124] Furthermore, the agent capable of binding to a pathogen (mentioned in the context of the at least one compound) may be selected from the group consisting of an antibody, a protein, a nucleic acid, a lipid, an antigen, and combinations of at least two of the aforementioned agents capable of binding to a pathogen. With respect to further details regarding the aforementioned agents capable of binding to a pathogen, reference is made in its entirety to the above description. In particular, the aforementioned antibodies and proteins may also be agents capable of binding to a pathogen according to the present invention.
    [0125] In a further embodiment of the present invention, the at least one compound comprises or means a blocking agent and an agent capable of binding to a pathogen. With respect to further details regarding the blocking agent and the agent capable of binding to a pathogen, reference is made in its entirety to the above description. The blocking agents and agents capable of binding to a pathogen mentioned above may also be blocking agents and agents capable of binding to a pathogen according to this embodiment.
    [0127] In a further embodiment of the present invention, the blocking agent or a moiety thereof is bound directly to the resorbable nanoparticle or to the surface of the resorbable nanoparticle, and the agent capable of binding a pathogen or a moiety of the agent capable of binding to a pathogen is bound to the blocking agent or a moiety thereof. In other words, the agent capable of binding to a pathogen or a moiety of the agent capable of binding to a pathogen is preferably bound indirectly, that is, through the blocking agent or a moiety thereof, to the resorbable nanoparticle or to the resorbable nanoparticle. the surface of the resorbable nanoparticle. Specifically, the blocking agent or a moiety thereof may be covalently and/or non-covalently bound, in particular via van der Waals forces and/or hydrogen bonds and/or coordination bonds and/or ionic interactions. , to the resorbable nanoparticle or to the surface of the resorbable nanoparticle. Furthermore, the agent capable of binding to a pathogen or a moiety of the agent capable of binding to a pathogen may be covalently and/or non-covalently bound, in particular via van der Waals forces and/or hydrogen bonds and /or coordination bonds and/or ionic interactions, to the blocking agent or a moiety thereof.
    [0129] In a further embodiment of the present invention, the nanoparticulate material is for use in the prevention and/or treatment, ie, prevention and/or treatment of a disease and/or disorder in a subject or for use in a method of prevention and/or treatment of a disease and/or disorder in a subject, wherein the method comprises the step of administering the nanoparticulate material. Preferably, the disease and/or disorder is caused by a pathogen. The pathogen may preferably be of fungal, viral or bacterial origin, ie it may have a fungal, viral or bacterial origin. Preferably, the pathogen is of viral origin.
    [0131] The term "subject", as used in accordance with the present invention, can mean a human or a non-human mammal, for example a horse, cow, dog, cat, rabbit, rat or mouse. Preferably, the term "subject", as used in accordance with the present invention, means a human or human patient.
    [0132] Preferably, the disease and/or disorder caused by a pathogen may be an infectious disease, in particular a fungal, viral or bacterial infectious disease.
    [0134] For example, the disease or disorder caused by a pathogen may be selected from the group consisting of coronavirus disease 2019 (COVID-19), chickenpox, common cold, diphtheria, E. coli, giardiasis, HIV/AIDS, infectious mononucleosis, influenza (flu), Lyme disease, malaria, measles, meningitis, mumps, poliomyelitis (Polio), pneumonia, Rocky Mountain spotted fever, rubella (German measles), salmonella infections, severe acute respiratory syndrome (SARS), diseases of sexually transmitted, shingles (Herpes zoster), tetanus, toxic shock syndrome, tuberculosis, viral hepatitis, West Nile virus, and whooping cough (pertussis).
    [0136] Preferably, the disease and/or disorder caused by a pathogen is coronavirus disease 2019 (COVID-19), that is, a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
    [0138] In an additional embodiment of the present invention, the pathogen of viral origin is SARS-CoV-2 or a coronavirus-like virus, such as severe acute respiratory syndrome coronavirus [1] (SARS-CoV[-1]) or coronavirus Middle East respiratory syndrome (MERS-CoV).
