Nitric oxide containing composite

Abstract

The present invention provides a nitric-oxide containing composite in the form of microparticles, wherein said microparticles comprise: (i) a core which comprises silica; (ii) a layer on said core which comprises a metal-organic framework; and (iii) nitric oxide;
wherein said metal-organic framework comprises organic ligands comprising at least one amine group, said metal-organic framework is uniformly distributed on the surface of said silica core and said nitric oxide is chemisorbed within said metal-organic framework.

Claims

1. A nitric-oxide containing composite in the form of microparticles, wherein said microparticles comprise: (i) a core which comprises silica; (ii) a layer on said core which comprises a metal-organic framework; and (iii) nitric oxide; wherein said metal-organic framework comprises organic ligands of formula (III) comprising at least one amine group, ##STR00005## wherein X.sup.1 is independently selected from NH.sub.2 and NHR, wherein R is C.sub.1-8 alkyl or C.sub.5-10 aryl; and each of X.sup.2 and X.sup.3 are independently selected from COOH, OH, OR, SH, SR, NH.sub.2, NHR, NR.sub.2, NO.sub.2, halide, C.sub.1-6 alkyl, OC.sub.1-6alkyl, C.sub.5-10 aryl, heteroaryl, SO.sub.3R and SO.sub.3H, wherein R is C.sub.1-8 alkyl or C.sub.5-10 aryl, and said metal-organic framework is uniformly distributed on the surface of said silica core, and completely covers the surface of said core, and said nitric oxide is chemisorbed within said metal-organic framework.

2. The composite as claimed in claim 1, wherein said metal-organic framework is in the form of nanocrystals having an average diameter of 1-200 nm.

3. The composite as claimed in claim 1, wherein said layer which comprises a metal-organic framework has a thickness of 5-100 nm.

4. The composite as claimed in claim 1, wherein said layer, which comprises a metal-organic framework, is a monolayer.

5. The composite as claimed in claim 1, wherein said core consists of silica.

6. The composite as claimed in claim 1, wherein said core has an average diameter of 1-200 μm.

7. The composite as claimed in claim 1, wherein each of X.sup.2 and X.sup.3 are independently selected from COOH, OH and NH.sub.2.

8. The composite as claimed in claim 1, wherein each of X.sup.2 and X.sup.3 are COOH.

9. The composite as claimed in claim 1, wherein said organic ligands are of formula (IV): ##STR00006##

10. The composite as claimed in claim 1, wherein said metal-organic framework further comprises a metal-containing secondary building unit comprising a metal selected from Zr, Hf, Ti, Zn, Cr, In, Ga, Cu, Fe, Mo, Cr, Co, Ru, Na, Mg, Mn, Ni, W, Al and V.

11. The composite as claimed in claim 10, wherein said metal is Zr.

12. The composite as claimed in claim 10, wherein said metal-containing secondary building unit is Zr.sub.6O.sub.4(OH).sub.4—(CO.sub.2).sub.12.

13. The composite as claimed in claim 1, wherein said composite comprises 20-90 wt % silica.

14. The composite as claimed in claim 1, wherein said composite comprises 10-80 wt % metal-organic framework.

15. The composite as claimed in claim 1, wherein said microparticles have an average diameter of 1 to 250 μm.

16. The composite as claimed in claim 1, wherein said composite has a porosity of 100-2000 m.sup.2/g.

17. A method of making a nitric-oxide containing composite as claimed in claim 1, comprising: (i) mixing silica microparticles and precursors for the preparation of a metal-organic framework, wherein said precursors comprise metal ions and an organic ligand of formula (III) comprising at least one amine group to form a mixture; (ii) stirring said mixture; (iii) obtaining a composite in the form of microparticles, wherein said microparticles comprise a core which comprises silica and a layer on said core which comprises a metal-organic framework, wherein said metal-organic framework comprises an organic ligand of formula (III) comprising at least one amine group and said metal-organic framework is uniformly distributed on the surface of said silica core; (iv) contacting said composite with nitric oxide under pressure; and (v) obtaining said nitric oxide-containing composite.

