Nanoparticle system comprising a metal coated with polyethylene glycol (PEG) and functionalised with a polyphenol organic acid, manufacturing method and use of said system

Abstract

The present invention relates to a nanoparticle system comprising a metal selected from silver and gold, coated with polyethylene glycol (PEG) and functionalised with a polyphenol organic acid selected from caffeic acid, gallic acid and ferulic acid. The present invention also relates to a method for manufacturing said nanoparticle system and to the therapeutic and cosmetic use of said nanoparticle system.

Description

[0001]NANOPARTICLE SYSTEM COMPRISING A METAL COATED WITH POLYETHYLENE GLYCOL (PEG) FUNCTIONALIZED WITH A POLYPHENOL-TYPE ORGANIC ACID, MANUFACTURING PROCESS AND USE OF SAID SYSTEM Field of the Invention The present invention relates to a system of metallic nanoparticles coated with polyethylene glycol (PEG), which is functionalized with a polyphenol-type organic acid. The present invention also relates to a manufacturing process for said nanoparticle systems and to the therapeutic and cosmetic use of said system. Background Polyphenols are secondary metabolites of plants produced in response to stress. These compounds are one of the main substances responsible for the health benefits of consuming fruits and vegetables (Del Rio et al. 2013. Antioxidants and Redox Signaling. 2013, 18 (14): 1818–1892).The high antioxidant and anti-inflammatory capacity of polyphenols appears to be partly responsible for several beneficial effects associated with their consumption, such as antidiabetic and cardioprotective effects. This antioxidant capacity is of great biological interest for preventing oxidative stress, an imbalance that occurs in the body when antioxidant defense mechanisms are unable to neutralize reactive oxygen species generated primarily by cellular respiration (Shahidi and Ambigaipalan. 2015. Journal of Functional Foods. 18:820-897).Oxidative stress contributes to the development and progression of various pathologies, including cardiovascular diseases (hypertension, atherosclerosis, myocardial fibrosis, cardiac hypertrophy, myocardial infarction, among others), rheumatic diseases, cancer, obesity, diabetes, and neurological diseases (Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease) (Dubois-Deruy et al. 2020, Antioxidants. 9 (9), 864; Prakash Reddy. 2023, Biomedicines. 11 (11): 2925). Therefore, the antioxidant capacity of polyphenols is of great interest for reducing oxidative stress and, consequently, for the prevention and treatment of associated pathologies. Another biological property associated with phenolic compounds is their melanogenic capacity in the skin (Orhan and Deniz. 2021. Current Pharmaceutical Biotechnology. 22 (11):1423).Melanogenesis is the biological process responsible for the synthesis of melanin, the pigment that determines the color of skin, hair, and eyes in humans and other organisms. In this context, the enzyme tyrosinase emerges as a central protein in the biochemical cascade that leads to melanin formation. Tyrosinase catalyzes the conversion of tyrosine to DOPA (3,4-dihydroxyphenylalanine), which is the first step in melanin production (Serre et al. 2018. International Journal of Cosmetic Science. 40 (4): 328-347). The molecular and cellular mechanisms that govern the regulation of tyrosinase activity play a substantial role in both pathological and aesthetic conditions associated with hyperpigmentation. Therefore, tyrosinase inhibition has emerged as a promising therapeutic strategy for treating skin diseases related to hyperpigmentation.Specifically, a wide variety of tyrosinase inhibitors have been studied, including polyphenols (Zolghadri et al. 2019. Journal of Enzyme Inhibition and Medicinal Chemistry. 2019.1: 279-309; Hassan et al. 2022. Molecules. 28 (1): 378). Furthermore, abnormal tyrosinase expression or activation has been associated with various pathologies such as albinism, vitiligo, melanoma, and Parkinson's disease (Qu et al. 2020. Journal of Pharmaceutical Analysis. 10 (5): 414-425). Finally, another beneficial effect of phenolic compounds is their antimicrobial or antibacterial capacity (Manso et al. 2022. Antibiotics. 11 (1): 46). One of the most common bacterial infections in humans is Staphylococcus aureus infection. This gram-positive bacterium is found on the skin and mucous membranes. In some people, its presence can be very significant (colonization up to 80%), and in many cases, they may be asymptomatic carriers.However, in certain individuals (e.g., immunocompromised individuals, the elderly, etc.), this bacterium causes multiple infections such as bacteremia, infective endocarditis, skin and soft tissue infections, osteomyelitis, septic arthritis, pulmonary infections, gastroenteritis, meningitis, and urinary tract infections, among others (Tong et al. 2015. Clinical Microbiology Review. 28 (3): 603-661). Therefore, inhibiting its growth is of great clinical relevance. Given the wide variety of beneficial effects of polyphenols, many of them are chemically synthesized or isolated / concentrated from different natural sources to produce ingredients used in the pharmaceutical, food, and cosmetic industries.However, many of these compounds have low water solubility, poor bioavailability, and rapid elimination via renal or fecal excretion, which limits their exposure time to target tissues and therefore their bioactivity (Aatif. 2023. Biomedicines. 11 (7): 2078). Consequently, their therapeutic efficacy is compromised, requiring the administration of high doses of the compound and / or increased treatment frequency. To mitigate these problems and improve the absorption and bioavailability of polyphenols, various strategies are being investigated, such as the development of nanoformulations with casein, gelatin, polysaccharides, or lipids, among others (Aatif. 2023. Biomedicines. 11 (7): 2078). Therefore, the present invention aims to improve the functionality of different phenolic compounds by developing novel, previously undescribed nanoparticle systems that address the aforementioned problems that compromise their efficacy.Summary Description of the Invention: The present invention relates, in a first aspect, to a nanoparticle system comprising a metal selected from silver and gold, coated with polyethylene glycol (PEG), which is functionalized with a polyphenol-type organic acid selected from caffeic acid, gallic acid, and ferulic acid. In a second aspect, the present invention relates to a method for manufacturing said nanoparticle system according to the first aspect of the present invention. In a third aspect, the present invention relates to said nanoparticle system according to the first aspect of the present invention for therapeutic use. In a fourth aspect, the present invention relates to the cosmetic use of said nanoparticle system according to the first aspect of the present invention.Brief description of the figures: Figure 1 is a schematic showing the synthesis, TEM image, and size distribution histogram of AgNPs(S-PEG2K-CA)(S-G1NMe3Cl)(2). In particular, Figure 1(a) shows the synthesis of AgNPs(S-PEG2K-CA)(1); Figure 1(b) shows the TEM image of AgNPs(S-PEG2K-CA)(1); Figure 1(c) shows the size distribution histogram of AgNPs(S-PEG2K-CA)(1); Figure 1(d) shows the synthesis of AgNPs(S-PEG2K-CA)(S-G1NMe3Cl)(2); Figure 1(e) shows the TEM image of AgNPs(S-PEG2K-CA)(S-G1NMe3Cl)(2). and Figure 1(f) shows the size distribution histogram of AgNPs (S-PEG2K-CA)(S-G1NMe3Cl) (2). Figure 2. Graphs of A) weight loss as a function of temperature and B) first derivative of weight loss for coating ligands (HS-PEG2K-CA (I) and HS-G1NMe3Cl (II)), AgNPs (S-PEG2K-CA) (1) and