    [0140] Furthermore, the nanoparticulate material can be administered topically, dermally, orally or parenterally, in particular intravenously, intradermally, intramuscularly, intraperitoneally, intraarterially, nasally or transmucosally.
    [0142] Furthermore, in particular to prevent and/or treat the disease and/or disorder, preferably caused by the pathogen, the nanoparticulate material can be irradiated with light, in particular UV light (ultraviolet light), in particular having a wavelength of 100nm to 380nm, and/or visible light (VIS light), in particular having a wavelength of >380nm to 750nm, preferably 400nm to 750nm, and/or UV-Vis light (ultraviolet light -visible), in particular having a wavelength of 100nm to 750nm, and/or near infrared light (NIR light), in particular having a wavelength of 750nm to 1200nm, preferably >750nm at 1200nm, in particular from 800nm to 900nm. More preferably, the nanoparticulate material can be irradiated with light having a wavelength of from 100 nm to 1200 nm, in particular from 100 nm to 800 nm or from 750 nm to 1200 nm, preferably from 400 nm to 800 nm or from 800 nm. nm to 900nm. Therefore, the temperature of the nanoparticulate material can be advantageously increased, which, in turn, can lead to the deactivation or destruction of the pathogen.
    [0143] In a further embodiment of the present invention, the nanoparticulate material is for use in the prevention and/or treatment, i.e. prevention and/or treatment of a disease and/or disorder in a subject or for use in a method of prevention and/or treatment of a disease and/or disorder in a subject, wherein the method comprises the step of administering the nanoparticulate material, wherein the disease and/or disorder is a proliferative disease.
    [0145] In a further embodiment of the present invention, the proliferative disease is a disease associated with, in particular at least to some degree, the proliferation of abnormal cells. The proliferative disease may be a benign proliferative disease or a malignant proliferative disease. Preferably, the proliferative disease is a cancer, in particular selected from the group consisting of carcinoma, lymphoma, blastoma, sarcoma, leukemia, non-localized cancer, squamous cell cancer, small cell lung cancer, non-small cell lung cancer , adenocarcinoma of the lung, squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, skin cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, head cancer, and neck cancer.
    [0147] Furthermore, the nanoparticulate material can be administered topically, dermally, orally or parenterally, in particular intravenously, intradermally, intramuscularly, intraperitoneally, intraarterially, nasally or transmucosally.
    [0149] Furthermore, in particular to prevent and/or treat proliferative disease, the nanoparticulate material can be irradiated with light, in particular UV light (ultraviolet light), in particular having a wavelength of 100 nm to 380 nm, and/or visible light (VIS light), in particular having a wavelength of > 380 nm to 750 nm, preferably 400 nm to 750 nm, and/or UV-Vis light (ultraviolet-visible light), in particular having a wavelength from 100nm to 750nm, and/or near infrared light (NIR light), in particular having a wavelength from 750nm to 1200nm, preferably >750nm to 1200nm, in particular 800nm at 900nm. More preferably, the nanoparticulate material can be irradiated with light having a wavelength of from 100 nm to 1200 nm, in particular from 100 nm to 800 nm or from 750 nm to 1200 nm, preferably from 400 nm to 800 nm or from 800 nm. nm to 900nm. In this way, the temperature of the nanoparticulate material, advantageously, can increase, which, in turn, can lead to the deactivation or destruction of a proliferative cell, in particular a tumor cell.
    [0151] Furthermore, the nanoparticulate material according to the present invention may be for use in diagnosis, ie diagnosis of a disease and/or disorder in a subject. Preferably the disease and/or disorder is caused by a pathogen, in particular of fungal, viral or bacterial origin, or is a proliferative disease. With respect to further details of the disease and/or disorder and the pathogen, reference is made in its entirety to the description above.
