New ultraporous crystalline metal-organic framework solids containing bisphosphonic acid ligands

Abstract

The present invention is in the field of nanoporous materials, in particular metal-organic frameworks (MOFs), and the delivery and / or sustained release of Lewis basic gases or the detection of Lewis basic gases in gas or liquid streams. The present invention relates inter alia to novel ultramicroporous crystalline metal-organic framework solids containing bisphosphonate ligands (also called phosphonate MOFs), such as MIP-210(M), and their use as carriers in the delivery of Lewis basic gases (e.g., NO). The invention also relates to the controlled release of Lewis basic gases, for example, in wounds by topical application. The invention also encompasses synthetic methods for producing the novel ultramicroporous crystalline metal-organic framework solids of the invention. The MOFs of the present invention can be used in a variety of applications, such as gas carriers and / or controlled release of gases, and are therefore highly versatile, with therapeutic and non-therapeutic applications.

Description

[Technical Field]

[0001] The present invention is in the field of nanoporous materials, in particular metal-organic frameworks (MOFs), and the delivery and / or sustained release of Lewis-based gases or detection of Lewis-based gases in gas or liquid streams.

[0002] The present invention relates inter alia to novel ultra-microporous crystalline metal organic framework solids containing bisphosphonic acid ligands (also called phosphonate MOFs), such as MIP-210(M), and their use as carriers in the delivery of Lewis-based gases (e.g., NO). The present invention also relates to the controlled release of Lewis-based gases, for example, in wounds by topical application. The present invention also encompasses synthetic methods for producing the novel ultra-microporous crystalline metal organic framework solids of the present invention.

[0003] The phosphonate MOFs of the present invention can be used in a variety of applications, such as gas carriers and / or controlled release of biologically active gases (NO, HS, CO), making the phosphonate MOFs of the present invention highly versatile and with therapeutic and non-therapeutic applications.

[0004] Reference numbers in square brackets [X] refer to the reference list at the end of the Examples. [Background technology]

[0005] Metal-organic frameworks (MOFs) are a versatile class of porous hybrid crystalline structures developed over the past few decades. They are made from the combination of inorganic moieties and polycomplexing organic linkers to form microporous or mesoporous materials with tunable pore size, shape, surface area, and hydrophilic / hydrophobic balance for a wide range of potential applications. In the area of ​​adsorption, MOFs can possess active sites, such as Lewis bases, Bronsted bases, redox, or functional polar or apolar groups from organic linkers, which can specifically interact with polar or quadrupolar molecules, such as CO, SOx, NOx, and CO2, to enhance selectivity toward more inert species (e.g., alkenes).

[0006] MOFs have also been used for the controlled release of nitric oxide (NO), but not for long-term delivery in biological media. There is a need for MOFs that can capture and / or sustainedly release Lewis basic gases such as NO with high efficiency and selectivity.

[0007] Iron is one of the cheapest and most abundant metals and is an endogenous metal that is highly tolerated by humans and other organisms. Therefore, Fe(III)-based MOFs have attracted considerable attention since their initial discovery. Due to their low toxicity, biodegradability, and therefore improved biocompatibility, Fe(III) MOFs have also attracted interest in biomedical applications, particularly in drug delivery [1], biosensing [2], imaging [3], and antibacterial materials [4, 5]. Furthermore, they have been widely used in environmental remediation as an economical and effective low-toxicity strategy [6, 7].

[0008] However, they have two major drawbacks.

[0009] First, the diversity of iron(III) MOFs has always been somewhat limited, focusing on polycarboxylate linkers. This is mainly due to the difficulty of obtaining crystalline and pure-phase products, and very few scalable examples have been reported under green conditions (MIL-88A, functionalized Fe-MIL-53 or MIL-88B(Fe), Fe-MIL-100, and Fe-MIL-127 [8]). Although these compounds are chemically very stable, the iron-carboxylate bond is not strong enough in body fluids (e.g., phosphate buffer solution mimicking blood conditions at pH 7.4), making these MOFs in contact with body fluids for NO delivery.

[0010] Second, although several iron-containing MOFs have been synthetically produced and employed in biomedical applications, their chemical stability in biological media remains insufficient, and as a result, they are not suitable for long-term delivery applications in contact with these media.

[0011] These two difficulties are particularly important in the application of controlled release of biological gases from MOFs [9].

[0012] MOFs have also been developed for the storage and delivery of various therapeutic gases, known as gaseous transmitters [10, 11]. This family consists of CO, HS, and NO, the latter being the most commonly utilized gas due to its better understood biological signaling functions. NO is known to bind strongly to Lewis acid sites in certain types of MOFs (e.g., MIL-100(Fe))

[12] before being released upon contact with water (gas or liquid phase). NO is a gaseous transmitter that exerts numerous signaling effects on several biological targets, and despite its high level of acute toxicity, exogenous administration at controlled rates (picomolar to micromolar) has proven to be of therapeutic interest in a number of antithrombotic, antibacterial, and wound healing applications

[13] . Currently proposed molecular NO donors have significant drawbacks, in particular their instability leading to non-targeted NO release, along with the potential co-release of toxic, carcinogenic, and / or pro-inflammatory by-products [14,15].

[0013] Therefore, the design of functionalized solid carriers can be an effective strategy to overcome these limitations by ensuring higher stability of NO donors through less toxic degradation products while allowing control of release kinetics at target sites.

[0014] Nanoporous materials, especially MOFs, are among the most suitable scaffolds for storing and releasing NO because of their highly efficient packing of NO and the localized delivery of pure NO without leaching of unwanted species, in addition to their tunable composition, which allows for the development of stable and biocompatible frameworks. The loading mechanism of NO into these porous materials is generally achieved by direct physical sorption or by using coordinatively unsaturated metal sites (CUS) as binding moieties for NO coordination (chemisorption) [16,17]. The latter allows for tuning of the NO payload by changing the number of metals or available CUS and ensures stable binding of NO compared to purely physisorbed NO. NO release is primarily triggered by contact with water, which replaces NO on the CUS through competitive sorption.

[0015] Various MOF structures have already been investigated, with a wide range of storage capacities (1–7 μmol NO mg -1 , with the highest value achieved for Ni-CPO-27) [15,18], stability in biological media (e.g., MIP-177 decomposed by less than 9% in 72 hours)

[19] , low toxicity (e.g., Fe-MIL-100, BioMIL-3, MIP-177 [19-21]), and a suitable release lifetime (the longest duration was approximately 2 hours for MIP-177).

