INTRODUCTION:

Metal–organic frameworks (MOFs) is nanoporous materials, where metal ions are connected by organic linkers into a three-dimensional lattice, which form a bond with the metal by the donor–acceptor mechanism^1-8. MOF possess some properties such as various structural topologies^9-12, large surface area and nanoscale porosity, good thermal stability^{13, 14} possible functional groups addition in framework structure and high flexibility of some metal-organic frameworks that can change their size pore^15-19.

These properties make MOF promising material in various areas of industry, such as gas storage^20-22, adsorption^23,24, accumulation²⁵, catalysis^26,27, gas chromatography and high-performance liquid chromatography^28-31. In addition, these polymers are promising candidates for targeted drug delivery and controlled drug release^32-41. There is approach based on the storage of biologically active inside the MOF pores. Payload release from pores can be triggered by various stimuli: pH, temperature, ions, and it is accompanied by framework degradation^42-47.

The well-characterized MIL-101(Fe) deserves the attention as drug carrier and its possible biomedical applications due to its low toxicity (rat oral dose: DL₅₀(Fe) = 30 g/kg, DL₅₀(BDC) = 5g/kg) and biodegradability^44,48-51. This mesoporous polymer crystal lattice is constructed from terephthalic acid as an organic ligand and trinuclear Fe₃O cluster as an inorganic node. It has high surface area, large pore size (12 Å × 29 Å; 16 Å × 34 Å)⁵². Therefore, based on the above mentioned reasons, we have chosen MIL-101(Fe) as a drug carrier.

Metronidazole - 2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethanol (MTR) can be used as a model molecule of a drug substance being one of the most commonly antibacterials. This drug is widely applicable in various areas of medicine, including stomatology. MTR is used to treat amebiasis, vaginitis, trichomonas infections, giardiasis, anaerobic bacteria and treponemal infections ^53,54. It is also known, that MTR is used for internal and topical application, can act in various parts of an organism^55-57. The oral absorption of metronidazole is excellent, with bioavailability often reported as > 90%, the peak plasma drug concentration it is reached after 1-3 hours. Metronidazole has rapid diffusion and distribution of metronidazole into various tissues and body fluids. At the same time, long-acting drugs for metronidazole are unknown⁵⁸. This drug is a compendial pharmaceutical substance which is approved for medical use in many countries^59,60. Its monographs are presented in Indian Pharmacopoeia, The United States Pharmacopoeia and The National Formulary. MTR is FDA-approved for treating infections, and it is on the World Health Organization's List of Essential Medicines ⁶¹. Besides, MTR molecular size (7 × 8 × 12 Å) enables its encapsulation in MIL-101(Fe) pores⁶² .

In the present work, MIL-101(Fe) was synthesized by hydrothermal method. MOF pores were loaded with MTR. The drug loading capacity of MIL-101(Fe) was investigated for MTR. We demonstrated MTR release kinetic analysis from the MOF in water and various body fluids - saliva and blood serum. We show the MTR release profile depend on composition of the fluid.

MATERIALS AND METHODS:

Materials:

We used MTR, extra puris (Merck, Germany); MTR, analytical standard (Sigma-Aldrich, USA); terephthalic acid (H₂BDC), puris (Sigma-Aldrich, USA); N,N-dimethylformamide (DMF), puris (Vecton, Russia); deionized water (resistivity — 17.8 MOm∙cm); mucin from bovine submaxillary glands (Sigma-Aldrich, USA); albumin (BSA), 99% (Macklin, China); disodium phosphate dihydrate, puris (Vecton, Russia); sodium monophosphate dihydrate, puris (Vecton, Russia); sodium hydroxide, puris (Vecton, Russia).

Preparation artificial saliva:

Artificial saliva solution was prepared by dissolving the following salts in distilled and deionized water: mucin from bovine submaxillary glands = 2 mg/ml; Na₂HPO₄ = 2.34mg/ml; NaH₂PO₄ = 6.66mg/ml. To the prepared solution albumin was added = 2mg/ml. The artificial saliva pH was set at 6.4 with 1M NaOH ⁶³.

Blood serum preparation:

20 residual blood serum samples (unbound phosphates = 1.34mmol/l) was taken from patients of the multidisciplinary hospital of the Samara State Medical University Clinics without hemolysis and lipemia. Initially, venous blood was collected in serum tubes (BD Vacutainer). Tubes with blood were centrifuged at 3000 rpm for five minutes and serum was collected from tubes.

Methods:

a) Powder X-Ray Diffraction (PXRD):

X-ray diffraction measurements were investigated through a Phaser D2 powder X-ray diffraction analyzer and LynxEye XE-T 1D detector (Bruker, USA). The measurements were performed using Cu-Kα (λ = 1.5406 Å) in the scan range of 2θ from 2 to 35°.

b) Porosimetry (BET analysis):

The specific surface area of samples were measured by nitrogen sorption at 77 K using Autosorb iQ (Quantachrome Instruments, USA) porosimeter, relative pressure was P/P₀ 9∙10^–3– 0.995. Before the analysis, the samples were preliminary degassed at 60°C within 24 h.

c) Scanning Electron Microscopy (SEM) with Energy Dispersive Spectroscopy (EDS):

The surface morphology of the synthesized and MTR loaded MIL-101(Fe) was identified using a scanning electron microscope Vega 3 (Tescan, Czech Republic).