    [0153] In a further embodiment of the present invention, the nanoparticulate material is for use in imaging applications, in particular non-medical imaging applications or medical imaging applications. Preferably, the nanoparticulate material is for use in medical imaging.
    [0155] The term "medical imaging", as used in accordance with the present invention, refers to a technique and process for obtaining images of the interior of the body for clinical analysis and/or medical intervention and/or for the visual representation of the organ or tissue function.
    [0157] Imaging may be selected from the group consisting of radiology, x-ray radiography, magnetic resonance imaging, ultrasound, endoscopy, elastography, tactile imaging, thermography, medical photography, nuclear medicine functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT).
    [0159] In a further embodiment of the present invention, the nanoparticulate material is for use in the generation of radicals, in particular by light irradiation or mediated by light irradiation, preferably for the treatment of a disease and/or disorder in a subject. . More preferably, the disease and/or disorder is a disease and/or disorder caused by a pathogen, in particular of fungal, viral or bacterial origin, or a proliferative disease. With respect to further details of the disease and/or disorder and the pathogen, reference is made in its entirety to the description above.
    [0161] In a further embodiment of the present invention, the nanoparticulate material is for use in disinfecting, that is, disinfecting, surfaces, in particular devices. medical, such as surgical instruments and/or surgical implants, in particular selected from the group consisting of surgical sutures, arterial prostheses, venous prostheses, stents, stent grafts, wound dressings, surgical meshes, wound fixation devices, catheters, such as balloon catheters, hip replacements and knee replacements.
    [0163] In a further embodiment of the present invention, the nanoparticulate material is for use in detection, ie detection of a pathogen or for the development of a method for detection, ie detection of a pathogen. Preferably, the pathogen is of fungal, viral or bacterial origin. Preferably, the pathogen is a coronavirus, in particular selected from the group consisting of SARS-CoV-2, SARS-CoV[-1] and MERS-CoV.
    [0165] In a further embodiment of the present invention, the nanoparticulate material is for use in detecting, ie detecting, an analyte or for developing a method for detecting, ie detecting, an analyte. The analyte can be selected from the group consisting of an antibody, a protein, a tumor marker, a nucleic acid, a small molecule, or a combination of at least two of the aforementioned analytes. The antibody may be an antibody against a pathogen. The protein may be a protein associated with a pathogen, such as a spike protein, in particular from SARS-CoV-2.
    [0167] In a further embodiment of the present invention, the nanoparticulate material is for use in the development of a sensor or sensor technology.
    [0169] A second aspect of the present invention relates to a process for obtaining a nanoparticulate material according to the first aspect of the invention. The process includes the stages of
    [0171] a) coating a resorbable nanoparticle with an antioxidant agent and
    [0173] b) replacing the antioxidant agent coating by functionalizing the resorbable nanoparticle with at least one compound that is different from the antioxidant agent.
    [0175] Preferably, step a) is carried out in the presence of an organic solvent. More specifically, step a) can be carried out by forming a dispersion containing the resorbable nanoparticle, antioxidant agent and organic solvent. organic solvent it can be selected, in particular, from the group consisting of alcohols, such as methanol and/or ethanol and/or isopropanol, saturated hydrocarbons, such as hexane, unsaturated hydrocarbons, and mixtures of at least two of the aforementioned organic solvents. More specifically, the dispersion containing the resorbable nanoparticle, antioxidant agent and organic solvent can be formed by sonication.
    [0177] Furthermore, step a) can be carried out using an unsaturated fatty acid, in particular oleic acid, as an antioxidant agent. With respect to other useful unsaturated fatty acids, reference is made in its entirety to the description above. The unsaturated fatty acids mentioned here can also be used for the process according to the second aspect of the present invention.
    [0179] By carrying out step a), the resorbable nanoparticle can advantageously be prevented from oxidation.