[0016] When considering the use of MOFs as medical delivery systems, their stability in physiological media and biocompatibility must be considered, as they must at least remain intact while delivering therapeutic agents and not induce toxicity in target tissues. These lack of properties poses some challenges for MOFs, as they contain organic acids and metals (often toxic) and generally exhibit lower stability to heat and moisture than inorganic materials (e.g., zeolites) [12,22]. For example, CPO-27 (Ni or Co) and HKUST-1 are among the porous materials reported to have the highest NO adsorption capacity, but they decompose when exposed to aqueous solutions, leaching out toxic metals present in their structure, making them less toxicologically ideal [23,24]. In contrast, iron carboxylate MOFs such as MIL-88, MIL-100, and MIL-127, or the endogenous metal(II) MOF CPO-27(Mg,Zn), do not pose toxic effects when in contact with cells.[2,20] However, they tend to degrade rapidly (within hours) in biological media, resulting in poor control of gas release, especially when long-term therapeutic delivery is required.

[0017] Therefore, it is crucial to implement MOFs in clinical practice that combine both low toxicity and stability in biological fluids for several days.

[0018] Finding a structure that meets all the requirements and provides an extended and controlled delivery period (preferably hours or days) to achieve therapeutic efficacy across a wide range of applications remains challenging.

[0019] Therefore, there remains a need to find stable means for a new class of nanoporous materials, especially MOFs, that not only exhibit good or even high stability in biological media but also exhibit sustained (continuous) release properties of Lewis basic gases, especially NO, in the same biological media. DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0020] To address this need, the inventors have conducted extensive research to find a new class of MOFs that allow for highly efficient and selective adsorption and controlled release of Lewis basic gases, preferably NO.

[0021] These drawbacks have been overcome by the new ultraporous crystalline metal-organic framework solids (such as MIP-210(M)) containing bisphosphonate ligands according to the present invention, which not only have high chemical stability but can also be synthesized under mild and environmentally friendly conditions. Furthermore, the phosphonate MOFs according to the present invention can also be used as carriers and / or for the controlled release of Lewis basic gases such as NO.

[0022] The inventors have successfully synthesized the phosphonate MOFs of the present invention, which fully meet the above requirements for NO delivery systems and exhibit unprecedented controlled release times. The products are obtained through a simple, environmentally friendly (water as a solvent) and robust synthesis (insensitive to reactant ratios, concentrations, and even modulators), making them highly suitable for industrial large-scale production. Furthermore, the toxicity of the phosphonate MOFs of the present invention, such as MIP-210(M), and particularly MIP-210(Fe), MIP-210(Al), and MIP-210(Ti), is favorable because they contain iron, aluminum, or titanium as metal sources, which are significantly less toxic than some of the other metals used in MOFs. Therefore, phosphonate MOFs such as MIP-210(M), especially MIP-210(Fe), MIP-210(Al), and MIP-210(Ti), are ideally positioned to coordinate NO instead of water. Their porous structure, characterized by iron, aluminum, or titanium metal sites, on inorganic building blocks, fulfills the requirements for a narrow-pore NO delivery system, thereby prolonging NO release in biological fluids. After confirming their stability and low toxicity in biological media, the inventors explored the application of the NO-loaded MOFs of the present invention, especially MIP-210(M) where M = Fe, Al, or Ti, to demonstrate their potential as NO donors and promote cellular processes related to wound healing—cell migration and angiogenesis. Other advantages are described in the Examples section. [Means for solving the problem]

[0023] Before proceeding to a description of the invention itself, some terms and phrases will be defined here to facilitate understanding of the invention: As used herein outside the claims, the terms "a," "an," "the," and / or "said" mean one or more. As used in the claims herein, when used in conjunction with the terms "comprise," "comprises," and / or "comprising," the terms "a," "an," "the," and / or "said" can mean one or more. As used in this specification and claims, the terms "having," "has," "is," "having," "including," "includes," and / or "include" have the same meaning as "comprising," "comprises," and "comprise." As used in this specification and claims, the term "another" means at least a second or more. As used in this specification and claims, the term "about" refers to the inherent measurement error or rounding of a value (e.g., a measurement, calculation of a ratio, etc.), and thus the term "about" may be used with any value and / or range. The following lists, phrases such as "combinations thereof," "mixtures thereof," the use of "and / or" as part of a list, lists within tables, the use of "etc." as part of a list, the phrase "such as," and / or parenthetical lists with "e.g.," and "ie" refer to any combination (e.g., any subset) of the set of listed elements; although not directly set forth in such lists, combinations and / or mixtures of related species and / or examples described herein are also contemplated. Such related and / or similar genera(s), sub-genera(s), species(s), and / or examples described herein are contemplated both in the form of individual elements that may be recited in the claims, as well as in the form of mixtures and / or combinations that may be described in the claims as "at least one selected from," "mixtures thereof," and / or "combinations thereof." In general, the term "substituted," whether preceded by the term "optionally" or not, and the substituents contained in the formulae of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When multiple positions in a given structure are substituted with multiple substituents selected from a particular group, the substituents can be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. As used herein, the term "about" may refer to a variation of ±5%, ±10%, ±20%, or ±25% of the specified value. For example, "about 50" percent may, in some examples, involve a variation of 45 to 55 percent. In the case of integer ranges, the term "about" may include one or two integers greater than and / or less than the stated integer. Unless otherwise indicated (disclaimer) herein, the term "about" is intended to include values ​​close to the stated range that are equivalent with respect to the functionality of an individual component, composition, or example, e.g., concentration values. - As used herein, the term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. As will be understood by those skilled in the art, all numerical values ​​expressing properties such as quantities of ingredients, cavity / pore size and BET specific surface area, reaction conditions, etc., are approximations and are understood to be optionally modified in any case by the term "about." These values ​​may vary depending on the desired properties sought to be obtained by one skilled in the art using the teachings of this specification. It is also understood that these values ​​inherently include variability necessarily resulting from the standard deviation found in each test measurement. As will be understood by those skilled in the art, for all purposes, particularly in terms of providing descriptive language, all ranges recited herein encompass the individual values, particularly integer values, comprising the range, along with any and all possible subranges and combinations thereof. The recited ranges include each specific value, integer, decimal, or identity value within the range. Any recited range can be readily recognized as fully descriptive and allowing for division of the same range into at least one half, third, quarter, fifth, or tenth. As a non-limiting example, each range recited herein can be readily divided into a lower third, middle third, upper third, etc. One skilled in the art will readily understand that when members are grouped in a common manner, such as a Markush group, the invention encompasses not only the entire recited group as a whole, but also each member of the group individually and all possible subgroups of the main group. Moreover, for all purposes, the invention encompasses not only the main group, but also main groups in which one or more of the group members are absent. Thus, the invention contemplates the explicit exclusion of all members of one or more of the recited groups. Consequently, qualifications may apply to any of the disclosed categories or embodiments, thereby excluding any one or more of the recited elements, species, or embodiments from such category or embodiment, e.g., as used in an express negative limitation. As used herein, the expression "three-dimensional structure" is understood to mean a three-dimensional arrangement or repetition of units or subvariants, as commonly understood in the field of MOF materials, also characterized as "organometallic polymers." As used herein, the term "solid" refers to any type of crystalline material. The solid may be, for example, in the form of crystals, powders, or particles of various shapes, for example, spherical, lamellar, etc. The particles may also be in the form of nanoparticles. -MOFs are constructed from bridging organic ligands, also called "linkers" or "spacers," which remain intact throughout the synthesis and function as linkers within the network of the resulting MOF structure. As used herein, the term "ligand" or "linker" or "spacer" refers to a ligand coordinated to at least two metals, providing distance between the metals and forming an empty space or pore, also called the "core," within the MOF. In the present invention, the ligand is a bisphosphonic acid ligand that interacts with trivalent cations to form a 3D structure. When incorporated into the MOF structure, the bisphosphonic acid molecule undergoes partial or complete deprotonation to yield a bisphosphonate ion with one, two, or three negative charges. Therefore, the term "bisphosphonic acid ligand" is used to describe a "bisphosphonic acid molecule" that is incorporated into the MOF structure and has undergone the above-mentioned modifications. As used herein, the term "Lewis basic gas" refers to a gas that has an electron pair that is not involved in a bond but that can coordinate with a Lewis acid to form a Lewis adduct (Lewis adduct). The Lewis basic gas can be selected from NO, CO, and HS, with NO being preferred. As used herein, "aliphatic" refers to acyclic or cyclic, saturated or unsaturated carbon compounds, excluding aromatic compounds (IUPAC). Open-chain compounds that are straight or branched and do not contain any rings are always aliphatic. Cyclic compounds can be aliphatic if they are not aromatic. Aliphatic compounds can be saturated, bonded through single bonds (alkanes), or unsaturated through double bonds (alkenes) or triple bonds (alkynes). In addition to hydrogen, other elements can be bonded to the carbon chain, the most common being oxygen, nitrogen, sulfur, and chlorine. As used herein, "aromatic" refers to a cyclically conjugated molecular entity that has significantly greater stability (due to delocalization) than hypothetical localized structures that are said to possess aromaticity (e.g., Kekulé structures). The use of this term is based on application of Hückel's rule (4n+2) and consideration of the topology of orbital overlap in the transition state (IUPAC).