AgNPs ((S-PEG2K-CA)(S-G1-NMe3Cl) (2)). Figure 3.Antioxidant activity of the compounds: for caffeic acid, HS-PEG2K-CA (I), AgNPs (S-PEG2K-CA) (1) and AgNPs ((S-PEG2K-CA)(S-G1-NMe3Cl) (2)) determined by their ability to sequester the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) (A) and reduce iron (FRAP) (B) and represented as IC50 (concentration required to obtain 50% antioxidant activity) and EC50 (the concentration of the compound needed to increase the FRAP capacity by 50%), respectively. Figure 4. (A) Survival of murine melanoma cells B16F10 after incubation with different concentrations of silver nanoparticles (AgNPs) for 48 hours by the MTT assay. Extracellular (B) and intracellular (C) melanin content of B16F10 cells treated with AgNPs for 48 hours. (D) Immunoblotting analysis of the amount of tyrosinase in B16F10 cells treated with AgNPs. (E) Densitometry analysis of the immunoblotting.The percentage values ​​in the treated cells were compared to the untreated control (100%). Lig: ligand; KA: kojic acid. Data are expressed as mean ± SEM for triplicate or duplicate samples (immunoblotting). * p<0.05 vs. control; **p<0.01 vs. control; ***p<0.001 vs. control. Description of the Invention Definitions As used herein, the term “nanoparticle system” is equivalent to “nanoparticles” or “nanoparticle assembly.” The nanoparticles of this system of the present invention are characterized by having an average particle size equal to or less than 1 µm, preferably an average size between 1 and 1000 nm. This size allows the nanoparticles to penetrate cells effectively.As used herein, the term “dendritic wedge” refers to a highly branched, cone-shaped macromolecule defined by a focal point, the growth units, branches, or ramifications emanating from that focal point, and the outer layer, surface, or periphery of those branches that incorporates functional groups. Furthermore, the focal point is used to bond to the metallic surface of the nanoparticle. As used herein, the term “generation” in the context of a dendritic wedge refers to the number of iterative branchings required for the preparation of the compound.As used herein, the term “alkyl” refers in the present invention to linear or branched aliphatic chains having from 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl or sec-butyl, preferably having from 1 to 2 carbon atoms, more preferably the alkyl group is a methyl group. As used herein, the terms “treat,” “treating,” or “treatment” and their equivalents refer to an improvement of at least one perceptible symptom of the disease, condition, or disorder to be treated, in particular hyperpigmentation or bacterial infection.In another embodiment, "treat," "treating," or "treatment" refers to inhibiting the progression of at least one perceptible symptom of the disease, condition, or disorder to be treated, particularly hyperpigmentation or bacterial infection, either physically (e.g., stabilization of a perceptible symptom), physiologically (e.g., stabilization of a physiological parameter), or both. In another embodiment, "treat" or "treatment" refers to slowing the progression or reversing the progression of at least one perceptible symptom of the disease, condition, or disorder to be treated, particularly hyperpigmentation or bacterial infection. As used herein, "prevent" or "prevention" and their equivalents refer to delaying the onset or reducing the risk of acquiring at least one perceptible symptom of the disease, condition, or disorder to be treated, particularly hyperpigmentation or bacterial infection.As used herein, the term "prevent and / or treat" includes "prevent and treat" and "prevent or treat." In this disclosure and in the claims, terms such as "comprises," "comprising," "containing," and "having" are open terms and may mean "includes," "including," and the like; whereas terms such as "consisting of" or "consists of" refer to the elements mentioned after these terms and exclude any others not mentioned. Unless otherwise explained, all technical and scientific terms used herein have the same meanings commonly understood by a person of ordinary knowledge in the subject matter to which this disclosure pertains. The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, the word "or" includes "and" unless the context clearly indicates otherwise.The term "approximately" applied to the values ​​used herein includes a margin of error of ± 5%, such as, for example, ± 4%, ± 3%, ± 2%, ± 1%. Abbreviations: NP: Nanoparticles AgNPs: Silver nanoparticles CA: Caffeic acid G1: First generation (dendron) PEG: Polyethylene glycol DMF: Dimethylformamide PEG2K: PEG2000 EDCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt: Hydroxybenzotriazole FBS: Fetal bovine serum DMSO: Dimethyl sulfoxide Detailed description of the invention The present invention relates to a nanoparticle system comprising a metal selected from silver and gold, coated with polyethylene glycol (PEG), which is functionalized with a polyphenol-type organic acid selected from caffeic acid, gallic acid, and ferulic acid.To avoid any doubt, the term “which” refers to polyethylene glycol, i.e., polyethylene glycol is functionalized with a polyphenol-type organic acid selected from caffeic acid, gallic acid, and ferulic acid. In a preferred embodiment, said metal is silver. In another preferred embodiment, said polyphenol-type organic acid is caffeic acid. In yet another preferred embodiment, the nanoparticle system of the present invention further comprises a first- or later-generation carbosilane-type dendritic wedge coating the metallic surface of the nanoparticle system, wherein said dendritic wedge comprises a focal point and an outer layer or periphery, wherein the focal point of the dendritic wedge is a chain of formula (I) –Si-(CH2). a -R 1 which is attached to the nanoparticles through the R 1 , where a is an integer ranging from 1 to 10; and R 1is a thiol group (-SH); and wherein the outer layer of the dendritic wedge consists of equal or different units of the group of formula (II): where R 2 is an alkyl group (C1-C4); p is an integer and varies between 1 and 3; R 3 is the group -(CH2)cS-(CH2)dR 4 ; e n el que c represents an integer ranging from 1 to 10; d represents an integer ranging from 2 to 5; and R 4 is a -NR'R'' group, wherein R' and R'' independently represent an alkyl (C1-C4) group or a hydrogen. In a preferred embodiment of said dendritic wedge nanoparticle system as defined above, in formula (I), a varies from 1 to 5. In another preferred embodiment of said dendritic wedge nanoparticle system as defined above, in formula (II): R 2 is a methyl group; p is 2; and R 3 is the group -(CH2)cS-(CH2)dR 4 ; e n el quec represents an integer ranging from 1 to 5; d is 2 or 3; and R 4 is a -NR'R'' group, wherein R' and R'' independently represent an alkyl (C1-C4) group or a hydrogen. In a further preferred embodiment of said dendritic wedge nanoparticle system as defined above, in formula (II), R 4is an -N(CH3)2 group or an ammonium group. In the latter case, the nanoparticles are then in salt form. Preferably, the salts are halogen salts, which can be selected from chloride, bromide, iodide, or triflate salts. Preferably, the salts are iodide and chloride. Naturally, in the case where a dendritic wedge, as defined above, is present in the nanoparticle system, the metallic surface will be coated by the functionalized PEG, as defined above, and by the dendritic wedge, as defined above. In another embodiment, the present invention relates to a composition comprising the nanoparticle system according to any of the preceding embodiments.In the present invention, said composition may comprise the same nanoparticle system with the defined metal and