Metal organic framework-albendazole drug delivery system and preparation method thereof

Abstract

The invention provides a metal organic framework-albendazole drug delivery system, the drug delivery system comprises a metal organic framework and albendazole, the albendazole (ABZ) is loaded in a metal organic framework (MOF) to form an ABZ-MOF nano material, and the MOF comprises UiO-66-NH2, MIL-125-NH2 or SU-101. The invention also provides a preparation method of the metal organic framework-albendazole drug delivery system. According to the drug delivery system, albendazole is loaded in the metal organic framework, the solubility of albendazole is improved, the bioavailability of albendazole is improved, MOF loaded albendazole of various different metal ions is synthesized, and universality is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a metal organic framework-albendazole drug delivery system and a preparation method thereof. Background Art

[0002] Hydatid disease is a serious zoonotic parasitic disease caused by the larvae of the tapeworm Echinococcus parasitizing humans or animals. It has a long incubation period, a slow course, is difficult to treat, and has a high mortality rate. Therefore, it is called "worm cancer." Albendazole (ABZ) is the only effective drug recommended by the World Health Organization for echinococcosis. According to the biopharmaceutics classification system (BCS), it is classified as a BCS Class II drug and has low solubility (solubility in water at 25°C is 0.0228 mg·mL). -1 ) and high permeability (logP 2.54). Due to its low water solubility and insoluble in organic solvents, ABZ is poorly absorbed in the intestine, resulting in low blood, liver, and local lesion concentrations. The intracystic concentration is only 1 / 10-1 / 100 of the blood concentration. Its bioavailability in humans is less than 5%, and its clinical cure rate is less than 30%. Its efficacy is particularly poor for alveolar coccidiosis, and the treatment course is long, which seriously limits its clinical use. Therefore, improving the solubility of albendazole has become a major direction for improving albendazole formulations.

[0003] Currently, many novel formulations, including solid dispersions, liposomes, and self-microemulsions, have been reported to enhance the absorption of ABZ. However, none of these ABZ formulations have entered clinical trials. Since their introduction by Sekiguchi et al. in 1961, solid dispersions have been extensively studied. However, due to difficulties in preparation and stability issues, very few marketed products have been developed. Whether using melt or solvent methods, drug and carrier aging is a persistent issue, significantly limiting albendazole dissolution. Current research focuses on the effects of cooling time and carriers on aging. Liposomes are readily available, research began early, and clinical efficacy is evident. Clinical use of oral formulations has begun, but they also present challenges such as carrier oxidation, drug leakage, poor stability, and a short duration of efficacy. Self-microemulsions and pre-micells offer simple preparation methods, better ensure the stability of the original drug prior to use, and have significantly improved the utilization of the original albendazole drug. However, research interest has declined in recent years, primarily due to numerous uncontrollable factors, such as incomplete micellization. Summary of the Invention

[0004] The present invention aims to address the deficiencies of the prior art and provide a metal-organic framework-albendazole drug delivery system and a preparation method thereof, by loading albendazole into the metal-organic framework to improve the solubility of albendazole and increase its bioavailability.

[0005] According to a first aspect of the present invention, a metal-organic framework-albendazole drug delivery system is provided, which comprises a metal-organic framework and albendazole, wherein the albendazole (ABZ) is loaded in the metal-organic framework (MOF) to form an ABZ@MOF nanomaterial, and the MOF comprises UiO-66-NH2, MIL-125-NH2 or SU-101.

[0006] As an optional embodiment, the average particle size of the ABZ@MOF nanomaterial is 200 nm to 600 nm, and the Zeta potential is -3.0 mV to 6 mV.

[0007] As an optional embodiment, the drug loading amount of the ABZ@MOF nanomaterial is 10% to 50%.

[0008] According to a second aspect of the present invention, a method for preparing a metal organic framework-albendazole drug delivery system is provided, comprising: mixing albendazole with metal ions and organic ligands to form a mixed solution, and preparing ABZ@MOF nanomaterials by a solvothermal synthesis method.

[0009] As an optional embodiment, when the MOF is UiO-66-NH2, the preparation process includes:

[0010] adding zirconium oxychloride octahydrate (ZrOCl2·8H2O) and 2-aminoterephthalic acid (BDC-NH2) into deionized water to obtain a first solution;

[0011] dissolving albendazole in acetic acid to obtain a second solution;

[0012] adding the second solution to the first solution and stirring uniformly to obtain a third solution;

[0013] The third solution was refluxed in an oil bath. After the reaction was completed, the solid was collected, washed, and dried to obtain ABZ@UiO-66-NH2 nanomaterials.

[0014] As an optional embodiment, the molar ratio of ZrOCl2·8H2O and BDC-NH2 is (1-2):1, and the oil bath condition is oil bath reflux at 100-110°C for 24h.

[0015] As an optional embodiment, when the MOF is MIL-125-NH2, the preparation process includes:

[0016] adding diaminoterephthalic acid (NH2-BDC) to a mixed solution of methanol and N,N-dimethylformamide (DMF) to obtain a fourth solution;

[0017] dissolving albendazole in acetic acid to obtain a fifth solution;

[0018] The fifth solution is added to the fourth solution, titanium isopropoxide is added under stirring, and the mixture is mixed uniformly to obtain a sixth solution;

[0019] The sixth solution was transferred into a reactor, heated for reaction, filtered, and activated under vacuum after removing the solvent. The solid was then collected to obtain the ABZ@MIL-125-NH2 nanomaterial.

[0020] As an optional embodiment, the molar ratio of NH2-BDC and titanium isopropoxide is 2:1, the heating reaction conditions are heating at 433K for 48 hours, and the vacuum activation conditions are activation at 393K under vacuum for 12 to 24 hours.

[0021] As an optional embodiment, when the MOF is SU-101, the preparation process includes:

[0022] adding bismuth acetate and ellagic acid to deionized water to obtain a seventh solution;

[0023] dissolving albendazole in acetic acid to obtain an eighth solution;

[0024] The eighth solution was added to the seventh solution, stirred at room temperature, centrifuged, and solids were collected; the solids were then washed and dried to obtain ABZ@SU-101 nanomaterials.