[0024] Through this invention, the inventors have shown that it is possible to potently modulate the release of Lewis basic gases (preferably NO) in wounds, using the novel phosphonate MOFs of the invention, such as MIP-210(M).

[0025] Here, we describe the development of novel phosphonate MOFs, specifically iron, aluminum, and titanium MOFs—MIP-210(Fe), MIP-210(Al), and MIP-210(Ti)—that exhibit unusual sustained (continuous) release due to their narrow pores and exceptional Lewis basic gas (preferably NO) adsorption mechanism. The strong interaction of Lewis basic gases (preferably NO) with the metal moiety slows the displacement of the coordinated gas by HO upon exposure to serum or a pH 7.4 phosphate buffer (serum mimicking solution), resulting in significantly extended NO delivery times (at least 72 hours or more), far longer than any other materials reported for such applications. Furthermore, MIP-210(Fe), MIP-210(Al), and MIP-210(Ti) possess high stability and excellent biocompatibility in biological media compared to other MOFs, promising their potential for future biomedical applications.

[0026] A first object of the present invention is an ultramicroporous crystalline metal-organic framework solid comprising a three-dimensional succession of units of formula (I'): M m X nL·yH2O(I') where: M independently represents a metal selected from Fe, Al, V, Mn, Ti, Zr and mixtures thereof, wherein M is in oxidation state III or IV and is preferably a metal selected from Fe, Al and Ti, more preferably Fe. -L represents a bisphosphonic acid ligand. -X represents an anion, preferably O 2- , H.O. - , F - , SO4 2- , HSO4 - , H2PO4 - , HPO4 2- and PO4 3- is selected from, preferably O 2- and H.O. - is selected from. - m is an integer from 1 to 4, preferably m is an integer from 1 to 4; -n=0 or 1, -y=0, 1 or 2.

[0027] Advantageously, the ultramicroporous crystalline metal-organic framework solid comprises a continuous three-dimensional structure made up of units of formula (I): M m X n L H2O (I) where: M independently represents a metal selected from Fe, Al, V, Mn, Ti, Zr and mixtures thereof, wherein M is in oxidation state III or IV and is preferably a metal selected from Fe, Al and Ti, more preferably Fe. -L represents a bisphosphonic acid ligand. -X represents an anion, preferably O 2- , H.O. - , F - , SO4 2- , HSO4 - , H2PO4 - , HPO4 2- and PO4 3-is selected from, preferably O 2- and H.O. - is selected from. -m is an integer from 1 to 4. -n=0 or 1, -y=0, 1 or 2.

[0028] In the present invention, the "ultramicroporous crystalline metal-organic framework solid comprising a continuous three-dimensional structure consisting of units of formula (I)" may be abbreviated as "phosphonate MOF."

[0029] Advantageously, water can be present inside the pores or on the outer surface of the particle. If the MOF is completely dry before loading with gas, then y=0.

[0030] This refers to a "bisphosphonic acid ligand," i.e., a ligand derived from a bisphosphonic acid molecule (or ligand precursor). When incorporated into a MOF structure, the bisphosphonic acid molecule undergoes partial or complete deprotonation to yield a bisphosphonate ion with one, two, or three negative charges. Therefore, the term "bisphosphonic acid ligand" is used to indicate a "bisphosphonic acid molecule" incorporated into a MOF structure and subjected to the above modifications.

[0031] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising a continuous three-dimensional structure made up of units of formula (I), where M represents a metallic center. M may be chosen from Fe, Al, V, Mn, Ti, Zr and mixtures thereof. Fe, Al, Ti and Zr are in oxidation state III. Mn and V may be in oxidation state III or IV. Preferably, M represents a metal chosen from Fe, Al and Ti, more preferably Fe.