    [0181] Preferably, step b) is carried out using an aqueous liquid, in particular an aqueous solution, containing the at least one compound that is different from the antioxidant agent. More specifically, the aforementioned dispersion containing the resorbable nanoparticle, antioxidant agent and organic solvent and the aqueous liquid, in particular aqueous solution, containing the at least one compound that is different from the antioxidant agent, is incubated, in particular at room temperature, ie 15°C to 30°C, preferably 20°C to 25°C, and/or 0.1 min to 3600 min, preferably 1 min to 60 min.
    [0183] Furthermore, step b) can be carried out using a blocking agent. With respect to useful blocking agents, reference is made in its entirety to the foregoing description. The blocking agents mentioned therein can also be used for the process according to the second aspect of the present invention.
    [0185] By carrying out step b), advantageously, the resorbable nanoparticle can be prevented from growing, in particular by agglomeration.
    [0187] The process may further comprise a step c) of isolation and/or purification of the resorbable nanoparticle that is functionalized with the at least one compound that is different from the antioxidant agent of an aqueous phase that has been formed during step b).
    [0188] With respect to other characteristics and advantages, in particular with respect to the resorbable nanoparticle and/or antioxidant agent and/or at least one compound that is different from the antioxidant agent, reference is made in its entirety to the respective embodiments made under the first aspect of the present invention. The respective features and advantages described therein apply, mutatis mutandis, with respect to the process according to the second aspect of the present invention.
    [0190] According to a third aspect, the present invention refers to a product that comprises and/or is coated with a resorbable functionalized nanoparticle, according to the first aspect of the present invention.
    [0192] The product can be selected from the group consisting of a pharmaceutical composition, a medical device, a medical kit, a drug delivery system, a photoelectrochemical device, and a sensor.
    [0194] The pharmaceutical composition may further comprise a pharmaceutically acceptable vehicle, diluent, excipient or carrier. The pharmaceutically acceptable vehicle, diluent, excipient or carrier can be any compound or combination of compounds that allow the administration of the nanoparticulate material within the pharmaceutical composition. Preferably, the pharmaceutically acceptable vehicle, diluent, excipient or carrier is in the form of an emulsion, an aqueous solution, a buffer, a lipid or any other suitable compound or composition, in particular suitable for infusion or instillation.
    [0196] The medical device can be, in particular, a surgical instrument or a surgical implant, in particular selected from the group consisting of a surgical suture, an arterial prosthesis, a venous prosthesis, a stent, a stent graft, a wound dressing, a surgical mesh, a wound fixation device, a catheter, such as a balloon catheter, a hip prosthesis, and a knee prosthesis.
    [0198] With regard to additional features and advantages of the product, in particular with respect to the nanoparticulate material, reference is made in full to the respective features and advantages described in the first aspect of the present invention. These characteristics and advantages apply, mutatis mutandis, with respect to the product according to the third aspect of the invention.
    [0199] Other features and advantages of the invention will become apparent from the following examples in conjunction with the subject matter of the dependent claims. The individual features may be embodied separately or separately in combination in one embodiment of the present invention. The preferred embodiments serve only to further illustrate and understand the present invention and are not to be construed as limiting the present invention in any way.
    [0203] For a better understanding of what has been described, some figures are attached that schematically or graphically and solely by way of non-limiting example, show a practical case of the embodiments of the present invention.
    [0205] Fig. 1 graphically shows a Raman spectrum of magnesium oxide nanopowder provided by Sigma.
    [0207] Fig. 2 graphically shows UV-Vis spectra of dispersed magnesium oxide nanopowder.
    [0209] Fig. 3 graphically shows the generation of reactive oxygen species and hydroxyl radical from magnesium oxide nanopowder after UV irradiation.
    [0211] Fig. 4 graphically shows the yield of magnesium oxide nanomaterial dissolution after overnight incubation under different conditions. The magnesium oxide concentration was 1 mg mL-1.
    [0213] Fig. 5 shows blocking agents for the functionalization of magnesium oxide nanoparticles.