[0025] As an optional embodiment, the mass ratio of bismuth acetate to ellagic acid is (7-8):3.

[0026] It can be seen from the above technical solutions of the present invention that the metal organic framework-albendazole drug delivery system proposed in the present invention uses MOF as a drug delivery system for albendazole to improve its solubility, thereby improving the bioavailability of the drug. In addition, cell proliferation and death experiments, hemolysis experiments, and in vivo toxicity experiments in rats found that ABZ@MOF has good biocompatibility.

[0027] The present invention adopts solvent thermal synthesis method to synthesize MOFs of various metal ions: UiO-66-NH2 (zirconium), MIL-125-NH2 (titanium) and SU-101 (bismuth), and loads albendazole to construct a metal organic framework drug delivery system of various albendazoles, which has universal applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1are the particle size and Zeta potential of MOF and ABZ@MOF; among them, A: particle size distribution diagram of UiO-66-NH2 and ABZ@UiO-66-NH2, B: particle size distribution diagram of MIL-125-NH2 and ABZ@MIL-125-NH2, C: particle size distribution diagram of SU-101 and ABZ@SU-101, D: Zeta potential of MOF and ABZ@MOF.

[0029] Figure 2 These are scanning electron micrographs of MOF and ABZ@MOF; A and D: UiO-66-NH2 and ABZ@UiO-66-NH2, B and E: MIL-125-NH2 and ABZ@MIL-125-NH2, C and F: SU-101 and ABZ@SU-101.

[0030] Figure 3 These are transmission electron micrographs of MOF and ABZ@MOF; A: UiO-66-NH2, B: MIL-125-NH2, C: ABZ@SU-101, D: ABZ@UiO-66-NH2, E: ABZ@MIL-125-NH2.

[0031] Figure 4 These are the EDS element mapping diagrams of ABZ@MOF; A: C, O, N, Zr, and S element distribution diagram of ABZ@UiO-66-NH2, B: C, O, N, Ti, and S element distribution diagram of ABZ@MIL-125-NH2, and C: C, O, Bi, and S element distribution diagram of ABZ@SU-101.

[0032] Figure 5 Characterization of ABZ@MOF; AC: powder X-ray diffraction, DF: Fourier transform infrared spectroscopy, GH: N2 adsorption-desorption isotherm.

[0033] Figure 6 is the X-ray photoelectron spectrum of ABZ@MOF; where A: ABZ@UiO-66-NH2, B: ABZ@MIL-125-NH2, and C: ABZ@SU-101.

[0034] Figure 7 Thermal stability analysis of MOF and ABZ@MOF; AC: TGA curve, DF: DTG curve.

[0035] Figure 8 is the in vitro release behavior of ABZ@MOF under different pH conditions; among them, A: ABZ@UiO-66-NH2, B: ABZ@MIL-125-NH2, C: ABZ@SU-101.

[0036] Figure 9 is the toxicity of ABZ and ABZ@MOF to Caco-2 cells (n=3); among them, A: ABZ, B: ABZ@UiO-66-NH2, C: ABZ@MIL-125-NH2.

[0037] Figure 10 This is a study on the transmembrane transport of ABZ@MOF in the Caco-2 cell model; A, C, E: detection concentrations of ABZ@MOF at high, medium, and low concentrations on the AP-BL side; B, D, F: detection concentrations of ABZ@MOF at high, medium, and low concentrations on the AP-BL side; G: transmembrane transport efficiency P at high, medium, and low concentrations of ABZ@MOF on the AP-BL side. app , H: transmembrane transport efficiency P on the AP-BL side at high, medium and low concentrations of ABZ@MOF app , I: transmembrane transport efficiency P at 37℃ and 4℃ app , J: Efflux rates (ER) of high, medium, and low concentrations of ABZ@MOF.

[0038] Figure 11 This is the blood concentration-time curve of ABZ and ABZ@MOF in rats (n=6).

[0039] Figure 12 It is the hemolysis experiment of ABZ@MOF; Among them, A: the hemolysis test results of ABZ@MOFs with different concentrations, B: the hemolysis rate of ABZ@MOFs with different concentrations (n=3).

[0040] Figure 13 These are the changes in mouse body weight and blood routine during drug administration; A: changes in mouse body weight during drug administration, B: white blood cells (WBC), C: red blood cells (RBC), D: hemoglobin (HGB), E: platelets (PLT), F: neutrophils (NEUT#), G: basophils (BASO#), H: eosinophils (EO#).

[0041] Figure 14 These are the liver and kidney function indicators of mice after 2 weeks of administration; among them, A: alanine aminotransferase (ALT), B: aspartate aminotransferase (AST), C: alkaline phosphatase (ALP), D: direct bilirubin (DBIL), E: total bilirubin (TBIL), F: albumin (ALB), G: total bile acid (TBA), H: urea nitrogen (BUN), I: creatinine (CREA), J: uric acid (UA).

[0042] Figure 15 These are H&E-stained sections of the main organs of mice (heart, liver, spleen, lung, and kidney). DETAILED DESCRIPTION

[0043] In order to better understand the technical content of the present invention, specific embodiments are given and described below with reference to the accompanying drawings.

[0044] Various aspects of the present invention are described in this disclosure with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. The embodiments of the present disclosure are not necessarily intended to be comprehensive. It should be understood that the various concepts and embodiments described above, as well as those described in more detail below, can be implemented in any of a number of ways.

[0045] The present invention selects albendazole as a model drug and synthesizes various ABZ@MOF preparations, thereby increasing the solubility of poorly soluble drugs and solving the problem of albendazole's bioavailability in vivo.

[0046] In an example of the present invention, a metal-organic framework-albendazole drug delivery system is provided, which includes a metal-organic framework and albendazole. Albendazole (ABZ) is loaded in the metal-organic framework (MOF) to form ABZ@MOF nanomaterials, and MOF includes UiO-66-NH2, MIL-125-NH2 or SU-101.

[0047] As an optional example, the average particle size of the ABZ@MOF nanomaterial is 200 nm to 600 nm, and the Zeta potential is -3.0 mV to 6 mV.