18. A pharmaceutical composition or dosage form comprising a composite as claimed in claim 1.

19. The composite as claimed in claim 1, wherein when the composite is exposed to pH of less than 6, NO is released from the metal organic framework.

Description

DETAILED DESCRIPTION OF THE FIGURES

(1) The invention will now be described with reference to the following non-limiting examples and Figures, wherein:

(2) FIG. 1 shows the nitric oxide sorption isotherms for UiO-66 and UiO-66-NH.sub.2. Adsorption (closed symbol) and desorption (open symbols);

(3) FIG. 2 shows the FTIR spectra of UiO-66-NH.sub.2 before and after treatment under an atmosphere of nitric oxide at 10 bar;

(4) FIG. 3 shows nitric oxide release profiles in PBS and after addition of 0.1 mL of 1M H.sub.2SO.sub.4 to the PBS buffer for UiO-66 (green) and UiO-66-NH.sub.2 (red);

(5) FIG. 4 shows the pH of the PBS buffer before and after the addition of 0.1 mL of 1M H.sub.2SO.sub.4 for UiO-66-NH.sub.2, UiO-66 and PBS samples;

(6) FIG. 5 shows the X-ray diffraction powder pattern of UiO-66-NH.sub.2 (before and after treatment under a high pressure atmosphere of nitric oxide);

(7) FIG. 6 shows the X-ray diffraction powder pattern of UiO-66 (before and after treatment under a high pressure atmosphere of nitric oxide);

(8) FIG. 7 shows the FTIR spectra of UiO-66-NH.sub.2 and UiO-66-NH.sub.2@silica;

(9) FIG. 8 shows N.sub.2 isotherms of the UiO-66-NH.sub.2, UiO-66-NH.sub.2@Silica, and the silica support (closed symbols for adsorption, open for desorption);

(10) FIG. 9 shows SEM images of the UiO-66-NH.sub.2@Silica showing complete coverage of the silica particles by the MOF (top) and the TEM image of the composite showing efficient compounding of the MOF nanoparticles grown on silica (bottom);

(11) FIG. 10 shows EDX maps for the UiO-66-NH.sub.2@Silica demonstrating homogenous distribution of the elements (labelled images) throughout the sample; and

(12) FIG. 11 shows the X-ray diffraction powder patterns for UiO-66-NH.sub.2 and UiO-66-NH.sub.2@silica.

EXAMPLES

(13) The examples were performed using the following materials and equipment, unless otherwise stated:

(14) Reagents

(15) Laboratory grade chemicals and reagents were purchased from Sigma-Aldrich or Fisher Scientific and used as received without further purification. Diethylamine NONOate sodium salt hydrate, was purchased from Sigma-Aldrich and used as received.

(16) Equipment

(17) Infrared absorption spectra were recorded using a Thermoscientific Nicoletis-10.

(18) X-ray powder diffraction patterns were recorded on XRD measurements were conducted on PanAlytical diffractometer with Cu source (λ=1.5406 Å) operated at 30 kV and 40 mA.

(19) Scanning electron microscopy images were acquired on a Nova NanoSEM 450.

(20) Transmission electron microscopy images were acquired on JEOL JEM-2100 at 200 KV.

(21) Energy-dispersive X-ray photoelectron spectroscopy was carried out on a Nova NanoSEM 450 equipped with EDAX Octane Silicon Drift Detector (SDD).

(22) Gas sorption analysis was conducted on a Micrometrics ASAP2020. The surface areas were determined from the nitrogen adsorption isotherms collected at 77 K by applying the Brunauer-Emmett-Teller and Langmuir models. Pore size analysis was conducted using the DFT model of cylindrical pores in oxide surface using the early adsorption data points in the corresponding isotherms.