polyphenol, or a combination of different nanoparticle systems, wherein the metal may vary independently between silver and gold, and the polyphenol may vary independently between caffeic acid, gallic acid, and ferulic acid. In particular, said composition is a pharmaceutical composition. More particularly, said pharmaceutical composition is an antioxidant composition. In a more preferred embodiment, said pharmaceutical composition further comprises a pharmaceutically acceptable vehicle, adjuvant, diluent, or excipient, and optionally at least one other active ingredient.Said pharmaceutically acceptable vehicle, adjuvant, diluent, or excipient may be any of the following: preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersing media, coatings, isotonic agents, absorption retardants, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except where a conventional medium or agent is incompatible with the active ingredient, its use is contemplated in the compositions of the present invention. In another embodiment, the present invention relates to a composition in the form of a food supplement, a functional food, or a nutraceutical product. In another embodiment, the present invention relates to a composition that is a cosmetic, dermocosmetic, or nutricosmetic composition.In a second aspect of the present invention, the present invention relates to a process for obtaining the dendritic wedge-less nanoparticle system, as defined above, comprising the following steps: a) obtaining the HS-PEG-polyphenol compound by reacting HS-PEG-NH2 and polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, and ferulic acid; b) obtaining the metallic nanoparticle by reacting a silver or gold metallic precursor with a reducing agent; c) reacting the HS-PEG-polyphenol compound obtained in step a) with the metallic nanoparticle formed in step b), wherein steps a) and b) are carried out in the sequence a)-b) or b)-a). In a preferred embodiment, in step a) the polyphenol is caffeic acid. In another preferred embodiment, in step a) the PEG is PEG2K.In another preferred embodiment, the reaction in step a) is carried out in the presence of a non-protic polar solvent. Preferably, this non-protic polar solvent is dimethylformamide (DMF). In another preferred embodiment, the reaction in step a) is carried out in the presence of at least one coupling agent. Preferably, this at least one coupling agent is EDCl·HCl or HOBt. In another preferred embodiment, the reaction in step a) is carried out at a temperature between 55 and 65 °C. In another preferred embodiment, the metal precursor in step b) is a silver metal precursor, preferably AgNO3. Alternatively, the metal precursor in step b) is a gold metal precursor, preferably tetrachloroauric acid H[AuCl4] or any of its salts. In another preferred embodiment, the reaction in step b) is carried out in the presence of a polar solvent. Preferably, this polar solvent is water.In another preferred embodiment, the reaction in step b) is carried out in the presence of a reducing agent, which is sodium tetrahydroborate. In another embodiment within the second aspect of the invention, the present invention relates to a process for obtaining the dendritic wedge nanoparticle system, as defined above, comprising the following steps: a) obtaining the HS-PEG-polyphenol compound by reacting HS-PEG-NH2 and polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, ferulic acid; b) obtaining the metallic nanoparticle by reacting a metallic precursor of silver or gold with a reducing agent; c) reacting the HS-PEG-polyphenol compound obtained in step a) with the metallic nanoparticle formed in step b) and the dendritic wedge, as defined above, wherein step a) and step b) are carried out in the sequence a)-b) or b)-a).In a preferred embodiment of the process for obtaining the dendritic wedge nanoparticle system, the polyphenol is caffeic acid. In another preferred embodiment, the metal precursor in step b) is a silver metal precursor, preferably AgNO3. Alternatively, the metal precursor in step b) is a gold metal precursor, preferably tetrachloroauric acid H[AuCl4] or any of its salts. In a preferred embodiment of the process for obtaining the dendritic wedge nanoparticle system, the ratio between the dendritic wedge and the HS-PEG-polyphenol compound is equimolar. In another preferred embodiment of said process for obtaining the dendritic wedge nanoparticle system, steps b) and c) are carried out in the presence of a polar solvent. Preferably, said polar solvent is water.In another preferred embodiment of said process for obtaining the dendritic wedge nanoparticle system, in step b) said reducing agent is sodium tetrahydroborate. In another embodiment, the present invention relates to an intermediate compound for obtaining the nanoparticle system according to any of the embodiments indicated above, of formula HS-PEG-polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, and ferulic acid. In a more preferred embodiment, the PEG is PEG2K. In another more preferred embodiment, the polyphenol is caffeic acid.In a third aspect of the invention, the present invention relates to a nanoparticle system, as defined above, in any of its individual or combined embodiments, or a pharmaceutical composition, as defined above, in any of its individual or combined embodiments, or a composition in the form of a food supplement, functional food, or nutraceutical product, as defined above, in any of its individual or combined embodiments, or an intermediate compound, as defined above, in any of its individual or combined embodiments, for use as a medicament. Preferably, said medicament is an antioxidant medicament, i.e., with antioxidant properties.The present invention also relates to a nanoparticle system, as defined above, in any of its individual or combined embodiments, or a pharmaceutical composition, as defined above, in any of its individual or combined embodiments, or a composition in the form of a food supplement, functional food, or nutraceutical product, as defined above, in any of its individual or combined embodiments, or an intermediate compound, as defined above, in any of its individual or combined embodiments, for use as an antioxidant medicament in the prevention and / or treatment of a disease selected from diabetes, obesity, diabetic nephropathy, neurodegenerative diseases, cardiovascular diseases, cancer, and eye diseases.The present invention also relates to a nanoparticle system, as defined above, in any of its individual or combined embodiments, or a pharmaceutical composition, as defined above, in any of its individual or combined embodiments, or a composition in the form of a food supplement, functional food, or nutraceutical product, as defined above, in any of its individual or combined embodiments, or an intermediate compound, as defined above, in any of its individual or combined embodiments, for use in the prevention and / or treatment of a disease related to the abnormal expression or activation of tyrosinase, selected from skin hyperpigmentation, albinism, vitiligo, melanoma, and Parkinson's disease. Preferably, this disease is skin hyperpigmentation.The present invention also relates to a nanoparticle system, as defined above, in any of its individual or combined embodiments, or a pharmaceutical composition, as defined above, in any of its individual or combined embodiments, or a composition in the form of a food supplement, functional food, or nutraceutical product, as defined above, in any of its individual or combined embodiments, or an intermediate compound, as defined above, in any of its individual or combined embodiments, for use in the prevention and / or treatment of bacterial infection or diseases arising