[0048] As an optional example, the drug loading of the ABZ@MOF nanomaterial is 10% to 50%.

[0049] In another example of the present invention, a method for preparing a metal organic framework-albendazole drug delivery system is provided, comprising: mixing albendazole with metal ions and organic ligands to form a mixed solution, and preparing ABZ@MOF nanomaterials by a solvent thermal synthesis method.

[0050] As an optional example, when the MOF is UiO-66-NH2, the preparation process includes:

[0051] adding zirconium oxychloride octahydrate (ZrOCl2·8H2O) and 2-aminoterephthalic acid (BDC-NH2) into deionized water to obtain a first solution;

[0052] dissolving albendazole in acetic acid to obtain a second solution;

[0053] adding the second solution to the first solution and stirring uniformly to obtain a third solution;

[0054] The third solution was refluxed in an oil bath. After the reaction was completed, the solid was collected, washed, and dried to obtain ABZ@UiO-66-NH2 nanomaterials.

[0055] As an optional example, the molar ratio of ZrOCl2·8H2O and BDC-NH2 is (1-2):1, and the oil bath condition is oil bath reflux at 100-110°C for 24 hours.

[0056] As an optional example, when the MOF is MIL-125-NH2, the preparation process includes:

[0057] adding diaminoterephthalic acid (NH2-BDC) to a mixed solution of methanol and N,N-dimethylformamide (DMF) to obtain a fourth solution;

[0058] dissolving albendazole in acetic acid to obtain a fifth solution;

[0059] The fifth solution is added to the fourth solution, titanium isopropoxide is added under stirring, and the mixture is mixed uniformly to obtain a sixth solution;

[0060] The sixth solution was transferred into a reactor, heated for reaction, filtered, and activated under vacuum after removing the solvent. The solid was then collected to obtain the ABZ@MIL-125-NH2 nanomaterial.

[0061] As an optional example, the molar ratio of NH2-BDC and titanium isopropoxide is 2:1, the heating reaction conditions are heating at 433K for 48 hours, and the vacuum activation conditions are activation at 393K under vacuum for 12 to 24 hours.

[0062] As an optional example, when the MOF is SU-101, the preparation process includes:

[0063] adding bismuth acetate and ellagic acid to deionized water to obtain a seventh solution;

[0064] dissolving albendazole in acetic acid to obtain an eighth solution;

[0065] The eighth solution was added to the seventh solution, stirred at room temperature, centrifuged, and solids were collected; the solids were then washed and dried to obtain ABZ@SU-101 nanomaterials.

[0066] As an optional example, the mass ratio of bismuth acetate to ellagic acid is (7-8):3.

[0067] In other optional examples, the concentration of the albendazole solution is 100 mg / mL to 200 mg / mL.

[0068] For better understanding, the present invention is further described below with reference to several specific examples, but the preparation process is not limited thereto, and the content of the present invention is not limited thereto.

[0069] Unless otherwise specified, the materials in the examples were prepared according to existing methods or purchased directly from the market.

[0070] Example 1

[0071] [ABZ@UiO-66-NH2]

[0072] 1) Weigh zirconium oxychloride octahydrate ZrOCl2·8H2O (850 mg, 2.6 mmol) and 2-aminoterephthalic acid BDC-NH2 (457 mg, 2.5 mmol) into a round-bottom flask and add 10 ml of deionized water.

[0073] 2) Weigh 200 mg of albendazole and dissolve it in 20 mL of acetic acid.

[0074] 3) Add the above 2) to 1) to form a mixed solution, stir the mixed solution on a magnetic stirrer for 10 minutes, and then reflux in an oil bath at 105° C. for 24 hours.

[0075] 4) After the reaction, the solid was collected, washed three times with deionized water and ethanol respectively, and dried at 100°C to obtain ABZ@UiO-66-NH2.

[0076] [UiO-66-NH2]

[0077] 1) Weigh zirconyl chloride octahydrate ZrOCl2·8H2O (850 mg, 2.6 mmol) and 2-aminoterephthalic acid BDC-NH2 (457 mg, 2.5 mmol) into a round-bottom flask, add 10 mL of deionized water, and slowly add 20 mL of acetic acid.

[0078] 2) The mixed solution was stirred on a magnetic stirrer for 10 minutes, and then refluxed in an oil bath at 105°C for 24 hours;

[0079] 3) After the reaction is completed, the solid is collected, washed three times with deionized water and ethanol respectively, and dried at 100° C. to obtain UiO-66-NH2.

[0080] Example 2

[0081] [ABZ@MIL-125-NH2]

[0082] 1) Weigh diaminoterephthalic acid NH2-BDC (6 mmol, 1.086 g), add 25 mL of methanol and 25 mL of N,N-dimethylformamide (DMF) and mix.

[0083] 2) Weigh 200 mg of albendazole and dissolve it in 10 mL of acetic acid solution.

[0084] 3) The above 2) was added to 1) to form a mixed solution, and 3 mmol of titanium isopropoxide was further added under stirring.

[0085] 4) The mixed solution prepared in 3) was transferred to a reactor and heated at 433 K for 48 h. The pale yellow product was filtered out and washed with DMF to remove excess unreacted products. The DMF solvent was then exchanged with methanol.

[0086] 5) Activate under vacuum at 393 K overnight and collect the solid to obtain ABZ@MIL-125-NH2.

[0087] [MIL-125-NH2]

[0088] 1) Weigh diaminoterephthalic acid NH2-BDC (6 mmol, 1.086 g), add 25 mL of methanol and 25 mL of N,N-dimethylformamide (DMF) and mix, then add 10 mL of acetic acid solution;

[0089] 2) Under stirring, further add 3 mmol of titanium isopropoxide;

[0090] 3) The mixed solution from 3) was transferred to a reactor and heated at 433 K for 48 h. The pale yellow product was filtered out and washed with DMF to remove excess unreacted products. The DMF solvent was then exchanged with methanol.

[0091] 4) Activate under vacuum at 393K overnight and collect the solid to obtain MIL-125-NH2.