[0032] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising a continuous three-dimensional structure made up of units of formula I, where X represents an anion: when n=1, X is O2 - , H.O. - , F - , SO4 2- , HSO4 - , H2PO4 - , HPO4 2- , and PO4 3- X may be selected from O2 - and H.O. - You may choose from.

[0033] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising a continuous three-dimensional structure made up of units of formula (I) or (I'), where L represents a bisphosphonic acid ligand. The bisphosphonic acid ligand may be chosen from bisphosphonic acid ligands comprising 4 to 12 carbon atoms. Preferably, the bisphosphonic acid ligand may be chosen from bisphosphonic acid ligands of formula (II): HPO3-CH2-R-CH2-PO3(II) wherein R is an optionally substituted C4 to C6 cyclic or heterocyclic moiety, optionally containing a heteroatom such as N, and optionally aromatic. For example, R can be a xylylene moiety or a piperazine moiety. More preferably, the ligand L may be selected from p-xylylenebisphosphonic acid ligand, 1,4-bis(phosphomethyl)piperazine acid ligand, 1,4-bis(phosphomethyl)-2-methylpiperazine acid ligand, and mixtures thereof. The bisphosphonic acid ligand may alternatively be selected from bisphosphonic acid ligands containing 1 to 2 carbon atoms. Preferably, the bisphosphonic acid ligand may be selected from bisphosphonic acid ligands of formula (III): HPO3-(CH2) z -PO3(III) wherein z is 1 or 2. More preferably, the ligand L may be selected from methylene bis(phosphonic acid), and ethylene bis(phosphonic acid), and mixtures thereof.

[0034] Advantageously, the phosphonate MOFs of the present invention may have an average pore diameter of 0.3 to 0.5 nm. The average pore diameter may be measured using the crystallographic information file (CIF) of the MOF. For example, it may be calculated from the isotherms of nitrogen, CO2, argon, or krypton by applying mathematical equations such as the Barret-Joyner-Halenda (BJH) method, DFT (density functional theory), or Dubinin-Astakhov method, which allow the determination of the average pore size distribution, preferably DFT

[25] .

[0035] Advantageously, the phosphonate MOFs according to the invention may have a gas loading capacity of 0.5-4 mmol of Lewis basic gas per gram of dry MOF, preferably 1-2 mmol / g.

[0036] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising a continuous three-dimensional structure made up of units of formula (I) or (I') chosen from: -M(HPO3-CH2-C6H4-CH2-PO3)X n H2O, M is in oxidation state III or IV, M is preferably Fe, Al or Ti, where n=0 when M=Al or Fe, and n=1 when M=Ti; -M(HPO3-CH2-C4H8N2-CH2-PO3)X n H2O, M is in oxidation state III or IV, M is preferably Fe, Al or Ti, and when M=Al or Fe, n=0, and when M=Ti, n=1.

[0037] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising the following consecutive three-dimensional structural units: Fe III (HPO3-CH2-C6H4-CH2-PO3)·H2O, Ti IV (HPO3-CH2-C6H4-CH2-PO3)OH·H2O, Al III (HPO3-CH2-C6H4-CH2-PO3)·H2O, Fe III (HPO3-CH2-C4H8N2-CH2-PO3)·H2O Ti IV (HPO3-CH2-C4H8N2-CH2-PO3)OH·H2O, Al III (HPO3-CH2-C4H8N2-CH2-PO3)·H2O

[0038] Advantageously, the MOF according to the invention may be chosen from phosphonate MOFs comprising a continuous three-dimensional structure made up of units chosen from: -M(HPO3-CH2-PO3)X n ·yH2O, M is in oxidation state III or IV, M is preferably Fe, Al or Ti, and when M=Al or Fe, n=0, and when M=Ti, n=1 and y=2.

[0039] Advantageously, the phosphonate MOF according to the invention may be chosen from phosphonate MOFs comprising the following three-dimensional successive units: Ti IV 1.5 (PO3-CH2-PO3)O·2H2O, Fe III (HO3P(CH2)2PO3)·H2O, Al III (HO3P(CH2)2PO3) 2H2O

[0040] The present invention also relates to the phosphonate MOFs of the present invention for use as carriers in the delivery of Lewis basic gases, preferably NO delivery. The delivery may be via a delivery system selected from composite polymers, creams, scaffolds, or hydrogels comprising the phosphonate MOFs of the present invention.

[0041] In another aspect, the present invention relates to an ultramicroporous crystalline metal-organic framework solid according to the present invention, loaded with at least one Lewis basic gas, at least a portion of which is coordinated with the metal M. The at least one Lewis basic gas may be selected from NO, CO, and HS, preferably NO. In the loaded MOF according to the present invention, at least 30% of the adsorbed amount of the Lewis basic gas can be coordinated with the metal M.

[0042] The present invention further relates to the use of the phosphonate MOFs according to the invention for the purification of gas streams from Lewis basic gases, preferably NO.

[0043] In another aspect, the present invention also encompasses the use of the phosphonate MOFs of the present invention, preferably as biosensors, for the detection of a Lewis basic gas in a gas or liquid stream, preferably the Lewis basic gas being NO.

[0044] On another level, the present invention relates to a loaded MOF according to the present invention for use in the controlled release of a Lewis basic gas, preferably NO, in a wound, preferably by topical application. The controlled release of the Lewis basic gas is sustained (continuous) release. By "sustained (continuous) release" is meant the release of the Lewis basic gas over a period of at least 24 hours, preferably between 24 and 72 hours.

[0045] The present invention also relates to other applications related to the in vivo delivery of Lewis basic gases, preferably NO. Accordingly, the present invention also relates to a filled MOF according to the present invention for use in the controlled release of Lewis basic gases, preferably NO, in therapeutic applications, preferably in anticancer therapy. The solid MOF according to the present invention may be used instead of NOonate, which has been used but is associated with severe side-toxicity effects. Thus, the present invention opens up the possibility of intracellular delivery of Lewis basic gases, preferably NO, in vivo, without such toxic effects.

[0046] Thus, the present invention also relates to a loaded MOF according to the present invention for use in the in vivo delivery of a Lewis basic gas, preferably NO. The loaded MOF according to the present invention may be used for the controlled release of a Lewis basic gas, preferably NO, in therapeutic applications, preferably in wound, anti-infectious, or anti-cancer therapy. The loaded MOF according to the present invention may be used for the controlled release of a Lewis basic gas in a wound, preferably by topical application. The loaded MOF according to the present invention may be used for the controlled release of a Lewis basic gas in anti-cancer therapy, preferably by inserting the loaded MOF near the tumor to be treated using a medical device. The controlled release of the Lewis basic gas can be sustained for at least 12 hours or more, preferably 24 to 72 hours.