therefrom. In a preferred embodiment, said bacterial infection is due to Gram-positive bacteria. More preferably, said Gram-positive bacteria is Staphylococcus aureus.In a preferred alternative embodiment, said bacterial infection is due to gram-negative bacteria, for example, Escherichia coli. In an embodiment of said therapeutic uses, said nanoparticle system, as defined above in any of its individual or combined embodiments, or a pharmaceutical composition, as defined above in any of its individual or combined embodiments, or a composition in the form of a food supplement, a functional food, or a nutraceutical product, as defined above in any of its individual or combined embodiments, or an intermediate compound, as defined above in any of its individual or combined embodiments, is administered topically, orally, or parenterally.In a preferred embodiment, the administration is topical in a dosage form selected from aerosol, cream, lotion, ointment, microsphere suspension, and liposomes. In another preferred embodiment, the administration is oral in a dosage form selected from powders, capsules, minicapsules, nanocapsules, tablets, lozenges, granules, and sachets. In a fourth aspect, the present invention relates to the cosmetic use of the nanoparticle system, as defined above, in any of its individual or combined embodiments, or of a composition that is a cosmetic, dermocosmetic, or nutricosmetic composition, or of an intermediate compound, as defined above, in any of its individual or combined embodiments, for skin depigmentation.The present invention also relates to the cosmetic use of the nanoparticle system, as defined above, in any of its individual or combined embodiments, or of a composition that is a cosmetic, dermocosmetic, or nutricosmetic composition, or of an intermediate compound, as defined above, in any of its individual or combined embodiments, for preventing or delaying skin aging. It should be noted that the present invention encompasses any combination of the above embodiments or examples that a person skilled in the art considers feasible in the context of the present invention. The various examples cited above, as well as the following examples, are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way. EXAMPLES 1. Materials and Methods 1.1.Synthesis of the compounds. General conditions: All reactions were carried out in an inert atmosphere, with solvents obtained and handled under anhydrous conditions. The compound HS-PEG2K-CA (compound I) was synthesized as indicated below. The compound HS-G1-NMe3Cl (compound II) was synthesized as indicated in Fuentes-Paniagua et al. 2013. Organometallics. 32, 1789-1796, 2013). 1.1.1 Synthesis of HS-PEG2K-CA (I) Under an inert atmosphere, a solution in DMF of caffeic acid (41.03 mg, 0.300 mmol) was added to a solution in DMF of a mixture of EDCI-HCl (57.51 mg, 0.300 mmol) and HOBt (40.53 mg, 0.300 mmol). The reaction mixture was stirred for one hour. Subsequently, a mixture of HS-PEG2K-NH2-HCl (300 mg, 0.150 mmol) and triethylamine (15.19 mg, 0.150 mmol) in DMF was added dropwise at 0 °C under stirring and maintained for 15 min. Finally, the reaction mixture was stirred at 60 °C for 12 h overnight.After purification by size exclusion chromatography in acetone, the compound HS-PEG2K-CA was obtained as a yellow solid (288.5 mg, 90.2%). 1.1.2 Synthesis of AgNPs(S-PEG2K-CA) (compound 1) To an aqueous deoxygenated solution of AgNO3 (1.56 mL, 0.047 mmol, 30 mM, 7.96 mg), an aqueous solution of compound I (3.75 mL, 0.047 mmol, 12.5 mM, 100 mg) was added dropwise. Then, NaBH4 in deoxygenated water (1.17 mL, 0.234 mmol, 200 mM, 8.87 mg) was added dropwise, and the mixture was stirred for 4 hours. The AgNPs were purified by dialysis (MWCO: 20 kDa), yielding a brown solid dispersed in water. The synthesis was performed in triplicate. Mean silver core diameter (TEM): 1.0 nm. Results are expressed as mean ± SEM: Zeta potential (mV): +1.18 ± 3.09. DLS (mean Z diameter, nm): 37.22 ± 3.091.1.3 Synthesis of AgNPs(S-PEG2K-CA)(S-G1-NMe3Cl) (compound 2) Deoxygenated aqueous solutions (1.87 mL, 12.5 mM) of a mixture of compound I (50 mg, 0.023 mmol) and compound II (10.01 mg, 0.023 mmol) were added dropwise to a deoxygenated aqueous solution of AgNO3 (0.78 mL, 0.0272 mmol, 30 mM, 3.98 mg). A deoxygenated aqueous solution of NaBH4 (0.59 mL, 0.117 mmol, 200 mM, 4.44 mg) was then added dropwise, and the reaction mixture was stirred for 4 hours. Purification by dialysis (MWCO: 20 kDa) yielded compound 2 as a brown solid dispersed in water. The synthesis was performed in triplicate. The results are expressed as mean ± SEM: Zeta potential (mV): +16.90 ± 3.27 DLS (mean Z diameter, nm): 28.53 ± 7.63.1.2.Characterization of the compounds: The different synthesized compounds were characterized using various analytical techniques. NMR spectra were acquired using a Varian 500 Hz or Bruker NeoAdvance 400 Hz spectrometer with CD3OD as the solvent. Chemical shifts (δ) are expressed in parts per million (ppm). Resonance signals were assigned using HSQC, HMBC, and COSY NMR experiments. Elemental analyses were performed using a LECO CHNS-932 instrument. UV-visible spectra of dilute compound samples were recorded in a quartz cell (optical path length: 1 cm) using a Perkin-Elmer Lambda 18 spectrophotometer. Transmission electron microscopy (TEM): A carbon-coated copper grid (400 mesh) covered with a drop of a dilute compound solution was dried. Subsequently, TEM images were recorded using a JEM 2100HT transmission electron microscope.The ImageJ program was used to measure the size of the nanoparticles. Thermogravimetric analysis (TGA): The TA TGA55 instrument was used to analyze pure, dried compound samples (2–10 mg). The sample was placed in a platinum sample holder under a nitrogen atmosphere and heated to a temperature of 25–1000 °C (10 °C per min). Zeta potential (ZP): Zeta potential experiments were performed using a Zetasizer Nano ZS instrument (Malvern Instruments Ltd., UK). Compound solutions in deionized water (1 mg / mL) were filtered through a 0.22 μm syringe filter and measured in disposable Malvern plastic cuvettes.Dynamic light scattering (DLS): Measurements of the hydrodynamic diameter of compound solutions filtered in deionized water (1 mg / mL) were performed using a Malvern Zetasizer Nano ZS instrument equipped with non-invasive backscatter optics (NBS). Experiments were conducted at 25 °C after a prior equilibration period (typically 5 min), and results are presented as the mean of at least three measurements per sample. 1.3. Evaluation of the antioxidant activity of the compounds 1.3.1 DPPH radical scavenging activity: Antioxidant capacity was evaluated based on the ability of the compounds to sequester / neutralize the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. Specifically, 180 µl aliquots of DPPH methanolic solution (111.11 µM) were dispensed into 96-well plates.Next, 20 µl of compounds I, 1, and 2 were added to water at concentrations ranging from 0 to 12 µg / mL (compound 1) and 0 to 14 µg / mL (compound 2), and the well plate was kept in the dark at room temperature for 30 min. After this period, the absorbance was recorded at 530 nm using a microplate reader (Epoch™, BioTek Instruments, Winooski, VT, USA). All assays were performed in triplicate, and a methanol / water solution was used as a control (the same solution used for the samples). Antioxidant activity was determined from the reduction in DPPH absorbance. The IC50 (concentration that produces 50% of the antioxidant activity) was calculated. To do this, it was necessary to calculate the DPPH remnant.1.3.2 Ferric Reducing Antioxidant Power (FRAP) Tests were performed based on the ability of the compounds to reduce Fe. +3 to Faith +2in the presence of TPTZ (2,4,6-tripyridyl-striazine), forming an intense blue Fe+2 - TPTZ complex with maximum absorption at 593 nm. 180 µl aliquots of FRAP solution (a mixture of TPTZ (10 mM solution in 40 mM hydrochloric acid), FeCl3 (20 mM solution in ACS water), and acetate buffer (20 mM in ACS water, pH 3.6) in a 1:1:10 ratio) were placed in 96-well plates. Subsequently, 20 µl of compounds I, 1, and 2 in methanol were added, and the plates were incubated in the dark at room temperature for 30 minutes. After this incubation, absorbance was measured at 593 nm using a microplate reader (Epoch™, BioTek Instruments, Winooski, VT, USA). All experiments were performed in triplicate, using methanol as a control. Finally, the EC was calculated. 