[0092] Example 3

[0093] [ABZ@SU-101]

[0094] 1) Weigh 760 mg of bismuth acetate and 300 mg of ellagic acid and add 600 mL of deionized water.

[0095] 2) Weigh 200 mg of albendazole and dissolve it in 10 mL of acetic acid solution.

[0096] 3) The above 2) was added to 1) to form a mixed solution, which was stirred at room temperature for 48 hours, centrifuged, and the solid was collected.

[0097] 4) The obtained solid was washed with NN-dimethylformamide (DMF), deionized water, and ethanol, and the solid was dried to obtain ABZ@SU-101.

[0098] [SU-101]

[0099] 1) Weigh 760 mg of bismuth acetate and 300 mg of ellagic acid, add 600 mL of deionized water and 10 mL of acetic acid solution.

[0100] 2) Stir at room temperature for 48 h, centrifuge and collect the solid.

[0101] 3) The obtained solid was washed with N,N-dimethylformamide (DMF), deionized water, and ethanol, and the solid was dried to obtain SU-101.

[0102] Example 4

[0103] [Particle size and potential]

[0104] The particle size and Zeta potential were determined using a Malvern laser particle size analyzer. Each sample was measured three times. Figure 1 shown.

[0105] The particle sizes of ABZ@UiO-66-NH2, ABZ@MIL-125-NH2, and ABZ@SU-101 are (228.3±12.3) nm, (502.3±16.2) nm, and (222.2±9.2) nm, respectively; the zeta potentials are 5.6 mV, -3.3 mV, and -3.2 mV, respectively.

[0106] Example 5

[0107] [Microscopic morphology]

[0108] The morphology was observed by field emission scanning electron microscopy and field emission transmission electron microscopy. Figure 2-4 shown.

[0109] ABZ@UiO-66-NH2 is an irregularly shaped polyhedron with a smooth surface and uniform particle size distribution after drug loading; ABZ@MIL-125-NH2 is a rhombic dodecahedron with a regular shape and sharp edges and corners, attached with impurity particles, and a square pore structure can be clearly observed on its surface; ABZ@SU-101 has an overall columnar morphology, consisting of nanorods with a length of 150-250nm, a uniform particle size distribution, and easy aggregation.

[0110] EDS element mapping shows that C, N, O and metal elements constitute the skeleton of UiO-66-NH2 and MIL-125-NH2, and SU-101 contains Bi, O and C. S is a unique element of ABZ, and S can be detected in all three ABZ@MOFs, proving that ABZ was successfully loaded in UiO-66-NH2, MIL-125-NH2 and ABZ@SU-101, and ABZ@MOF was successfully synthesized.

[0111] Example 6

[0112] [Powder X-ray Diffraction (PXRD)]

[0113] The Cu-Kα target was used for the measurement, the scanning range was 2θ = 5-35° and 5-60°, the scanning speed was 10°·min with a scanning step of 0.02°. -1 , the results are as follows Figure 5 As shown in AC.

[0114] The PXRD spectrum shows that ABZ@UiO-66-NH2 has high-intensity sharp diffraction peaks. ABZ@UiO-66-NH2 has characteristic diffraction peaks at 2θ7.32°, 8.46°, 12.08°, and 14.18°, indicating good crystallinity and stable crystal form. ABZ@MIL-125-NH2 has obvious absorption peaks at 2θ6.71°, 9.69°, and 11.61°, and the peak positions are consistent with those of the simulated spectrum. ABZ@SU-101 has characteristic diffraction peaks at 2θ6.93°, 9.73°, 13.76°, 22.36°, 27.14°, and 29.44°, which are consistent with the standard spectrum.

[0115] The above results show that ABZ@UiO-66-NH2, ABZ@MIL-125-NH2 and ABZ@SU-101 were successfully synthesized.

[0116] Example 7

[0117] [Fourier Transform Infrared Spectroscopy (FT-IR)]

[0118] Take an appropriate amount of sample and mix it with dry KBr, grind it evenly and press it into a transparent sheet. -1 Infrared absorption spectrum in the range of Figure 5 As shown in DF.

[0119] In UiO-66-NH2, at 3400 cm -1 There are strong and broad peaks around 1400cm, which are due to the stretching vibration of NH bond; -1 There are strong peaks around 1250cm, which are due to the bending vibration of NH bond. -1 There are strong peaks around 660cm, which are due to the stretching vibration of CO bond. -1 The peak at is attributed to the vibration absorption of Zr-O bonds in the metal clusters.

[0120] MIL-125-NH2 at 1580 and 1540 cm -1 The series of characteristic absorption peaks at 1370 cm-1 should be attributed to the stretching vibration of the C=C benzene ring in the structure of terephthalic acid, an organic ligand. -1 and 1660cm -1The two absorption peaks at wavenumbers 700-1000cm correspond to the stretching vibration absorption of CO and C=O functional groups of the carboxyl group in the terephthalic acid structure. In addition, -1 The characteristic absorption peaks appearing at are attributed to the stretching vibrations of the Ti-O bond and the Ti-O-Ti bond; this shows that the synthesized MIL-125-NH2 maintains the main structure of the terephthalic acid framework agent and has an O-Ti-O skeleton structure.

[0121] SU-101 at 2700-3700cm -1 There is a broad and strong peak corresponding to the -OH functional group at 1363 cm -1 The characteristic absorption peak at 1600-1500 cm corresponds to the stretching vibration of C=O. -1 The double peaks at 583 and 465 cm are caused by the vibration of the typical aromatic ring characteristic bands. -1 The absorption peak at is attributed to the stretching vibration of Bi-O bond.

[0122] The infrared spectra of MOF and ABZ@MOF are generally consistent, and the main characteristic peaks have not changed, which indicates that the MOF structure has not changed significantly before and after drug loading.

[0123] The above data show that ABZ@UiO-66-NH2, ABZ@MIL-125-NH2 and ABZ@SU-101 were successfully synthesized.

[0124] Example 8

[0125] [N2 adsorption-desorption test]

[0126] The BSD-PS2 specific surface area and pore size analyzer was used to measure the N2 adsorption-desorption isotherm of the sample at 77K, and the specific surface area and the corresponding pore size distribution were tested and calculated. The results are as follows: Figure 5 GH shown.