    [0215] Fig. 6 shows coupling reaction schemes of blocking ligands to PEG.
    [0217] Fig. 7 graphically shows the dispersion performance of magnesium oxide nanomaterial with different ligands.
    [0219] Fig. 8 graphically shows the labeling of magnesium oxide nanomaterials with fluorescent probes.
    [0221] 1. Raw material for magnesium oxide nanoparticles
    [0223] Magnesium oxide nanoparticles were purchased from Sigma (catalog number 549649-5G, nanopowder, particle size < 50 nm). Sigma provided the value for the specific surface area (50-80 m2g-1) and the Raman spectra of the product (see figure 1).
    [0225] 2. Characterization of functionalized nanoparticles
    [0227] 2.1. Characterization by UV-Vis-NIR
    [0229] UV-Vis-NIR spectra of the raw material (magnesium oxide nanoparticles) were obtained. The raw material was dispersed in aqueous medium after sonication in a water bath for 30 minutes of a suspension of magnesium oxide nanopowder at 20 mg mL-1 in water. The suspension was not completely stable and tended to settle within several hours even though some dispersed material remained in suspension. UV-Vis-NIR spectra of the dispersed nanoparticles were obtained in order to determine the position of the surface plasmon resonance.
    [0231] The UV-Vis spectrum showed a shoulder around 235 nm that could correspond to the surface plasmon of the magnesium oxide nanoparticles. Ideally, magnesium-based nanoparticles should exhibit localized surface plasmon resonance (LSRP) in the near-infrared region, particularly around 800nm, for biomedical purposes, as this is the biological window where tissues (i.e. , biological tissues) show maximum transparency.
    [0233] 2.2. Light-induced generation of reactive oxygen species (ROS)
    [0235] The generation of reactive oxygen species was evaluated using fluorescent probes. DFC-DA is a non-selective fluorescent probe for reactive oxygen species. Hydroxyphenylfluorescein (HPF) selectively detects highly reactive oxygen species (hROS), such as hydroxyl radical ( OH) and peroxynitrite (ONOO—), while not reacting with other reactive oxygen species (eg superoxide and hydrogen peroxide) .
    [0236] Magnesium oxide nanopowder was pressed into 24-well plates and incubated with the selected fluorescence probes. The generation of ROS species was evaluated after irradiation with UV light. As can be seen in Figure 3, ROS species and hydroxyl radicals were generated after UV exposure. Magnesium oxide nanopowder controls without UV irradiation were also prepared along with control probes without interaction with the magnesium oxide material.
    [0238] 23. Studies in bacteria and cells
    [0240] Cell viability of treated cells was evaluated by different assays (trypan blue, MTT). The antibacterial efficacy was also evaluated by means of the corresponding tests. Cells and bacteria were incubated with magnesium oxide nanoparticles and then irradiated with light according to their surface plasmon resonance position. Controls with cells and bacteria without previous incubation with magnesium oxide nanoparticles and with incubation with magnesium oxide nanoparticles, but without irradiation with light, were also prepared.
    [0242] 2.4. Dissolution of magnesium oxide nanoparticles in biological media
    [0244] Magnesium oxide nanoparticles were incubated under physiological conditions to evaluate their dissolution in these media. Incubation was carried out in phosphate buffered saline and at endosome/lysosome pH to consider a possible degradation pathway under biological conditions. After incubation under these conditions, the released magnesium was quantified by ICP-MS. As can be seen in Figure 4, the magnesium oxide nanomaterial was dissolved at a pH below 5, which is the pH found in endosomes and lysosomes, demonstrating that magnesium oxide nanoparticles can be degraded after absorption. cellular internalization if the intracellular entry and trafficking mechanisms introduce these nanomaterials inside these organelles.