50(the concentration of antioxidant compound that increases FRAP capacity by 50%). 1.4 Evaluation of antibacterial activity. The in vitro evaluation of the antibacterial properties of compounds II, 1, and 2 and caffeic acid was performed according to the international standard method ISO 20776-1:2006. Antibacterial activity was evaluated against two bacterial strains: E. coli (CECT 515) and S. aureus (CECT 240). To prepare the assay, stock solutions of each compound were prepared in water, followed by further dilutions on Mueller-Hinton agar to achieve assay concentrations ranging from 0.25 ppm to 1024 ppm. The assay was performed in 96-well plates, with two wells allocated to each concentration and including various controls (e.g., biocide, inoculum, and culture medium). Bacterial inoculation was performed at a concentration of 107 CFU / mL in the wells.After 24 hours of incubation with the biocides at 37 °C, the increase in turbidity was measured at 630 nm using an UltraMicroplate reader (BIO-TECK Instruments, model epoch 2). From the assay results, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ​​were determined. 1.5 Evaluation of antimelanogenic activity 1.5.1 Cell culture and treatments. B16F10 ATCC CRL-6475™ mouse melanoma cells were acquired from the American Type Culture Collection (Manassas, VA). Cells were cultured and maintained in Dulbecco's modified Eagle medium (DMEM; Gibco Life Technologies, Carlsbad, CA, USA) supplemented with 10% FBS, 1% antibiotics (penicillin and streptomycin), and 2 mM L-glutamine (at 37°C in a 5% CO2 atmosphere). Compound 2 was diluted in DMSO and re-diluted with DMEM to achieve the final concentrations indicated (0.1, 0.5, 1, 5, 10, and 20 μg / mL). 1.5.2. Melanin Assay.Cells were cultured at 8 x 10⁴ cells / mL in 12-well plates and treated with 300 nM alpha-melanocyte-stimulating hormone (α-MSH), except for the negative control, and with AgNPs at 0.1, 1, 5, 10, or 20 µg / mL for 48 hours. For the melanin secretion assay, the absorbance of the culture media was measured using an optical density reader at 490 nm. Cells from each well were lysed with 300 μL of lysis buffer and precipitated by centrifugation (12,000 rpm, 10 min). The pellets were dissolved in 300 μL of dissolution buffer (1 M NaOH, 10% dimethyl sulfoxide (DMSO)) and melted at 80 °C for 30 min. Absorbance was measured at 405 nm using an Ultra Microplate optical density reader (BIO-TECK Instruments, model epoch 2). Experiments were performed in triplicate. 1.5.3. Cell viability assay.The MTT cell viability assay was evaluated to determine the viability of B16F10 cells exposed to different concentrations of AgNPs. Cells were seeded at 1 × 10⁴ cells / well in 96-well plates. After treatment with 0.1, 1, 5, 10, 20, or 50 µg / mL of AgNPs, the cells were incubated at 37°C for 48 hours. Cell viability was determined using a 3-(4,5-cymethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution (1 mg / mL, 50 µL / well) added to each well, and the cells were incubated at 37°C for 4 hours. After removal of the MTT solution, 100 μl of DMSO were added to the well and incubated for 10 min. Absorbance was determined at 595 nm using a plate reader (EpochTM, BioTek Instruments, Winooski, VT, USA). 1.5.4. Western Blotting After treatment, B16F10 cells were lysed with RIPA buffer containing a cocktail of protease inhibitors.Twenty-five micrograms of protein extracted from whole cells were loaded onto a plate and separated by 10% SDS-PAGE. The resulting particles were then transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore). The membranes were blocked in 5% milk for one hour and then incubated overnight at 4°C with either anti-tyrosinase antibody (Ab 170905) or anti-beta-actin antibody (Sigma A2228). After washing with PBST, the membranes were incubated for one hour with either anti-rabbit or anti-mouse secondary antibodies. All bands were visualized using Western blotting reagents (Pierce). Images of the different membranes were captured using a Syngene imager (Fisher Scientific, USA). Western blotting data (band densitometry) were quantified using ImageJ 1.5.5. Statistical Analysis: The Student's t-test was chosen for data analysis. Statistical analysis was performed using PRISM 5 software (GraphPad Software, La Jolla, CA, USA). 2.Results and Discussion 2.1 Synthesis and Characterization of Silver Nanoparticles (AgNPs) As previously stated, the homofunctionalized nanoparticles were synthesized in an aqueous medium in which the silver ion precursor AgNO3 was reduced by NaBH4 in the presence of the stabilizing ligand I. Purification by dialysis (molecular weight cutoff (MWCO): 20 kDa) yielded the compound (AgNPs(S-PEG2K-CA)) (compound 1) as a brown solid dispersed in water. The heterofunctionalized nanoparticles were readily synthesized in water by the direct reaction of AgNO3 with a mixture of both thiol derivatives and the reducing agent NaBH4. Furthermore, these nanoparticles (AgNPs(S-PEG2K-CA)(S-G1-NMe3Cl) (compound 2) were obtained by dialysis purification (molecular weight cutoff (MWCO): 20 kDa) as a brown solid dispersed in water. See Figure 1.The particle size and size distribution of silver nanoparticles (AgNPs) were determined using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Transmission electron microscopy (TEM) provides direct images of individual particles, allowing for detailed visualization of particle morphology, structure, and size distribution within the sample. TEM images demonstrate the formation of the described nanoparticles from homofunctionalized (1) and heterofunctionalized (2) AgNPs. The results highlight that the size and spherical shape of the AgNPs remain unchanged regardless of the presence of one or two coating ligands, with most nanoparticles measuring approximately 1 nm in diameter.On the other hand, dynamic light scattering (DLS) provides information on particle size distribution in solution, encompassing hydrodynamic mean size and polydispersity, although it lacks the ability to reveal specific morphological details. In the case of DLS, measurements consist of analyzing the fluctuations in scattered light intensity resulting from the Brownian motion of particles dispersed in a liquid. This analysis allows the calculation of diffusion coefficients and the hydrodynamic particle size by applying the Stokes-Einstein equation. The theoretical core diameter of the AgNPs was calculated using the polydispersity (PDI) value from DLS (^^ / (^ + ^^^)^ ).The data presented in Table 1 reveal a larger particle size for the heterofunctionalized nanoparticles (71.60 ± 0.20 nm, mean diameter Z) compared to the homofunctionalized nanoparticles (37.22 ± 1.03 nm, mean diameter Z). This observation is consistent with the results of previous studies on other metallic nanoparticles, in which the presence of exposed positive charges on the metal surface promotes aggregate formation, leading to an increase in size detected by DLS. The presence of a positive