[0127] Both UiO-66-NH2 and MIL-125-NH2 before and after drug loading showed type I adsorption isotherms, which is a characteristic of microporous structure. After drug loading, the BET specific surface area of ​​ABZ@UiO-66-NH2 increased from 1179.8 m 2 ·g -1 Descending to 613.5m 2 ·g -1 The BET specific surface area of ​​ABZ@MIL-125-NH2 is from 1103.1m 2 ·g -1 Descending to 515.6m 2 ·g -1 .

[0128] The different degrees of reduction in BET specific surface area indirectly indicate that ABZ is loaded on the material.

[0129] Example 9

[0130] [X-ray photoelectron spectroscopy (XPS)]

[0131] XPS was used to measure the entire energy band and selectively measure specific elements. Full spectrum scans were performed with a 1 eV step, 100 eV current energy, and a 50 ms dwell time. Element scans were performed with a 0.1 eV step, 50 eV current energy, and a 100 ms dwell time, over 10 scans. The results are shown in Figure 6.

[0132] ABZ@UiO-66-NH2 is composed of O, C, N and Zr elements. The XPS full spectrum shows corresponding characteristic peaks at 532eV, 400, 285eV and 184eV respectively. The high-resolution spectrum of C1s after drug loading uses the C1s peak at 284.8eV as a reference to perform charge correction on the spectrum, which are CC, CO and C=O functional groups respectively; the O 1s spectrum is divided into three absorption peaks at 530.4, 532 and 533.6eV, namely Zr-O, CO and C=O. After loading ABZ, the positions of the three peaks shifted, among which the CO and C=O functional groups shifted by 0.5eV and 0.7eV respectively towards the direction of low binding energy. Therefore, the carboxyl functional groups on the material play an important role in the drug loading process, providing abundant sites for the binding of ABZ. Zr in the material exists in the +4 valence form. After drug loading, Zr 3d 5 / 2 and Zr 3d 3 / 2 It also moved towards the direction of lower binding energy.

[0133] ABZ@MIL-125-NH2 is composed of C, O, N and Ti elements. XPS characterization of MIL-125 shows that the Ti2p curve is a typical double peak, where the characteristic peak corresponds to Ti 4+ After drug loading, the binding energy increases to 464.3 and 458.5 eV. + The binding energy is 399.1 and 402.8 eV, and the peaks of the XPS spectra of N 1s and Ti 2p shift, indicating that there may be an interaction with ABZ.

[0134] ABZ@SU-101 is composed of C, O, and Bi. The high-resolution C 1s spectrum uses the C1s peak at 284.8 eV as a reference for charge correction, which is divided into three absorption peaks at 530, 531.6, and 533.5 eV, respectively, for Bi-O, CO, and C=O. In the high-resolution Bi 4f spectrum, the peaks centered at 159.5 and 165 eV correspond to Bi 3+ Bi 4f ions 7 / 2 and Bi 4f 5 / 2 orbit, indicating that the metallic Bi in ABZ@SU-101 is mainly Bi 3+ Exists in ionic form.

[0135] Example 10

[0136] [Thermal stability analysis]

[0137] The thermal stability of the preparation was evaluated by a simultaneous thermal analyzer. -1 The heating rate is increased from 30℃ to 800℃, and the relationship between the mass loss percentage and temperature is recorded. The results are as follows Figure 7 shown.

[0138] ABZ@UiO-66-NH2 experienced significant weight loss in the range of 30-200℃, at which point the loss was mainly due to the adsorbed water molecules on the surface and the residual acetic acid solvent. The mass loss was faster in the range of 380-450℃, and the weight loss in this process can be attributed to the decomposition of organic ligands. The mass loss at 500-600℃ was about 8%, which was due to the collapse of the UiO-66-NH2 skeleton and the metal Zr 4+ The Zr-O clusters between the organic ligand 2-aminoterephthalic acid began to gradually transform into ZrO2 metal oxide at high temperature, and finally the mass loss stabilized at around 600℃ and no longer changed, with a residual mass of 54.2%.

[0139] TGA shows that MIL-125-NH2 has good thermal stability, and the TGA curve is divided into three stages: obvious weight loss is shown between 30-300℃, which is attributed to the desorption of surface adsorbed water and the volatilization of residual organic solvents methanol and DMF in the porous structure; the mass loss between 300-400℃ is attributed to the breaking of metal coordination bonds in the metal-organic framework structure and the decomposition of ABZ. At this time, the skeleton collapses, causing the destruction of the metal-organic framework structure and significant mass loss; between 400-800℃, the TGA curve does not change significantly, and it transforms into a more stable TiO2 structure. The final residual mass of ABZ@MIL-125-NH2 is 64.8%.

[0140] The weight loss of SU-101 is mainly divided into two stages. The first is at 100-200℃, which is mainly due to the loss of water molecules in the pores of SU-101. The second stage is 500-600℃, with a weight loss rate of about 10%, which is mainly due to the collapse and decomposition of the SU-101 framework structure. The final residual product is Bi2O3.

[0141] The above shows that ABZ@UiO-66-NH2, ABZ@MIL-125-NH2 and ABZ@SU-101 of the present invention have good thermal stability.

[0142] Example 11

[0143] [Drug loading and adsorption capacity]

[0144] Accurately weigh 6 mg of ABZ@MOF and dissolve it in 6 mL of a mixed solution of hydrochloric acid and PBS (v / v = 1:1). After standing for 48 h, the absorbance of ABZ was measured at 295 nm by UV-visible spectrophotometry, and the drug loading was calculated using the formula:

[0145]

[0146] The drug loading amounts of ABZ@UiO-66-NH2, ABZ@MIL-125-NH2, and ABZ@SU-101 were 12.13%, 26.17%, and 43.89%, respectively.

[0147] Example 12

[0148] [In vitro release test]

[0149] The release of ABZ@MOF under different pH conditions was investigated. A hydrochloric acid solution with a pH of 1.2 and PBS solutions with pHs of 6.8 and 7.4 were used to simulate the physiological environments of the stomach, intestine, and normal body fluids, respectively. 3 mg of ABZ@MOF was dissolved in 35 mL of either hydrochloric acid or PBS solution at different pH values. Drug release experiments were performed at 37°C with constant temperature and shaking at 150 rpm.