[0047] According to the present invention, the phosphonate MOF is preferably in a form that allows a large exchange surface between the MOF and the environment where Lewis basic gases can be captured by adsorption. The MOF may be in the form of, for example, a powder, granules, pellets, extrudates, monoliths, thin films, composites embedded in particles, hydrogels, films, or coatings. For example, WO2009 / 123484

[26] , published in October 2009, discloses a useful process for producing polyurethane foam filter materials with adsorption properties that can be used to support MOFs for implementing the present invention. Other examples include electropinning of polymers containing MOF particles as disclosed in M. Rose et al. Adv. Eng. Mater. 2011, 13, 356-360

[27] , R. Ostermann at al. Chem. Commun. 2011, 47, 442-444

[28] , J. Ren et al. Int. J. Hydrogen Energy 2015, 40, 9382-9387

[29] , and MR Khan et al. J. Mater. Eng. Perform. 2016, 25, 1276-1283

[30] , which results in a final composite fiber material with supported MOFs, simplifying the application of MOFs for the adsorption of volatile organic compounds. Other examples include the use of MOFs in various shapes, such as granules as previously disclosed in Valekar et al., RSC Adv, 2017

[31] , pellets as in Q. Ren, et al., Chem. Eng. J., , 2015

[32] , or coatings on specific supports as disclosed in Gkaniatsou et al., Nano Energy, 2020

[33] .

[0048] According to the present invention, the powdered phosphonate MOF or phosphonate MOF in the form described in the previous paragraph may be included in a device, preferably an antibacterial device.

[0049] The present invention also encompasses an antimicrobial device comprising a loaded MOF according to the present invention, which may be a transdermal patch or a coating for a biomedical device.

[0050] On another level, the present invention relates to a synthetic method for producing a porous crystalline metal-organic framework solid comprising a continuous three-dimensional structure of units corresponding to formula (I) or (I') as defined above, comprising the following steps: a) introducing into a solvent a metal source, preferably in the form of a salt, alkoxide, hydroxide or oxide, and a bisphosphonic acid precursor of the ligand L; b) stirring the mixture obtained in step a) for at least 15 minutes, preferably at least 30 minutes; c) heating the solution obtained in step b) under solvothermal conditions at a temperature of 30 to 180°C, preferably 100°C, for 5 to 48 hours, preferably 20 hours; A porous crystalline metal-organic framework solid is then obtained, where M and L are defined as above.

[0051] Advantageously, the metal source may be a salt (e.g., Fe(NO3)3, FeCl3, or AlCl3), an alkoxide (e.g., Ti(OR)4, where R is a C1-C4 hydrocarbon chain), a hydroxide (e.g., Fe(OH)3, or Al(OH)3), an oxide (e.g., Fe2O3, Al2O3, or TiO2), a sulfate (e.g., FeSO4, Fe2(SO4)3, Al2(SO4)3, or TiOSO4, or Ti(SO4)2), or an acetate (e.g., Fe3O(Z)(CO2CH3)3 (Z = OH, Cl, or ClO4), Al(CO2CH3)2, or Ti(CO2CH3)2).

[0052] Advantageously, the bisphosphonic acid precursor of the ligand L may be chosen from bisphosphonic acid ligand precursors containing from 4 to 12 carbon atoms. Preferably, the bisphosphonic acid ligand precursor may be chosen from bisphosphonic acid ligand precursors of formula (II'): H2PO3-CH2-R-CH2-PO3H2(II'), wherein R is an optionally substituted C4 to C6 cyclic moiety, optionally containing a heteroatom such as N, and optionally aromatic. For example, R may be a xylylene moiety or a piperazine moiety. More preferably, the precursor of the ligand L may be selected from p-xylylenebisphosphonic acid, 1,4-bis(phosphomethyl)piperazine acid, 1,4-bis(phosphomethyl)-2-methylpiperazine acid, and mixtures thereof. The bisphosphonic acid ligand may alternatively be selected from bisphosphonic acid ligands containing 1 to 2 carbon atoms. Preferably, the bisphosphonic acid ligand may be selected from bisphosphonic acid ligands of formula (III'): HPO3-(CH2) z -PO3H2(III'), wherein z is 1 or 2. More preferably, the ligand L may be selected from methylene bis(phosphonic acid), and ethylene bis(phosphonic acid), and mixtures thereof.

[0053] Advantageously, the solvent is chosen from water, an organic solvent, or a mixture thereof. The organic solvent may be chosen from ethanol, isopropanol, and a mixture thereof.

[0054] This stands for "solvothermal conditions," a synthesis carried out in a closed vessel under autogeneous pressure at a temperature above the boiling point of the solvent.

[0055] Advantageously, the method of the invention may further comprise a step of washing the MOF with water and / or ethanol.

[0056] The present invention also relates to a synthetic method for producing a filled MOF according to the invention by contacting the phosphonate MOF according to the invention with a pure gas selected from Lewis basic gases in a closed cell at a pressure of 20 to 100 kPa, preferably 80 kPa, at a temperature of 15 to 25° C. for 1 to 5 days, preferably 3 days.

[0057] The following experiments and results confirm the advantages of the present invention compared to prior art solutions.

[0058] The following representative examples and figures are intended to facilitate explanation of the present invention and are not intended to, and should not be construed as, limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the entire contents of the specification, including references to the scientific and patent literature cited herein.

[0059] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof. [Brief explanation of the drawings]

[0060] [Figure 1] Figure 1 shows the structure of MIP-210(Fe), (a) viewed along the a-axis, (b) viewed along the b-axis, and (c) showing a corner-sharing chain of MO octahedra. The iron atoms are octahedra, the phosphonate groups are tetrahedra, and the carbon atoms are represented as gray spheres.

[0061] [Figure 2]Figure 2 shows the PXRD patterns (λ = 1.5406 Å) of MIP-210(Fe), MIP-210(Al), and MIP-210(Ti) compared with the patterns simulated from the single crystal structures.

[0062] [Figure 3] FIG. 3 shows the profile of NO release from MIP-210(Fe) in liquid media obtained as described in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0063] In accordance with the present invention, phosphonate MOFs such as MIP-210(M), and their production and manufacture, can be further understood by the following examples, which illustrate some of the processes by which these materials are made or used. However, it will be fully understood that these examples are not to be construed as limiting the invention. Variations of the invention, now known or further developed, are considered to be within the scope of the invention as described herein and as set forth in the following claims.