charge on the surface also influences the zeta potential values, resulting in more positive values ​​for nanoparticles containing the dendron carbosilane with peripheral ammonium groups anchored to the metal surface of the heterofunctionalized AgNPs (compound 2) (+14.4 ±1.36 mV) than for the homofunctionalized AgNPs (compound 1) (+5.44 ±3.12 mV). Table 1. TEM and DLS characterization data of the AgNPs. A.gNPs Da PDIb D c d x CDx ZPe (1) AgNPs(S-PEG2K-CA 1 0.241 37.22 ± 1.03 12.64 + 5.44 ± 3.12(2) AgNPs(S-PEG2K-1 0.266 71.60 ± 0.20 22.02 + 16.9 ± 3.27CA)(S-G1-NMe3Cl)aAverage diameter size (nm) obtained by TEM. b Polydispersity index (PDI) obtained by DLS. c Hydrodynamic diameter (nm) obtained by DLS.d Calculated diameter (nm). eZeta Potential (mV) A thermogravimetric analysis (TGA) was performed to quantify the amount of organic material surrounding the metal cores. For this purpose, compound 1, compound 2, and the coating ligands HS-PEG2K-CA (I) and HS-G1NMe3Cl (II) were heated from 25 to 1000 °C under a nitrogen atmosphere. The weight loss observed during the heating process corresponded to the degradation of the organic matter within the compound. Due to the difference in degradation temperature found for both ligands, 200–300 °C for HS-NMe3Cl (II) and 300–600 °C for HS-PEG2K-CA (I), it is possible to establish the percentage of each present in both nanoparticles by analyzing the first derivative of the weight loss as a function of temperature.Significantly, both the homofunctionalized (1) and heterofunctionalized (2) AgNPs showed weight loss between 300 and 600 °C, indicating the thermal decomposition of the S-PEG2K-CA coating ligands. However, the weight loss between 100 and 300 °C, related to the thermal decomposition of the S-G1NMe3Cl carbosilane dendron coating ligands, was observed exclusively in the case of the heterofunctionalized AgNPs (2). See Figures 2A-2B. The estimation of the ligands anchored to each AgNP was derived from the results obtained. Considering the average diameter of the nanoparticle core obtained by TEM (1.0 nm diameter), the silver atoms (NAg) in the cores of AgNPs 1 and 2 can be determined.With this estimate, which assumes spherical nanoparticle shapes and incorporates the weight loss determined by TGA and the determination of the core area of ​​the AgNPs, the average surface coverage (Γ) could be estimated (Table 2). Estimation of the ligands anchored to each AgNP and the total surface coverage based on the results obtained from the TGA (% organic matter) and TEM (1.0 nm AgNP size) analyses. gNPs Molécula % a 2TGAL / AgNP Γ (Å / molecule) b1 -S-PEG2K-CA 91.3 16 20-S-PEG2K-CA 88.46 142 20 -S-G1-NMe3Cl 2.30 22.2 Antioxidant Activity As mentioned in the background, polyphenols are widely recognized for their robust antioxidant properties, due to their ability to effectively neutralize free radicals and other oxidizing agents within the human body. To determine the antioxidant activity of compounds I, 1, and 2, two different chemical assays were used: the “scavenging” activity of the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the reduction of metal ions (ferric ion reducing antioxidant potential (FRAP)). The interpretation of the results, represented in Figure 3, was approached from two different perspectives.The IC50 (the concentration of antioxidant dendrimer required to sequester 50% of DPPH free radicals) and EC50 (the concentration of antioxidant dendrimer required to increase FRAP capacity by 50%) were evaluated. Analysis of the DPPH data showed that compound I exhibited an IC50 value of 1.61 µg / mL, demonstrating excellent performance as a DPPH radical scavenger, even surpassing the activity of free caffeic acid. As expected, compound 1, which contains only derivative I in its structure, was more active (IC50 value of 4.18 µg / mL) than compound 2 (IC50 value of 12.35 µg / mL), which, in addition to ligand I, contains part of the structure functionalized with the cationic carbosilane dendritic wedge. In the analysis of the antioxidant capacity of the systems using FRAP, again the heterofunctionalized nanoparticle was the least active (EC50 value of 1.41 µg / mL).However, nanoparticle 1 (EC50 value of 0.57 µg / mL) proved to be slightly more active than derivative I (EC50 value of 0.18 µg / mL) and free caffeic acid. The combination of data obtained by both methods indicates that the obtained nanoparticles maintain the antioxidant activity of caffeic acid when it is supported on the nanoparticle surface. 2.3 Antibacterial activity against S. aureus Given that certain polyphenols exhibit antibacterial activity, along with the fact that AgNPs and cationic carbosilane dendrons have shown to be good antibacterial agents, a study of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the newly synthesized NPs was carried out on S. aureus bacteria.In addition to evaluating the antibacterial activity of the homofunctionalized (1) and heterofunctionalized (2) AgNPs, the activity of free caffeic acid and the first-generation cationic dendrocarboxylase used in the heterofunctionalization of the AgNPs was also evaluated. The results are shown in Table 3. The results showed bacteriostatic and bactericidal activity against S. aureus for the heterofunctionalized AgNPs (2) with an MIC of 4-8 ppm and a MBC of 8-16 ppm, unlike what was observed with the homofunctionalized AgNPs (1) and the free polyphenol, which did not show activity in the concentration range tested against this bacterial strain.The increased antibacterial activity of heterofunctionalized AgNPs (2) compared to homofunctionalized AgNPs (1) is probably due to the presence of the cationic dendron carbosilane, which provides a higher concentration of surface charges in the system, thus increasing interaction with the bacterial membrane, as well as the greater solubility of the system in aqueous media. Table 3. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of caffeic acid and AgNPs against S. aureus. . aureus Compound C MI (ppm) CMB (ppm)Free caffeic acid >256 >256HS-G1-(S-NMe3Cl)2 (II) 16 16AgNP homofunctionalized (1) >256 >256AgNP heterofunctionalized (2) 4-8 8-162.4 Antimelanogenic effect As shown in Figure 4A, treatment with AgNPs(S-PEG2K-CA) did not significantly affect cell viability at any of the tested concentrations. However, treatment with AgMNPs((S-PEG2K-CA)(S-G1-NMe3Cl)) caused a 20-25% decrease in cell viability at concentrations of 10 and 20 µg / mL, and a 46% reduction at the highest concentration, 50 µg / mL. The results of the melanin content assays are shown in Figure 4 (B, C). For both compounds, concentrations from 5 µg / mL significantly reduced extracellular melanin content compared to the positive control (stimulated with α-MSH but not treated).For S-PEG2K-CA, extracellular melanin content was similar to that of the negative control (not stimulated with α-MSH) in treatments with doses equal to or greater than 1 μg / mL, and even improved the activity of kojic acid at the highest doses (10 and 20 μg / mL). Both compounds at 20 μg / mL reduced intracellular melanin accumulation (18%) similarly to kojic acid at 100 μg / mL (20%). Immunoblotting analysis showed significant activity of the compounds against tyrosinase (Figure 4, D, E), significantly decreasing its levels. Thus, cells treated with doses of 20, 10, and 5 μg / mL reduced protein tyrosinase expression for both compounds, and also to 0.1 μg / mL in the case of S-PEG2K-CA. For this compound, tyrosinase levels after the highest dose treatments were similar to those of the negative control.These results indicate that one of the ways in which these compounds are exerting their anti-melanogenic activity is through the reduction of tyrosinase enzyme levels.