[0150] 0.5 mL of sample was taken at 0.5, 1, 2, 4, 6, 8, 12, and 24 h, respectively, and an equal volume of release medium was added. The obtained samples were centrifuged at 13,000 rpm and 4°C for 10 min (13,000 rpm, 10 min). The supernatant was diluted with an equal volume of hydrochloric acid (v / v = 20%), and the concentration of ABZ was determined using a UV-visible spectrophotometer at an absorption wavelength of 295 nm.

[0151] The cumulative release of the drug was calculated using the formula:

[0152]

[0153] V is the volume of the drug solution sampled each time; V0 is the total volume of the release medium; C t is the drug concentration at the corresponding time point measured by UV; m drug is the total mass of drugs loaded by ABZ@MOFs.

[0154] The results are as follows Figure 8 As shown in the figure, ABZ@UiO-66-NH2 is almost not released under acidic conditions, and only 4.21% is released in 24 hours, that is, it is basically stable in the gastric fluid environment. The release rate is faster in PBS solution with a pH of 6.8, and the cumulative release rate can reach more than 40% in 24 hours. In PBS solution with a pH of 7.4, more ABZ can be released, and the cumulative release rate in 24 hours is 62.4%.

[0155] The 24h cumulative release rate of ABZ@MIL-125-NH2 under three pH conditions was less than 20%, and showed a continuous and slow release trend.

[0156] ABZ@SU-101 was rapidly released at pH = 1.2, with a release of nearly 30% in 24 h, which means it was unstable in acidic conditions and almost not released in PBS solutions with pH 6.8 and 7.4.

[0157] In addition, the first-order release model, zero-order release model and Higuchi model were used to fit and analyze the in vitro release of ABZ@MOF.

[0158] As shown in Table 1-3, the results show that the primary release of R 2 The value is closest to 1 and the model fits best, indicating that the release behavior of ABZ@MOF is more consistent with first-order release. Drug release is mainly based on diffusion, which is manifested as a large release rate at the beginning. As time goes by, the concentration of the drug in the drug delivery system gradually decreases, and the release rate also gradually decreases.

[0159] The release behavior of ABZ@SU-101 is more consistent with the Higuchi release model. The drug release process is a synergistic effect of skeleton dissolution and diffusion. During release, the drug molecules diffuse within the pores or channels formed by the skeleton material. The drug release is rapid in the early stage and accelerates in the later stage, but the entire release process shows a relatively stable and sustained release trend. This release pattern allows the drug to reach a certain blood concentration within a relatively short period of time to exert its therapeutic effect and maintain an effective therapeutic concentration over the subsequent period, thereby improving the drug's bioavailability and efficacy. However, all formulations are oral drug preparations and need to remain stable in the acidic environment of gastric fluid. ABZ@SU-101 clearly does not meet this condition, so it was not examined in subsequent experiments.

[0160] Table 1 Fitting equations of ABZ@UiO-66-NH2 in vitro drug release model

[0161]

[0162] Table 2 Fitting equations of ABZ@MIL-125-NH2 in vitro drug release model

[0163]

[0164]

[0165] Table 3 Fitting equations of ABZ@SU-101 in vitro drug release model

[0166]

[0167] Example 13

[0168] [Transmembrane transport research]

[0169] 1) Caco-2 cells were cultured in DMEM high glucose complete medium supplemented with 10% fetal bovine serum and 1% double-antibody in a 37°C incubator containing 5% CO2. Caco-2 cells in the logarithmic growth phase were digested with 0.25% trypsin and prepared into a single cell suspension in complete medium. 5×10 cells were plated per well. 4 Cells were seeded in a 96-well culture plate with a volume of 100 μL per well. After culturing in an incubator for 24 h, 10 μL of ABZ@MOF at 100, 80, 60, 40, 20, 10, or 5 μg / mL was added to each well. After culturing in an incubator for 24 h, 10 μL of CCK-8 reagent was added to each well. The light absorbance of each well was measured at a wavelength of 450 nm using a microplate reader to calculate the cell survival rate:

[0170]

[0171] OD P is the OD value of the experimental group; ODN is the OD value of the negative control group; OD B is the OD value of the blank group and the control group.

[0172] 2) Caco-2 cells were cultured at 2×10 5 Cells were seeded into a 12-well Transwell culture plate, with 0.5 mL of cell suspension added to the apical side (AP side) of the Transwell plate and 1.5 mL of complete medium added to the basolateral side (BL side). The plates were cultured at 37°C, 5% CO2, and saturated humidity for 21 days to establish a Caco-2 cell monolayer model. Based on the cytotoxicity results, high, medium, and low concentrations of ABZ@MOF were determined. After successfully establishing the Caco-2 monolayer cell model, high, medium, and low concentrations (20, 10, and 5 μg / mL) of ABZ@MOF were added to the AP side of the Transwell plate, respectively. 1.5 mL of PBS was added to the BL side. The plates were cultured in a 37°C, 5% CO2 incubator for 30, 60, 90, and 120 minutes. Samples were taken from the BL side and centrifuged at 13,000 rpm for 5 minutes. The sample concentration was detected using high-performance liquid chromatography (HPLC). The transmembrane permeability of the drug, P, was calculated according to the formula app and ER value.

[0173]

[0174] dQ / dt is the permeation rate per unit time; A is the surface area of ​​the polycarbonate membrane, which is 1.12 (cm 2 ); C0 is the initial concentration of the drug (μg·mL -1 );P app (BL→AP) is the transmembrane permeability from the BL side to the AP side; P app (AP→BL) is the transmembrane permeability from the AP side to the BL side.

[0175] Chromatographic conditions: A Diamonsil C18 (250 mm × 4.6 mm, 5 μm) column was used; methanol: water (80:20) was used as the mobile phase, and the flow rate was 1 mL min -1 ; Detection wavelength 295nm; Column oven temperature 30℃, injection volume 20μL.