(23) Preparation of UiO-66-NH.sub.2@Silica

(24) In a scintillation vial, a mixture of 2-aminoterephthalic acid (135.86 mg, 0.75 mmol) and silica (100 mg) were mixed and sonicated in 10 ml DMF for 5 minutes. A separately prepared solution of ZrCl.sub.4 (125.8 mg, 0.54 mmol) in 5 ml DMF and 1 ml HCl 37% was then added. The vial was capped and the mixture was stirred vigorously at 400 rpm with a stirrer bar (1 cm) for 12 hrs at 80° C., then filtered and washed with ACN, then exchanged in heated ACN at 80° C. under autogenous pressure for 2 hrs. The powder was filtered then dried in an isothermal oven at 80° C. for 2 hours yielding 230 mg of UiO-66-NH.sub.2@Silica (81.5% yield).

(25) For comparison purposes, samples of UiO-66 and UiO-66-NH.sub.2 were also prepared by conventional techniques.

Example 1 Treatment of UiO-66, UiO-66-NH.SUB.2 .and UiO-66-NH.SUB.2.@Silica Samples Under a High Pressure Nitric Oxide Atmosphere

(26) Each sample (30 mg) was placed in a closed Eppendorf tube and sealed. The Eppendorf tube caps were punctured with a needle to enable efficient gas exchange and transferred to a BuchiGlasuster miniclave stainless steel pressure reactor, equipped with Teflon inserts and a pressure gauge. The pressure reactor was flushed with nitrogen gas, then filled with nitric oxide gas to a pressure of 10 bar (BOC, AK 35 bar Nitric Oxide N2.5) at room temperature for 12 hours. After this time, the nitric oxide pressure was gradually vented in a fume hood, and the pressure reactor was flushed with nitrogen at a pressure of 10 bar. The pressure reactor was then opened to the air and the samples transferred to a desiccator for the nitric oxide release study.

Example 2 Gas Sorption Isotherms

(27) FIG. 1 shows the nitric oxide sorption isotherms for UiO-66 and UiO-66-NH.sub.2 at various pressures. UiO-66-NH.sub.2 demonstrated a large increase in the amount of nitric oxide absorbed at low pressures. The amount of nitric oxide absorbed further increased to 160 cm.sup.3/g when the pressure was increased to 760 torr (1 bar). In contrast, UiO-66 demonstrated very limited sorption capability towards nitric oxide.

(28) It was not possible to remove all of the nitric oxide absorbed by UiO-66-NH.sub.2 after the first nitric oxide sorption isotherm, due to pronounced desorption hysteresis. These data indicate that nitric oxide was either trapped or chemisorbed within the metal-organic framework structure.

(29) The nitric oxide uptake for UiO-66-NH.sub.2 was calculated to be 6.98 mmol/g (based on a formula unit of ZrO.sub.5C.sub.8NH.sub.5, a calculated molecular mass of 286.35 g/mol, 3.49 mmol/g of primary amine groups and two nitric oxide molecules chemisorbed per amine functionality). The amount of trapped nitric oxide, following desorption, was determined to be 139 cm.sup.3/g, equivalent to 6.2 mmol/g. These data collectively suggest chemisorption of the nitric oxide onto the primary amine functional groups within the UiO-66-NH.sub.2 framework.

Example 3 IR Spectra of UiO-66-NH.SUB.2 .Treated with Nitric Oxide

(30) FIG. 2 shows the Fourier-transform infrared (FTIR) spectra of UiO-66-NH.sub.2 before and after treatment under an atmosphere of nitric oxide at 10 bar. The samples were removed from the pressure reactor as detailed in Example 1 before the spectra were measured. The spectrum of UiO-66-NH.sub.2 previously treated under a pressurised nitric oxide atmosphere, revealed two new peaks at 1294 and 1710 cm.sup.−1. These peaks can be assigned to the presence of N-diazeniumdiolate species, which form following the reaction of a primary amine with two equivalents of nitric oxide.

(31) A peak at 1429 cm.sup.−1 was observed in nitric oxide free UiO-66-NH.sub.2, which can be assigned to a v.sub.C—NH2 stretching mode coupled with v.sub.C—C ring modes. This peak was not observed in the spectra of UiO-66-NH.sub.2 treated with nitric oxide.