Claims

CLAIMS 1. A nanoparticle system comprising a metal selected from silver and gold, coated with polyethylene glycol (PEG), which is functionalized with a polyphenol-type organic acid selected from caffeic acid, gallic acid, and ferulic acid.

2. A nanoparticle system according to claim 1, wherein the metal is silver.

3. A nanoparticle system according to claim 1 or 2, wherein the polyphenol-type organic acid is caffeic acid.

4. A nanoparticle system according to any of the preceding claims, further comprising a first- or later-generation carbosilane-type dendritic wedge coating the metallic surface of the nanoparticle system, wherein said dendritic wedge comprises a focal point and an outer layer or periphery, wherein the focal point of the dendritic wedge is a chain of formula (I) –Si-(CH2)aR 1 which is attached to the nanoparticles through the R 1, where a is an integer ranging from 1 to 10; and R 1 is a thiol group (-SH); and wherein the outer layer of the dendritic wedge consists of equal or different units of the group of formula (II): where R 2 is an alkyl group (C1-C4); p is an integer and varies between 1 and 3; R 3 is the group -(CH2)cS-(CH2)dR 4 ; e n el que c represents an integer ranging from 1 to 10; d represents an integer ranging from 2 to 5; and R 4 is a -NR'R'' group, wherein R' and R'' independently represent an alkyl group (C1-C4) or a hydrogen.

5. Nanoparticle system according to claim 4, wherein a in formula (I) varies from 1 to 5.

6. Nanoparticle system according to claim 4 or 5, wherein in formula (II): R 2 is a methyl group; p is 2; and R 3 is the group -(CH2) c -S-(CH2) d -R 4 ; e n el quec represents an integer ranging from 1 to 5; d is 2 or 3; and R 4 is a -NR'R'' group, wherein R' and R'' independently represent an alkyl group (C1-C4) or a hydrogen.

7. Metallic nanoparticle system, according to any of claims 4 to 6, wherein in said dendritic wedge R 4 is a -N(CH3)2 group.

8. Metallic nanoparticle system, according to any of claims 4 to 6, wherein R 4is an ammonium group.

9. Metallic nanoparticle system, according to the preceding claim, wherein the nanoparticles are in salt form.

10. Composition comprising the nanoparticle system according to any of the preceding claims or a combination thereof.

11. Composition according to claim 10, which is a pharmaceutical composition.

12. Pharmaceutical composition according to claim 11, which is an antioxidant composition.

13. Pharmaceutical composition according to claim 11 or 12, further comprising a pharmaceutically acceptable vehicle, adjuvant, diluent, or excipient, and optionally at least one other active ingredient.

14. Composition according to claim 10, which is in the form of a food supplement, a functional food, or a nutraceutical product.

15. Composition according to claim 10, which is a cosmetic, dermocosmetic, or nutricosmetic composition.

16. A process for obtaining the nanoparticle system according to any of claims 1 to 3 comprising the following steps: a) obtaining the HS-PEG-polyphenol compound by reacting HS-PEG-NH2 and polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, and ferulic acid; b) obtaining the metallic nanoparticle by reacting a silver or gold metallic precursor with a reducing agent; c) reacting the HS-PEG-polyphenol compound obtained in step a) with the metallic nanoparticle formed in step b), wherein steps a) and b) are carried out in the sequence a)-b) or b)-a).