[0176] The cytotoxicity of ABZ@UiO-66-NH2 and ABZ@MIL-125-NH2 to Caco-2 cells was determined by CCK-8 assay. When the drug concentration was greater than 20 μg / ml, the cell survival rate was less than 80% ( Figure 9 ).

[0177] like Figure 10As shown in the figure, the drug concentration and permeability of ABZ@UiO-66-NH2 detected on the BL side and AP side in the high, medium and low concentration groups are higher than those of ABZ@MIL-125-NH2. app The P app P less than 37℃ app Its transmembrane transport is affected by temperature, that is, transport depends on energy; the ER values ​​of ABZ@UiO-66-NH2 at high and medium concentrations are in the range of 1 to 1.5, and the ER values ​​of ABZ@MIL-125-NH2 at medium and low concentrations are both less than 1.

[0178] This shows that ABZ@UiO-66-NH2 has better transmembrane transport ability than ABZ@MIL-125-NH2; when ABZ is encapsulated in MOF, the transmembrane transport mode of ABZ@UiO-66-NH2 is the coexistence of passive diffusion and active transport, while ABZ@MIL-125-NH2 is mainly passive transport.

[0179] Example 14

[0180] [Bioavailability Study]

[0181] 1) Eighteen Wistar rats were divided into three groups, with half male and half female in each group. The ABZ dose was 25 mg·kg -1 The dose was administered by gavage. 200-500 μL of blood was collected at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration, respectively, and placed in a pre-prepared anticoagulant centrifuge tube. The tube was centrifuged at 13000 rpm for 10 minutes, and the upper plasma was taken and stored in a -80°C ultra-low temperature refrigerator. Sample processing method: After the sample plasma melted, 100 μL was taken, 300 μL of methanol was added, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes, 300 μL of the supernatant was taken, and 200 ng mL -1 A mebendazole internal standard solution was added and vortexed for 1 minute. The supernatant was filtered through a microporous filter and the drug content was determined by UHPLC-MS / MS. Pharmacokinetic parameters were calculated using Das 2.0 software.

[0182] Chromatographic conditions: Accucore aQ UHPLC column (150 mm × 2.1 mm × 2.6 μm); column temperature (40 ± 1)°C; sample tray temperature (15 ± 0.5)°C; mobile phase: 0.1% formic acid in water (phase A), acetonitrile (phase B); isocratic elution: 0–5 min, 95% B; flow rate 0.3 mL min -1 ; Injection volume 1μL.

[0183] Mass spectrometry conditions: Full MS scanning mode, electrospray ionization (ESI) source; high-purity nitrogen (purity >99.9%) carrier gas, sheath gas flow rate 35 units, auxiliary gas flow rate 10 units, purge gas flow rate 0 unit; spray voltage 3.0 kV; capillary temperature 320°C, ion lens voltage frequency (S-lens RF level) 60, auxiliary gas heat source temperature 350°C; positive ion scanning mode, mass scanning range m / z 150-800.

[0184] The results showed that after rats were orally administered with ABZ and ABZ@MOF ( Figure 11 and Table 4), the area under the plasma concentration-time curve (AUC 0-∞ ) increased significantly. The AUC of ABZ@UiO-66-NH2 0-∞ (2269.66±707.32) μg·L -1 ·hr, which is ABZ API (219.91±25.27) μg·L -1 hr is 10.3 times that of ABZ@UiO-66-NH2. As shown in the figure, the blood concentration of ABZ@UiO-66-NH2 is higher than that of ABZ within 24 hours after administration, the half-life is prolonged, and the mean residence time (MRT) of the drug in the body is 0-∞ ) is prolonged, further increasing the concentration of ABZ in plasma, thereby improving the bioavailability of ABZ.

[0185] The area under the plasma concentration-time curve (AUC 0-∞ ) was 1.8 times higher than that of ABZ, and the peak blood concentration (C max) Compared with the raw material drug, its clearance rate is significantly improved, and it is metabolized faster in the body. The drug is quickly excreted from the body after entering the blood circulation. At this time, ABZ may not have been released from the preparation.

[0186] The above experiments show that the ABZ@MOF of the present invention increases the oral bioavailability of ABZ.

[0187] Table 4 Pharmacokinetic parameters of ABZ and ABZ@MOFs (n=6)

[0188]

[0189]

[0190] Note****: p<0.0001; ***: p<0.001; **: p<0.01; *: p<0.05, compared with ABZ.

[0191] Example 15

[0192] [Safety Evaluation]

[0193] 1) Fresh rat plasma was washed with physiological saline and resuspended at a cell density of 4% (volume fraction) to prepare a 4% red blood cell suspension. Then different concentrations (200, 500, 800, 1000, 2000 μg mL -1 ) ABZ@MOF was mixed with a red blood cell suspension and incubated at 37°C for 2 hours. The mixture was then centrifuged (3000 rpm, 10 minutes), and the absorbance of the supernatant was measured at 540 nm using a UV-visible spectrophotometer (UVmini-1280, SHIMADZU, Japan). Additionally, physiological saline and distilled water were incubated with the red blood cell suspension under the same conditions as negative and positive controls, respectively. The hemolysis rate was calculated using the formula.

[0194]

[0195] Among them, A s is the absorbance of the sample, A p is the absorbance of the positive control, A n is the absorbance of the negative control.

[0196] 2) Twelve Kunming mice were divided into two groups: saline and ABZ@UiO-66-NH2, with half male and half female in each group. After one week of adaptation, the mice were given ABZ at a dose of 9.1 mg·kg -1 The mice were administered with different doses via tail vein injection on days 1 and 4, and their body weights were observed over two weeks. After 14 days, blood was collected from the mice, and routine blood tests, liver and kidney function tests, were performed to assess the drug's safety on the blood system, liver, and kidneys. The mice were dissected and their major organs, including the heart, liver, spleen, lungs, and kidneys, were isolated. These tissues and organs were sectioned, stained with H&E, and photographed under a microscope for pathological analysis.