[0064] <Example 1: Material synthesis> All chemicals were purchased from commercial suppliers and used as received without further purification: p-xylylenebisphosphonic acid (H4mbpa), 99%, from SIKEmia; ferric chloride hexahydrate, 98%, from Fisher; absolute ethanol, ≥99%, from Acros; MilliQ water, Millipore system; sodium hydrosulfite (≥82% (RT)) and human hemoglobin lyophilized powder (Sigma-Aldrich); nitric oxide gas (99.99%), from Air Liquide.

[0065] For cell culture and analysis, HeLa cells (HeLa) were obtained from American Type Culture Collection (Manassas, VA, USA), normal human neonatal keratinocyte cells (HEKn) from Thermo Fisher Scientific, and human umbilical vein endothelial cells (HUVEC) from Live Technologies. RPMI-1640 without L-glutamine was obtained from Corning; Epilife medium containing penicillin-streptomycin, L-glutamine, fetal bovine serum (FBS), trypsin (2.5%, phenol red-free), calcium (60 μM), human keratinocyte growth additive kit, Medium 200 PRF, low-serum growth additive (LSGS), trypsin-EDTA (0.25%, phenol red-free), trypsin neutralizing solution, and Geltrex TM All LDEV-free reduced growth factor basement membrane matrices were purchased from Thermo Fisher Scientific.

[0066] Powder X-ray diffraction (PXRD) data were recorded on a high-throughput Bruker D8 Advance diffractometer equipped with a focusing Goebel mirror and a LynxEye detector operating in transmission mode and generating CuKα radiation (λ = 1.5418 Å). Nitrogen adsorption isotherms were collected on a Micromeritics Tristar instrument at 77 K. SEM-EDX (scanning electron microscope-energy dispersive X-ray spectroscopy) results were recorded on an FEI Magellan 400 scanning electron microscope. TGA data were collected on a Mettler Toledo TGA / DSC 2 STAR system instrument under oxygen or nitrogen flow at a heating rate of 5 °C / min. The structural model was further confirmed by single-crystal synchrotron diffraction data collected on the microfocus X-ray beamline Proxima 2A (Synchrotron SOLEIL) using appropriate single crystals.

[0067] MIP-210(Fe)(Fe IIISynthesis of (HPO3-CH2-C6H4-CH2-PO3)·H2O: FeCl3·6H2O (150 mg, 0.555 mmol) and H4MBPA (111 mg, 0.417 mmol) were mixed with 5 mL of water in a 50 mL Duran clear glass vessel with a blue polypropylene screw cap by sonication for 15 minutes. The solution was then placed in a 120 °C oven for 20 hours to form MIP-210(Fe). The product was collected by centrifugation, washed with water and ethanol, and air-dried to yield 120 mg of a bright yellow powder. This corresponds to a 90% yield based on the ligand (due to the excess metal salt). The synthesis can be increased fivefold without altering the quality of the sample.

[0068] Furthermore, under similar conditions, the same product was obtained using iron salt to ligand molar ratios ranging from 0.5 to 1.5, and also by changing the water content from 5 to 10 mL or adding formic acid or acetic acid to the reaction mixture.

[0069] Synthesis of MIP-210(Al): AlCl3·6H2O (134 mg, 0.555 mmol) and H4mbpa (111 mg, 0.417 mmol) were mixed with 5 mL of water in a 50 mL round-bottom flask by stirring and allowed to react overnight under reflux to form MIP-210(Al). The solid was then washed with 500 mL of water under reflux, followed by 30 mL of acetone. The product was then collected by centrifugation and air-dried. The entire reaction can be scaled up five-fold to yield the same reaction product with similar properties.

[0070] Synthesis of MIP-210(Ti): TiOSO4 (50 mg, 0.320 mmol) and H4mbpa (50 mg, 0.188 mmol) were mixed with 5 mL of water in a 50 mL round-bottom flask by stirring and reacted overnight under reflux to form MIP-210(Ti). The solid was then washed with water under reflux and then with 30 mL of acetone. The product was then collected by centrifugation and air-dried.

[0071] Synthesis of MIL-22(Ti): A mixture of hydrous TiO, H2O3P-(CH2)-PO3H2, HF, and H2O in a molar ratio of 1:0.5:1:500 was placed in a Teflon-lined steel autoclave in this order without stirring and heated at 220 °C for 4 days.

[0072] Fe III Synthesis of -(HO3P(CH2)2PO3)·(HO): FeCl3.6HO (1.00 mmol) and 1,2-ethylenediphosphonic acid (4.03 mmol) in 1.79 mL of water were placed in the polytetrafluoroethylene (PTFE) liner of a 23 mL autoclave and stirred for 10 min. The autoclave was then sealed and heated at 200 °C for 2 days. The solid was washed and dried at 60 °C.

[0073] Example 2: Evaluation of material properties The structure of MIP-210(Fe) was determined by single crystal X-ray diffraction. The compound crystallized in the monoclinic space group P2(1) / n with unit cell parameters a = 5.1440 Å, b = 10.7106 Å, c = 21.0654 Å, β = 93.222°, and a lattice volume of 1191.1 Å. 3 The structure contains 1D channels along the a-axis, a characteristic of typical bnn topological networks. One diphosphonate group binds to two iron atoms, and the other binds to three iron atoms to form a chain (Figure 1). The simulated PXRD patterns of MIP-210(M) (M = Fe, Al, Ti) are in good agreement with the structure determined from single crystals, indicating that the three compounds are isostructural and confirming the purity of the three phases (Figure 2). Furthermore, thermogravimetric analysis of MIP-210(M) (M = Fe, Al, Ti) further confirmed the purity of the compounds.

[0074] Example 3: Results The thermal and chemical stability of A.MIP-210(Fe) was evaluated. VT-PXRD results indicate that its structure can withstand temperatures above 300°C. Chemical stability was evaluated in water, phosphate-buffered saline (PBS) at pH 7.4, and three representative cell growth media (RPMI-1640, Medium 200, and Epilife) at 37°C. Degradation was observed after 7 days in water and PBS, and slight degradation was detected after 3 days of incubation in biological medium, but no changes in morphology or crystallinity were observed. This MOF is more stable than other iron MOFs studied for NO adsorption, such as MIL-100(Fe) and MIL-127(Fe). MOF integrity is important to ensure controlled-release applications and prevent leaching of byproducts.