17. A process according to claim 16, wherein in step a) the polyphenol is caffeic acid.

18. A process according to claim 16 or 17, wherein in step a) the PEG is PEG2K. 19.A process according to any one of claims 16 to 18, wherein the reaction in step a) is carried out in the presence of a non-protic polar solvent.

20. A process according to claim 19, wherein said non-protic polar solvent is dimethylformamide (DMF).

21. A process according to any one of claims 16 to 20, wherein the reaction in step a) is carried out in the presence of at least one coupling agent.

22. A process according to claim 21, wherein said at least one coupling agent is EDCl·HCl or HOBt.

23. A process according to any one of claims 16 to 22, wherein the reaction in step a) is carried out at a temperature between 55 and 65 °C.

24. A process according to any one of claims 16 to 23, wherein the metallic precursor of silver in step b) is AgNO3. 25.A process according to any of claims 16 to 23, wherein the metallic precursor of gold in step b) is tetrachloroauric acid H[AuCl4] or any of its salts.

26. A process according to any of claims 16 to 25, wherein the reaction in. Step b) and step c) are carried out in the presence of a polar solvent.

27. A process according to claim 26, wherein said polar solvent is water.

28. A process according to any of claims 16 to 27, wherein said reducing agent in step b) is sodium tetrahydroborate. 29.A method for obtaining the particle system according to any of claims 4 to 9, comprising the following steps: a) obtaining the HS-PEG-polyphenol compound by reacting HS-PEG-NH2 and polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, and ferulic acid; b) obtaining the metallic nanoparticle by reacting a metallic precursor of silver or gold with a reducing agent; c) reacting the HS-PEG-polyphenol compound obtained in step a) with the metallic nanoparticle formed in step b) and the dendritic wedge as defined in any of claims 4 to 9, wherein step a) and step b) are carried out in the sequence a)-b) or b)-a).

30. A method according to claim 29, wherein the polyphenol is caffeic acid.

31. A process according to claim 29 or 30, wherein the ratio between the wengundite and the HS-PEG-polyphenol compound is equimolar.32.A process according to any one of claims 29 to 31, wherein steps b) and c) are carried out in the presence of a polar solvent.

33. A process according to claim 32, wherein said polar solvent is water.

34. A process according to any one of claims 29 to 33, wherein in step b) said reducing agent is sodium tetrahydroborate.

35. A process according to any one of claims 29 to 34, wherein the metallic precursor of silver in step b) is AgNO3.

36. A process according to any one of claims 29 to 34, wherein the metallic precursor of gold in step b) is tetrachloroauric acid H[AuCl4] or any of its salts.

37. An intermediate compound for obtaining the nanoparticle system according to any one of claims 1 to 9 of formula HS-PEG-polyphenol, wherein the polyphenol is selected from caffeic acid, gallic acid, and ferulic acid.

38. An intermediate compound according to claim 37 wherein PEG is PEG2K.

39. An intermediate compound according to claim 37 or 38 wherein the polyphenol is caffeic acid.

40. A nanoparticle system according to any one of claims 1 to 9, or a pharmaceutical composition according to any one of claims 11 to 13, or a composition according to claim 14, or an intermediate compound according to any one of claims 37 to 39 for use as a medicament. 41.

41. A nanoparticle system for use according to claim 40 or a pharmaceutical composition for use according to claim 40 or a composition for use according to claim 40 or an intermediate compound for use according to claim 40, wherein said use as a medicament is as an antioxidant medicament.

42. A nanoparticle system for use according to claim 41 or a pharmaceutical composition for use according to claim 41 or a composition for use according to claim 41 or an intermediate compound for use according to claim 41, wherein said use as an antioxidant medicament is for the prevention and / or treatment of a disease selected from diabetes, obesity, diabetic nephropathy, neurodegenerative diseases, cardiovascular diseases, cancer, and eye diseases. 43.A nanoparticle system according to any one of claims 1 to 9, or a pharmaceutical composition according to any one of claims 11 to 13, or a composition according to claim 14, or an intermediate compound according to any one of claims 37 to 39, for use in the prevention and / or treatment of a disease related to abnormal expression or activation of tyrosinase, selected from skin hyperpigmentation, albinism, vitiligo, melanoma, or Parkinson's disease.

44. A nanoparticle system for use according to claim 43, or a pharmaceutical composition for use according to claim 43, or a composition for use according to claim 43, or an intermediate compound for use according to claim 43, wherein the disease is skin hyperpigmentation.

45. A nanoparticle system according to any one of claims 1 to 9, or a pharmaceutical composition according to any one of claims 11 to 13, or a composition according to claim 14, or an intermediate compound according to any one of claims 37 to 39, for use in the prevention and / or treatment of a bacterial infection or diseases arising therefrom.

46. A nanoparticle system for use according to claim 45, or a pharmaceutical composition for use according to claim 45, or a composition for use according to claim 45, or an intermediate compound for use according to claim 45, wherein said bacterial infection is due to Gram-positive bacteria.

47. A nanoparticle system for use according to claim 46, or a pharmaceutical composition for use according to claim 46, or a composition for use according to claim 46, or an intermediate compound for use according to claim 46, wherein the Gram-positive bacterium is S.

48. A nanoparticle system for use according to claim 45 or a pharmaceutical composition for use according to claim 45 or a composition for use according to claim 45 or an intermediate compound for use according to claim 45, wherein said bacterial infection is due to gram-negative bacteria.

49. A nanoparticle system for use according to any of claims 40 to 48 or a pharmaceutical composition for use according to any of claims 40 to 48 or a composition for use according to any of claims 40 to 48 or an intermediate compound for use according to any of claims 40 to 48, wherein its use comprises administering said nanoparticle system or pharmaceutical composition or composition or intermediate compound topically, or orally, or parenterally. 50.A nanoparticle system for use according to claim 49, or a pharmaceutical composition for use according to claim 49, or a composition for use according to claim 49, or an intermediate compound for use according to claim 49, wherein administration is topical in a dosage form selected from aerosol, cream, lotion, ointment, microsphere suspension, and liposomes.

51. A nanoparticle system for use according to claim 49, or a pharmaceutical composition for use according to claim 49, or a composition for use according to claim 49.

51. Claim 49 or intermediate compound for use according to claim 49, wherein administration is by oral route in a dosage form selected from powders, capsules, minicapsules, nanocapsules, tablets, lozenges, granules, and sachets.

52. Cosmetic use of the nanoparticle system according to any of claims 1 to 9 or composition according to claim 15 or intermediate compound according to any of claims 37 to 39 for skin depigmentation.

53. Cosmetic use of the nanoparticle system according to any of claims 1 to 9 or composition according to claim 15 or intermediate compound according to any of claims 37 to 39 for preventing or delaying skin aging.

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