    [0246] 3. Procedures for the functionalization of magnesium oxide nanoparticles
    [0248] The following procedures were used for the functionalization of magnesium oxide nanoparticles:
    [0250] - Coating with blocking ligands with affinity for magnesium oxide forming hydrophilic nanoparticles
    [0251] - Pre-dispersion with oleic acid and transfer to aqueous phase
    [0253] - Pre-dispersion with oleic acid and oxidation to transfer to the aqueous phase
    [0255] - Functionalization with blocking ligands with affinity for magnesium oxide and PEG/protein derivatization to increase the stability of dispersed nanoparticles
    [0257] 3.1. Functionalization with blocking ligands with affinity for magnesium oxide
    [0259] Different blocking ligands were selected for the functionalization of magnesium oxide nanoparticles (see Figure 5). This method is applicable to ligands whose anchor groups form stable magnesium complexes, such as catecholates, salicylates, phosphates, and phosphonates. Even if the affinity of each individual group for the particle surface is low, the multiplicity of anchor groups provides strong adsorption. For example, polyaspartic and polyglutamic acids were tested for the functionalization of magnesium oxide nanoparticles. In this procedure, the blocking ligands were sonicated with the nanoparticles until complete dispersion was obtained. The stability of the dispersion was evaluated by means of the absorption spectra of the mixture obtained.
    [0261] As a starting point for the optimization of the procedure, the magnesium oxide nanoparticles (200 mg) were dispersed in 25 ml of 1% blocking agent with continuous stirring at different times. The concentration of nanoparticles and blocking agent in the dispersion mixture along with the incubation temperature were optimized to increase the stability of the dispersed nanoparticles. Excess blocking agent was removed by centrifugation and washing with water.
    [0263] The possibility of conjugating these blocking ligands (catecholates, phosphonates, bisphosphonates) to hydrophilic polymers was also evaluated. The resulting conjugate was also used to coat the magnesium oxide nanoparticles with the advantage of providing a polymeric hydrophilic coating that could increase the stability of the dispersed nanoparticles. The selected hydrophilic polymers were polyethylene glycol (PEG, Hydroxyl-PEG-COOH Sigma 670812, molecular weight 3,000 Da), polyglutamic acid and polyaspartic acid. BSA could also be used for this strategy. The carboxyl groups of these polymers were conjugated with dopamine, 2-aminoethylphosphonic acid or alendronate by coupling reaction with carbodiimide (see Figure 6 for derivatization of PEG as an example). The activated carboxyl group reacted with the amine group of the blocking ligands. Excess reagents were removed by gel permeation chromatography. The conjugated PEG was sonicated with magnesium oxide nanoparticles to disperse the material. The stability of the dispersion was evaluated by means of the absorption spectra of the mixture obtained.
    [0265] 3.2. Predispersion of nanoparticles with oleic acid and transfer to the aqueous phase
    [0267] Metal oxide nanoparticles are usually dispersed with oleic acid in a non-aqueous medium. In this approach, magnesium oxide nanoparticles were first coated with oleic acid in order to disperse them in a non-aqueous medium, and then the coating was replaced with a hydrophilic coating to transfer the nanoparticles to an aqueous medium. The functionalization of the surface through this biphasic protocol prevents the oxidation and agglomeration of the nanoparticles. In this approach, the nanoparticles are first dispersed in oleic acid in an organic phase, such as methanol or hexane. As a starting procedure, 100 mg of magnesium oxide nanoparticles were sonicated in 10 ml of methanol, while adding 1 ml of oleic acid. After dispersion of the nanoparticles, the mixture was incubated with 2.5 ml of a 1% aqueous solution of the selected ligand (see section 3.1). If necessary, sonication was applied to the mixture. The nanoparticles dispersed in the aqueous phase were washed with water by centrifugation.
    [0269] Oleate-blocked nanoparticles can also be oxidized with sodium periodate in aqueous solution to cause transfer to the aqueous phase. Oleic acid is an unsaturated fatty acid with a carbon double bond at the C9 position that can be cleaved by oxidation to produce azelaic and pelargonic acids, causing the nanoparticles to disperse in aqueous media.