[0075] B. Cytotoxicity evaluation was performed using three different cell lines: HeLa (an immortalized cell line derived from cervical cancer cells), HEKn (normal human neonatal keratinocytes), and HUVEC (human umbilical vein endothelial cells). MIP-210(Fe) was administered at appropriate concentrations (45–450 μg mL) for NO application. -1 ) showed excellent biocompatibility (>70% viability). This feature, along with its high stability in biological environments and the fact that it contains non-toxic metals within its structure, proves that this MOF can be safely used in biomedical applications. Most MOFs studied for the same purpose do not combine all of these features, either because they contain toxic metals in their structure (e.g., CPO-27 (Ni, Co), Vitamin B3 MOF (Ni, Co)) or because they easily degradate in biological media (e.g., HKUST-1), both of which usually increase toxicity.

[0076] C. NO therapeutic release application To verify the ability of MIP-210(Fe) to adsorb and release NO in a controlled manner, a series of analyses were performed: -DFT calculations; - Gravimetric NO adsorption; -monitoring of in situ NO adsorption / release by FTIR; and -NO release measurement in liquid phase -Assessment of cellular processes related to wound healing

[0077] Computational analysis was performed to predict the adsorption of NO and HO. The N-end geometry toward Fe was found to be energetically favorable compared to the O-end and side-on analogues. Because NO has an unpaired electron, two situations are possible: the NO molecule has an adsorption energy (E ads ) is -27kJ mol -1 It is parallel to Fe, which is E ads =-53kJ mol -1 This is consistent with the corresponding Fe-N distances in the two scenarios (2.91 Å and 2.37 Å). Therefore, the adsorption of the N-terminal of the NO molecule, whose spin is antiparallel to the Fe, was considered the most stable adsorption structure in the following calculations. On the other hand, the interaction of HO with Fe-CUS (O-terminal adsorption) is considered to be the most stable adsorption structure in the following calculations. ads -82kJ mol -1 , about 30 kJ mol -1 will also become stronger.

[0078] Next, the NO adsorption / storage capacity was investigated using gravimetric measurements. Briefly, when MIP-210(Fe) (previously outgassed at 120 °C for 12 h) was left in contact with NO at 80 kPa, after 3 days the material absorbed 1.86 mmol g -1 The adsorption capacity was within the range of MOFs studied and reported for NO applications (0.8–7 mmol g). -1)

[15] , and the amount of unsaturated Fe centers (i.e., Fe-MIL-100, Fe-MIL-127, and Fe-MIL-88-A) had NO adsorption capacities of 4.5 mmol g -1 , 2.2 mmol g -1 , 2.5 mmol g -1 ) show lower capacity compared to [20,34].

[0079] To understand the mechanism of NO adsorption in this material, FTIR studies were performed in the presence of NO. The IR spectrum showed a peak at 1578 cm -1 The figure shows the appearance of an NO adsorption band at 1800 cm−1, the intensity of which increased with time as a result of the gradual NO adsorption / desorption characteristics that characterize this material. This peak corresponds to NO coordinated to the Fe sites, but it is a rare structure in which the resulting Fe-NO bond angle is shortened to 119°. This NO adsorption structure is not observed in other Fe-based MOFs (e.g., MIL-100, MIL-127, MIL-88) [20, 34], and in other Fe-based MOFs, the band assigned to NO coordinated to the Fe sites is located at approximately 1800 cm−1. -1 The bond angle formed is approximately 180°. The bond formed between MOF-210(Fe) and NO persists even after outgassing, confirming the strong stability of the formed Fe-NO species. This observed strong chemisorption is the most favorable adsorption mechanism for therapeutic delivery, providing a more controlled release and safer storage of the loaded material.

[0080] Quantification of NO release in biological media was performed using the oxyhemoglobin assay previously described by Feelish et al.

[35] . The NO release rate from this MOF was very slow, ensuring gradual NO delivery over at least 70 hours (shown in Figure 3). This period could indicate either complete release of oxyhemoglobin present in the buffer medium or its complete conversion to methemoglobin. Nevertheless, it exhibits an initially sustained, very slow NO release rate over 70 hours (almost 3 days), which has not been observed in other reported NO-releasing porous (nanoporous) materials, which are limited to minutes to hours. For example, the longest release obtained by this class of materials was 4 hours with a modified ETS-4, which incorporates copper into its structure

[36] .

[0081] In addition to this exceptional release lifetime, MIP-210(Fe) ensures sustained release from the start, suppressing the initial burst of release characteristic of many NO delivery strategies. Considering the risks associated with the release of concentrated NO into biological systems, this MOF is one of the most promising carriers for therapeutic delivery of NO, with unique features that enable its use in a wide range of applications.

[0082] To explore the potential of such a treatment, initial evidence was provided in vitro by performing cell migration and angiogenesis analyses. Both cellular responses are crucial for the wound healing process, and NO plays a signaling role in these processes, contributing to faster migration and tube formation. The ability of NO released by MIP-210(Fe) to induce HUVEC migration was demonstrated by Oris. TM Assessed using cell migration assay: 11.75 μg mL -1NO-loaded MIP-210(Fe) was able to induce significantly (p<0.01) faster HUVEC cell migration (approximately 8%) after 24 h compared with untreated cells and cells treated with NO-unloaded MIP-210(Fe).

[0083] The angiogenic effect of NO released by MIP-210(Fe) was investigated in endothelial cells (HUVECs) and Geltrex as a 3D extracellular matrix. TM This was observed through in vitro endothelial tube formation using NO-loaded MIP-210(Fe)-treated cells (11.75 μg mL -1 ) showed significantly (p<0.5) more abundant networks (approximately 25%) after 18 h compared with the cell control and empty MIP-210(Fe) groups.

[0084] Herein, biocompatible ultramicroporous iron(III), aluminum(III), and titanium(III) bisphosphonate MOFs based on green synthesis were developed for the storage and therapeutic release of NO.

[0085] New phosphonate MOFs, such as MIP-210(M) of the present invention, have demonstrated unprecedented, very slow and controlled NO release in biological fluids. This feature allows the safe use of these new donors without the usual toxic burst release of NO, avoiding the frequent replacement of delivery systems typically required to support continuous gas release at therapeutic levels. The angiogenic potential of the new compounds has been confirmed at the cellular level, providing encouraging first results for their potential therapeutic applicability.