(32) These data support the formation of N-diazeniumdiolate species within the UiO-66-NH.sub.2 framework through reaction of the primary amines therein with nitric oxide gas.

Example 4 Release of Nitric Oxide from UiO-66 and UiO-66-NH.SUB.2 .Samples

(33) The release of nitric oxide from the samples was measured in phosphate buffer saline (PBS, pH of 7.4) at room temperature. The concentration of nitric oxide released from the metal-organic frameworks was measured using a nitric oxide detection system (inNOII, Innovative instruments, Inc.) equipped with amiNO-700 electrodes. Each amiNO-700 electrode was calibrated prior to the experiment according to the manufacturer's instructions. Each sample (30 mg) was suspended in 25 mL of PBS buffer in a falcon tube equipped with a magnetic stirrer bar.

(34) FIG. 3 shows the concentration of nitric oxide released from UiO-66 and Ui-66-NH.sub.2 samples previously treated under a high pressure atmosphere of nitric oxide. Both of the UiO-66 and UiO-66-NH.sub.2 samples revealed an initial rapid increase in concentration of nitric oxide upon addition to the PBS solution. This initial rapid increase corresponds to the desorption of weakly adsorbed nitric oxide molecules within the metal-organic framework structure. Both the UiO-66 and UiO-66-NH.sub.2 samples revealed similar nitric oxide concentration profiles over the first 30 minutes.

(35) After 30 minutes, 0.1 mL of 1 M H.sub.2SO.sub.4 was added to each sample. A rapid increase in the concentration of nitric oxide was observed for UiO-66-NH.sub.2, reaching a maximum nitric oxide concentration of 42 ppm. In contrast, no detectable increase in concentration of nitric oxide was observed for UiO-66 upon the addition of acid.

(36) These data suggest the amine functionality within UiO-66-NH.sub.2 is crucial to achieving chemisorption of nitric oxide molecules, potentially as N-diazeniumdiolates, within the metal-organic framework. As UiO 66 contains the same metal-carboxylate clusters as UiO-66-NH.sub.2, the observed enhancement in the concentration of nitric oxide for UiO-66-NH.sub.2 can be attributed to the presence of the amine functionality.

(37) FIG. 4 shows the pH of each PBS sample before addition of acid, and at the completion of the experiment. For UiO-66-NH.sub.2, the pH of the solution at the end of the experiment was determined to be 3, representing the largest decrease in pH for any of the samples investigated. Notably, addition of the acid solution to PBS alone resulted in a decrease in pH to only 5.4. Under aqueous conditions, nitric oxide may react with water and oxygen to produce nitrous acid. These data are therefore consistent with the observed high concentration of nitric oxide released into solution (FIG. 3).

(38) These data also show that UiO-66-NH.sub.2 enables an acid triggered release of nitric oxide. In turn, this provides a mechanism to control when and where nitric oxide is released, i.e. controlled release.

Example 5 X-Ray Powder Diffraction Patterns (PXRDs) of UiO-66 and UiO-66-NH.SUB.2

(39) FIGS. 5 and 6 show the PXRDs of UiO-66-NH.sub.2 and UiO-66 respectively. These data indicate that the samples prepared have high levels of homogeneity and purity.

Example 7 IR Spectra of UiO-66-NH.SUB.2 .and UiO-66-NH.SUB.2.@Silica

(40) FIG. 7 shows the FTIR spectrum of UiO-66-NH.sub.2 and UiO-66-NH.sub.2@silica. The spectra of UiO-66-NH.sub.2@silica was found to be almost identical to that of UiO-66-NH.sub.2, with the exception of an additional peak at 1058 cm.sup.−1, which can be assigned to the silica Si—O stretching.