    [0271] 3.3. Preliminary results for the functionalization of magnesium oxide nanoparticles.
    [0273] Magnesium oxide nanopowder was sonicated in the presence of different ligands: 2-aminoethylphosphonic acid, alendronate, carboxylated polyethylene glycol, dopamine, and dihydroxyhydrocinnamic acid. 2-aminoethylphosphonic acid and catechol-based ligands dissolved the nanomaterial. Catechol-based ligands were also polymerized in the presence of magnesium oxide. Figure 7 shows the dispersion performance of the magnesium oxide nanomaterial with which it gave the best results.
    [0274] Given the good results with alendronate, a fluorescence probe synthesized by conjugating the TAMRA fluorophore with alendronate was evaluated for labeling these materials. As can be seen in Figure 8, this fluorescence probe labels the nanoparticles. This property has important implications in biodistribution studies of the nanomaterial.
    权利要求:
    Claims (20)
    [1]
    1. Nanoparticulate material comprising or consisting of a resorbable nanoparticle that is functionalized with at least one compound.
    [2]
    2. Nanoparticulate material, according to claim 1, wherein said resorbable nanoparticle comprises at least one metal, in particular at least one elemental metal, preferably selected from the group consisting of magnesium, iron and zinc.
    [3]
    3. Nanoparticulate material, according to claim 1 or 2, in which said reabsorbable nanoparticle comprises at least one metal salt, in particular at least one metal oxide and/or at least one metal hydroxide, in which the at least one oxide metal is preferably selected from the group consisting of magnesium oxide, iron oxide, zinc oxide and mixtures of at least two of the aforementioned metal oxides, and/or the at least one metal hydroxide is preferably selected from the group consisting of magnesium hydroxide, iron hydroxide, zinc hydroxide and mixtures of at least two of the aforementioned metal hydroxides.
    [4]
    4. Nanoparticulate material, according to claim 2 or 3, wherein said resorbable nanoparticle comprises a core-shell structure, wherein the core comprises or consists of at least one metal, in particular at least one elemental metal, and the shell comprises or consists of at least one metal salt, in particular at least one metal oxide and/or at least one metal hydroxide.
    [5]
    5. Nanoparticulate material, according to any of the preceding claims, in which said resorbable nanoparticle has an average diameter, in particular determined by means of a Transmission Electron Microscope (TEM), of 0.1 nm at 500 nm, in particular 1 nm. to 100nm, preferably from 10nm to 50nm.
    [6]
    6. Nanoparticulate material according to any of the preceding claims, wherein said resorbable nanoparticle has a shape selected from the group consisting of a cube shape, a cuboid shape, a prism shape, a tetrahedral shape, a cylindrical shape, a triangular shape, a pyramid shape, a cone shape, an egg shape, a spherical shape, a star shape, a rod shape, and combinations of at least two of the aforementioned shapes.
    [7]
    7. Nanoparticulate material, according to any of the preceding claims, wherein said at least one compound is covalently and/or non-covalently bound, in particular by van der Waals forces and/or hydrogen bonds and/or hydrogen bonds. coordination and/or ionic interactions, to a surface of said resorbable nanoparticle, preferably forming a layer of said resorbable nanoparticle.
    [8]
    8. Nanoparticulate material according to any of the preceding claims, wherein said at least one compound is bound directly or indirectly to a surface of said resorbable nanoparticle.
    [9]
    9. Nanoparticulate material according to any of the preceding claims, wherein said at least one compound is selected from the group consisting of an antioxidant agent, a blocking agent, an antibody, a protein, a nucleic acid, a lipid, a antigen, an agent capable of binding to a pathogen, and combinations of at least two of the aforementioned compounds.
    [10]
    10. Nanoparticulate material according to any of the preceding claims, wherein said at least one compound comprises a blocking agent and an agent capable of binding to a pathogen.