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Claims

1. An ultramicroporous crystalline metal-organic framework solid comprising a continuous three-dimensional structure consisting of units corresponding to the following formula (I'): M ｍ X ｎ t0.834597 ２ O(I') M independently represents a metal selected from Fe, Al, V, Mn, Ti, Zr and mixtures thereof, where M is in oxidation state III or IV and is preferably a metal selected from Fe, Al and Ti, more preferably Fe. -L represents a bisphosphonic acid ligand. -X represents an anion, preferably O ２－ , H.O. － , F － , S.O. ４ ２－ , HSO ４ － , H ２ P.O. ４ － , H.P.O. ４ ２－ and P.O. ４ ３－ is selected from, preferably O ２－ and H.O. － is selected from. - m is an integer from 1 to 4, preferably m is an integer from 1 to 4; - n=0 or 1, - y=0, 1 or 2. An ultra-microporous crystalline metal-organic framework solid (MOF) characterized by:

2. The ligand L consists of a bisphosphonic acid ligand containing from 4 to 12 carbon atoms, preferably selected from bisphosphonic acid ligands of formula (II): 209 ３ -3H ２ -2-3H ２ -OO ３ (99) where R is an optionally substituted C ４ From C ６ cyclic or heterocyclic moiety of the formula: optionally containing heteroatoms such as N, and optionally aromatic; 2. The MOF according to claim 1 .

3. 3. The MOF of claim 1, wherein the ligand L is selected from p-xylylenebisphosphonic acid ligands, 1,4-bis(phosphomethyl)piperazine acid ligands, 1,4-bis(phosphomethyl)-2-methylpiperazine acid ligands, and mixtures thereof.

4. The ligand L consists of a bisphosphonic acid ligand containing 1 to 2 carbon atoms, preferably selected from bisphosphonic acid ligands of formula (III): @OO ３ -(CH ２ ) ｚ -?O ３ (III) 2. The MOF of claim 1, wherein z is 1 or 2.

5. 5. The MOF of claim 4, wherein the ligand L is selected from methylene bis(phosphonic acid) and ethylene bis(phosphonic acid).

6. 6. The MOF according to any one of claims 1 to 5, wherein the MOF has an average pore diameter of 0.3 to 0.5 nm.

7. 7. The MOF according to any one of claims 1 to 6, characterized in that the solid has a gas loading capacity of 0.5 to 4 mmol of Lewis basic gas per gram of dry MOF, preferably 1 to 2 mmol / g.

8. MOFs have a continuous three-dimensional structure made up of units selected from: -M(HPO ３ -CH ２ -C ６ H ４ -CH ２ -PO ３ )X ｎ ・H ２ O, M is in oxidation state III or IV, M is preferably Fe, Al or Ti, where n=0 when M=Al or Fe, and n=1 when M=Ti; -M(HPO ３ -CH ２ -C ４ H ８ N ２ -CH ２ -PO ３ )X ｎ ・H ２ O, M is in oxidation state III or IV, M is preferably Fe, Al or Ti, and when M=Al or Fe, n=0, and when M=Ti, n=1; 8. The MOF according to claim 1, wherein the MOF is a cellulose ester.

9. MOFs have a continuous three-dimensional structure made up of units selected from: t0.75k ３ -CH ２ -PO ３ )X ｎ ・yH ２ O, M is in oxidation state III or IV, 9. A MOF according to any one of claims 1 to 8, characterized in that M is preferably Fe, Al or Ti, and n=0 when M=Al or Fe, and n=1 when M=Ti.

10. 10. A MOF according to any one of claims 1 to 9, for use as a carrier in the delivery of Lewis basic gases, wherein the delivery system comprises a mixed polymer, emulsion, scaffold, or hydrogel comprising the MOF.

11. 11. The ultramicroporous crystalline metal-organic framework solid of claim 1, which is loaded with at least one Lewis basic gas, at least a portion of which is coordinated with the metal M.

12. The at least one Lewis basic gas is NO, CO, and H ２ 12. The MOF according to claim 11, characterized in that the moiety is selected from S, preferably NO.

13. 13. The MOF of claim 1 or claim 12, wherein at least 30% of the adsorbed amount of Lewis basic gas can be coordinated with the metal M.

14. 10. Use of a MOF according to any one of claims 1 to 9, characterized in that the use of the MOF is for the purification of a gas stream from Lewis basic gases, preferably NO.

15. 10. Use of a MOF according to any one of claims 1 to 9, characterized in that the use of the MOF is for the detection of NO in a gas or liquid stream, preferably as a biosensor.

16. 14. Use of a filled MOF according to any one of claims 11 to 13, characterized in that the use of the filled MOF is for the in vivo delivery of a Lewis basic gas, preferably NO.

17. 17. Use of a loaded MOF according to claim 16, characterized in that the in vivo delivery (supply) of the loaded MOF is for the controlled release of a Lewis basic gas, preferably NO, in therapeutic applications, preferably in wound or anti-cancer treatment.

18. 18. Use of a loaded MOF according to claim 16 or claim 17, characterized in that in the use of the loaded MOF, the controlled release of Lewis basic gas is a controlled release of Lewis basic gas in a wound, preferably by topical application.

19. 18. Use of a loaded MOF according to claim 16 or claim 17, characterized in that the controlled release of a Lewis basic gas in the use of the loaded MOF is the controlled release of a Lewis basic gas in anti-infection or anti-cancer treatment, preferably by inserting the loaded MOF near a tumor to be treated using a medical device.

20. Use of a filled MOF according to any one of claims 17 to 19, characterized in that in the use of the filled MOF, the controlled release of Lewis basic gas is carried out by slow release for at least 24 hours or more, preferably 24 to 72 hours.

21. An antibacterial device comprising the filled MOF of any of claims 11 to 13.

22. A synthetic method for producing a porous crystalline metal-organic framework solid comprising a continuous three-dimensional structure of units corresponding to the following formula (I) as defined in any of claims 1 to 17, comprising the steps of: a) introducing into a solvent a metal source, preferably in the form of a salt, alkoxide, hydroxide or oxide, and a bisphosphonic acid precursor of the ligand L, b) stirring the mixture obtained in step a) for at least 15 minutes; c) heating the solution obtained in step b) under solvothermal conditions at a temperature between 30 and 180°C, preferably at 100°C, for a period of 5 to 48 hours, preferably 20 hours, to obtain a porous crystalline metal-organic framework solid, wherein M and L are defined as in any of claims 1 to 17.

23. 23. The method of claim 22, further comprising washing the MOF with water and / or ethanol.

24. 14. A synthetic process for producing filled MOFs according to any one of claims 11 to 13, by contacting the MOFs according to any one of claims 1 to 9 with a pure gas selected from Lewis basic gases in a closed cell at a pressure of 20 to 100 kPa, preferably 80 kPa, at a temperature of 15 to 25°C for 1 to 5 days, preferably 3 days.

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