Example 8 Microporosity of UiO-66-NH.SUB.2 .and UiO-66-NH.SUB.2.@Silica

(41) The microporosity of UiO-66-NH.sub.2@silica compared to UiO-66-NH.sub.2 was investigated by determining the nitrogen gas isotherms for each sample (FIG. 8). Following determination of the N.sub.2 gas isotherms, the Brauner-Emmet-Teller (BET) surface area for UiO-66-NH.sub.2@silica and UiO-66-NH.sub.2 were calculated (Table 2). The surface area of UiO-66-NH.sub.2 was calculated as 1256 m.sup.2/g. The calculated surface area for silica was 503 m.sup.2/g. In contrast, the calculated surface area of UiO-66-NH.sub.2@Silica, which comprised 48 wt % silica, was determined to be 730 m.sup.2/g. These data indicate that the microporosity of the UiO-66-NH.sub.2 metal-organic framework was maintained on the surface of the silica support.

(42) TABLE-US-00001 TABLE 2 Calculated BET surface areas of UiO-66-NH.sub.2@Silica, UiO-66-NH.sub.2 and Silica support. Entry Silica UiO-66-NH.sub.2 UiO-66-NH.sub.2@Silica BET SA (m.sup.2/g) 503 1256 730

Example 9 Uniformity of UiO-66-NH.SUB.2 .on the Surface of Silica in UiO-NH.SUB.2.@Silica

(43) Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) was used to investigate the morphology of UiO-66-NH.sub.2 on the silica support surface. FIG. 9 (top image) shows an SEM image of UiO-66-NH.sub.2@Silica, revealing homogenous distribution of the UiO-66-NH.sub.2 crystals across the silica surface and complete coverage thereof. FIG. 9 (bottom image) shows a TEM image of UiO-66-NH.sub.2@Silica revealing the tight attachment of UiO-66-NH.sub.2 nanoparticles to the silica surface, and the uniform size distribution of the UiO-66-NH.sub.2 nanoparticles (˜20-30 nm diameter). The uniformity of the nanoparticles can be attributed to mechanical stirring of the growth solution under solvothermal conditions.

(44) Energy-dispersive X-ray spectroscopy (EDX) was also used to confirm the homogeneous distribution of MOF onto the silica support. FIG. 10 shows the EDX spectra for UiO-NH.sub.2@Silica, mapped for the presence of Carbon, Oxygen, Zirconium and Silicon. As can be seen from the elemental distribution, the UiO-66-NH.sub.2 homogeneously covers the entirety of the silica surface.

Example 10 Elemental Analysis of UiO-66-NH.SUB.2 .and UiO-NH.SUB.2.@Silica

(45) The composition of UiO-NH.sub.2@Silica and UiO-66-NH.sub.2 were further investigated by elemental analysis (Table 3). The Carbon and Nitrogen content for UiO-66-NH.sub.2@Silica decreased compared to UiO-66-NH.sub.2 due to the incorporation of silica. The observed increased Hydrogen content can be attributed to the presence of silanol groups and/or adsorbed moisture in the silica. The overall decrease in the total Carbon, Hydrogen and Nitrogen (CHN) content for UiO-66-NH.sub.2@Silica can be attributed to the presence of the silica. The percentage weight of UiO-66-NH.sub.2 within the UiO-66-NH.sub.2@Silica composite was calculated to be 56 wt %. These data are in good agreement with that calculated based on the isolated yield of UiO-66-NH.sub.2@Silica after synthesis.

(46) TABLE-US-00002 TABLE 3 Elemental Analysis for the UiO-66-NH.sub.2 and UiO-66-NH.sub.2@Silica Compound C (%) N (%) H (%) Total UiO-66-NH.sub.2 28.60 4.11 2.77 35.49 UiO-66- 14.13 1.29 3.10 18.53 NH.sub.2@Silica

Example 11 X-Ray Powder Diffraction Pattern (PXRDs) of UiO-66-NH.SUB.2.@Silica

(47) FIG. 11 shows the PXRDs of UiO-66-NH.sub.2 and UiO-66-NH.sub.2@silica. The PXRDs observed for the UiO-66-NH.sub.2@Silica corresponded to that of UiO-66-NH.sub.2. These data further indicated the successful homogeneous formation of UiO-66-NH.sub.2 on the silica surface.