    [11]
    11. Nanoparticulate material according to claim 10 or 11, wherein said blocking agent is bound directly to a surface of said resorbable nanoparticle and said agent capable of binding a pathogen is bound through said blocking agent to the surface of said resorbable nanoparticle.
    [12]
    12. Nanoparticulate material according to any of claims 10 to 12, wherein said blocking agent is selected from the group consisting of catecholates, salicylates, phosphates, phosphonates, bisphosphonates, polyethylene glycol conjugated with a catecholate, polyethylene glycol conjugated with a salicylate, phosphate-conjugated polyethylene glycol, phosphonate-conjugated polyethylene glycol, bisphosphonate-conjugated polyethylene glycol, catechollate-conjugated polyglutamic acid, salicylate-conjugated polyglutamic acid, phosphate-conjugated polyglutamic acid, phosphonate-conjugated polyglutamic acid, a bisphosphonate, polyaspartic acid conjugated with a catecholate, polyaspartic acid conjugated with a salicylate, polyaspartic acid conjugated with a phosphate, polyaspartic acid conjugated with a phosphonate, acid polyaspartic acid conjugated with a bisphosphonate and mixtures of at least two of the aforementioned blocking agents.
    [13]
    13. Nanoparticulate material according to any of claims 10 to 13, wherein said agent capable of binding to a pathogen is selected from the group consisting of an antibody directed against said pathogen, a protein, a polypeptide, an oligopeptide, an acid nucleic, a lipid, an antigen, and mixtures of at least two of the aforementioned agents capable of binding to a pathogen.
    [14]
    14. Nanoparticulate material, according to any of the preceding claims, for use in the prevention and/or treatment of a disease and/or disorder in a subject or for use in a method of prevention and/or treatment of a disease and /or a disorder in a subject comprising the step of administering the nanoparticulate material, according to any of the preceding claims, wherein said disease and/or disorder is preferably caused by a pathogen, wherein said pathogen is preferably of fungal origin , viral or bacterial.
    [15]
    15. Nanoparticulate material, according to claim 15, wherein said pathogen of viral origin is SARS-CoV-2 or a coronavirus-type virus.
    [16]
    16. Nanoparticulate material, according to any of claims 1 to 14, for use in the prevention and/or treatment of a disease and/or disorder in a subject or for use in a method of prevention and/or treatment of a disease and/or disorder in a subject comprising the step of administering the nanoparticulate material according to any of claims 1 to 14, wherein said disease and/or disorder is a proliferative disease.
    [17]
    17. Nanoparticulate material according to claim 17, wherein said proliferative disease is a disease associated with some degree of abnormal cell proliferation, preferably cancer, wherein said cancer is preferably selected from the group consisting of carcinoma, lymphoma, blastoma , sarcoma, leukemia, non-localized cancer, squamous cell cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer , glioblastoma, skin cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, head cancer and neck cancer.
    [18]
    18. Nanoparticulate material, according to any of claims 1 to 14, for use in - imaging applications, in particular medical imaging, and/or - generating radicals, in particular mediated by light irradiation, preferably to treat a disease and/or a disorder in a subject or a method of treating a disease and/or a disorder in a subject, according to any of claims 15 to 17 and/or
    - disinfect surfaces and/or
    - detecting a pathogen and/or an analyte.
    [19]
    19. Process for obtaining a nanoparticulate material, according to any of the preceding claims, comprising the steps of
    a) coating a resorbable nanoparticle with an antioxidant agent and
    b) replacing the antioxidant agent coating by functionalizing the resorbable nanoparticle with at least one compound that is different from the antioxidant agent.
    [20]
    20. Product, in particular a pharmaceutical composition, a medical kit or a medical device, comprising a nanoparticulate material, according to any of claims 1 to 18.
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    公开号 | 公开日
    WO2021209511A1|2021-10-21|
    引用文献:
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