[0197] The distilled water group (DW) showed a clear, red solution with no residual red blood cells at the bottom of the tube, indicating complete hemolysis. The different drug concentration groups all had the same morphology as the normal saline control group (NS). At 15 minutes, the solution and red blood cells were observed to separate, with the red blood cells gradually sinking to the bottom of the tube. After shaking the tube, the cells dispersed and re-formed into a cell suspension, with no hemolysis or cell aggregation. At the same time, ultraviolet scanning of the full wavelength of the supernatant solution of different drug concentrations revealed that ABZ@UiO-66-NH2 and ABZ@MIL-125-NH2 concentrations of 200, 500, 800, 1000, and 2000 μg·mL -1 The absorption at 540nm was weak, and the hemolysis rate was less than 5% ( Figure 12 ).

[0198] ABZ@UiO-66-NH2 has good in vivo safety after multiple injections. Serological indicators are shown in the results ( Figure 13 ), the red blood cells, white blood cells, platelets, and hemoglobin in the ABZ@UiO-66-NH2 group showed no significant differences from those in the normal saline group, and the neutrophils, eosinophils, and basophils also showed no obvious changes, indicating that the preparation did not induce an inflammatory response.

[0199] The safety of the liver and kidneys is determined by testing the activity of enzymes related to liver and kidney function in the serum. Figure 14 As shown, the plasma indicators related to liver function, AST, ALT, ALB, ALP, ALB, DBIL, TBIL, and TBA, and the indicators related to kidney function, BUN, CREA, and UA in the mice in the ABZ@UiO-66-NH2 group showed no activity changes.

[0200] To further investigate the safety of ABZ@UiO-66-NH2 in mice after multiple administration, the heart, liver, spleen, lung, and kidney were sliced ​​and stained with H&E. Figure 15 Compared with the saline group, ABZ@UiO-66-NH2 showed no significant changes in myocardial tissue, with a relatively normal structure. Hepatocytes showed slightly disorganized arrangement, possibly indicating mild swelling. Splenic tissue density increased slightly, with possible lymphocyte aggregation. Alveolar structure was blurred, with interstitial thickening, suggesting a possible inflammatory response. Mild changes in the renal tubules and glomeruli were observed, possibly representing mild pathological changes. These results suggest that ABZ@UiO-66-NH2 may induce inflammatory changes. However, for most pathological changes, a comprehensive assessment should be made based on a combination of biochemical, metabolic, and clinical data. Therefore, although H&E staining of various organs revealed minor pathological changes, suggesting the potential for mild toxicity, mice gained weight during the dosing period, blood biochemical parameters remained normal, inflammatory cell counts did not increase, and liver and kidney function indicators showed no significant differences from the control group, indicating no functional changes in the affected organs and a non-adverse effect. Furthermore, the acute toxicity test involved a high dose, with multiple administrations within a week, necessitating comprehensive consideration of the toxicity of the formulation.

[0201] While the present invention has been disclosed above with reference to preferred embodiments, this is not intended to limit the present invention. Persons skilled in the art will readily appreciate that various modifications and variations can be made without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be determined by the claims.

Claims

1. A metal organic framework-albendazole drug delivery system, characterized in that: The drug delivery system includes a metal organic framework and albendazole. The albendazole (ABZ) is loaded in the metal organic framework (MOF) to form ABZ@MOF nanomaterials. The MOF includes UiO-66-NH2, MIL-125-NH2 or SU-101.

2. The metal organic framework-albendazole drug delivery system according to claim 1, characterized in that: The average particle size of the ABZ@MOF nanomaterial is 200nm to 600nm, and the Zeta potential is -3.0mV to 6mV.

3. The metal organic framework-albendazole drug delivery system according to claim 1, characterized in that: The drug loading amount of the ABZ@MOF nanomaterial is 10% to 50%.

4. A method for preparing a metal organic framework-albendazole drug delivery system, characterized in that: include: Albendazole was mixed with metal ions and organic ligands to form a mixed solution, and ABZ@MOF nanomaterials were prepared by solvothermal synthesis.

5. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 4, characterized in that: When the MOF is UiO-66-NH2, the preparation process includes: adding zirconium oxychloride octahydrate (ZrOCl2·8H2O) and 2-aminoterephthalic acid (BDC-NH2) into deionized water to obtain a first solution; dissolving albendazole in acetic acid to obtain a second solution; adding the second solution to the first solution and stirring uniformly to obtain a third solution; The third solution was refluxed in an oil bath. After the reaction was completed, the solid was collected, washed, and dried to obtain ABZ@UiO-66-NH2 nanomaterials.

6. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 5, characterized in that: The molar ratio of ZrOCl2·8H2O and BDC-NH2 is (1-2):1, and the oil bath condition is oil bath reflux at 100-110°C for 24h.

7. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 4, characterized in that: When the MOF is MIL-125-NH2, the preparation process includes: adding diaminoterephthalic acid (NH2-BDC) to a mixed solution of methanol and N,N-dimethylformamide (DMF) to obtain a fourth solution; dissolving albendazole in acetic acid to obtain a fifth solution; The fifth solution is added to the fourth solution, titanium isopropoxide is added under stirring, and the mixture is mixed uniformly to obtain a sixth solution; The sixth solution was transferred into a reactor, heated for reaction, filtered, and activated under vacuum after removing the solvent. The solid was then collected to obtain the ABZ@MIL-125-NH2 nanomaterial.

8. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 7, characterized in that: The molar ratio of NH2-BDC to titanium isopropoxide is 2:1, the heating reaction conditions are heating at 433K for 48 hours, and the vacuum activation conditions are activation at 393K under vacuum for 12 to 24 hours.

9. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 4, characterized in that: When the MOF is SU-101, the preparation process includes: adding bismuth acetate and ellagic acid to deionized water to obtain a seventh solution; dissolving albendazole in acetic acid to obtain an eighth solution; The eighth solution was added to the seventh solution, stirred at room temperature, centrifuged, and solids were collected; the solids were then washed and dried to obtain ABZ@SU-101 nanomaterials.

10. The method for preparing the metal organic framework-albendazole drug delivery system according to claim 9, characterized in that: The mass ratio of bismuth acetate to ellagic acid is (7-8):3.

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