Synthesis MIL-101(Fe):

MIL-101(Fe) was synthesized according to the following procedure ⁶⁴: 2 mmol of hexahydrate Iron(III) chloride, 2 mmol of terephthalic acid and 1.8 mL of acetic acid were mixed in 50 mL of N,N-dimethylformamide (DMF), then it was heated at 110 °C for 24 h. After of the reaction, the red precipitated product was isolated with a centrifuge. At the end, the product was activated by heating to 80°C for 24 h.

MTR loading procedure and in vitro release studies:

MIL-101(Fe), MTR and warm deionized water were placed in a round-bottomed flask. The resulting mixture was stirred for 24 hours and evaporated in vacuum at a temperature not exceeding 40°С. Resulting composite was dried at room temperature for 12 hours.

The in vitro release properties of MTR from MTR@MIL-101(Fe) were investigated on artificial saliva, blood serum and deionized water in dialysis bag ⁵⁶. The release was carried out with constant stirring and heating to 37°C on a magnetic stirrer.

There is literature data on the use of UV spectrophotometry to quantify MTR^65-68, therefore, the release of metronidazole from the composite was quantified using UV spectroscopy using a Tecan Infinity 200 Pro tablet reader (Tecan Instruments, Austria) at an analytical wavelength of 320 nm. The determination was carried out as follows: an aliquot of 400µl. artificial saliva or blood serum containing metronidazole was deproteinized by centrifugation in 800µl. acetonitrile⁶⁹. MTR isolated from the composite was evaluated on a tablet reader at a wavelength of 320nm. After taking each aliquot, the volume of liquid was replenished with the corresponding biological liquid.

Validation:

The validation was carried out using according to the State Pharmacopoeia of the Russian Federation XV edition, general monograph (G.M.) 1.1.0012 “Validation of analytical procedures”⁷⁰. Specificity/selectivity, linearity, lower limit of quantification (LLOQ) and intermediate precision of analytical measurements were estimated.

a) Specificity/selectivity:

MTR shows maximum absorbance at 320 nm, while the maximum absorbance of terephthalic acid occurs at a wavelength of 240nm (Figure 1). Therefore, presence of terephthalic acid does not impact the quantitation of MTR.

Figure 1. UV-VIS spectra measured for aqueous solutions.

b) Linearity:

The linearity of the analytical procedure was demonstrated over the concentration range 6.25-200 μg/mL. The calibration standards were prepared using water, blood serum or artificial saliva and the appropriate levels of MTR. The calibration curves were determined using the six calibration points composed of 3 individual replicates. The linear regression equation and the coefficient correlation were calculated using Microsoft Office Excel 2016.

c) LLOQ

The LLOQ for the developed UV method was calculated by using following formula:

LOQ = 3.3 x ----

where S = the standard deviation of the analytical signal;

b = the sensitivity coefficient, which is the ratio of the analytical signal to the determined value (the tangent of the angle of inclination of the calibration curve).

d) Intermediate precision:

The precision, defined as relative standard deviation (RSD%), was calculated by ten separate replicates of MTR determination at 100% of the test concentration at both intraday and inter-day.

Statistical Analysis:

The statistical analysis was carried out using Microsoft Office Excel 2016 with module AtteStat 11.5.

RESULTS AND DISCUSSION:

Characterization:

Before the loading procedure, MIL-101(Fe) was characterized by PXRD. The PXRD pattern of activated MIL-101 (Fe) is shown in Figure 2, which are matched to described earlier PXRD pattern of pure MIL-101(Fe) to the previously described figure PXRD of pure MIL-101(Fe)^71,72. The obtained diffractograms showed that MIL 101(Fe) and MTR@MIL-101(Fe) are single-phase samples.

We have selected several MTR and MIL-101(Fe) mass ratio (w:w). The obtained composites showed that with a mass ratio of MTR : MIL-101(Fe) - 1:4 (w:w), the appearance of MTR peaks on the PXRD is observed, indicates the impossibility of obtaining a composite with a given or higher MTR content. The sample with the MTR : MIL-101(Fe) mass ratio 1:10 (w:w) had no peaks of MTR reflection, which indicates the complete absorption of MTR into the pores of the MIL-101(Fe). The results obtained shows that MTR incorporation in MIL-101(Fe) does not affect the MIL-101(Fe) MOF crystal structure.

Since a sample with a mass ratio of 1:4 (w:w) did not completely absorb metronidazole, we used a sample with a mass ratio of 1:10 (w:w) for further studies.

Figure 2. PXRD patterns.

For confirmation MTR loading inside MOF pores, N₂ sorption experiments of MIL-101(Fe) and MTR@MIL-101(Fe) was carried out and its results are shown in Figure 3. The results obtained from nitrogen sorption measurements show reduced surface area the Brunauer–Emmett–Teller for MIL-101(Fe) after the drug loading process down to 80±08 m²/g. BET specific surface area (S_BET) of pristine MIL-101(Fe) is 1423±23 m²/g. The correlation coefficient of the calculated values was 0.999 upon using different p/p0 values. The difference was significant in case of p<0.05. Small values of S_BET indicate that the pores are almost completely filled.

Figure 3. Nitrogen adsorption isotherms: A - MIL-101(Fe); B - MTR@MIL-101(Fe).

The SEM images before and after drug loading are shown in Figure 4a,b. MTR@MIL-101(Fe) is different from MIL-101(Fe) agglomerated structures on the crystal surface. The observed difference can be explained by the presence of a thin MTR film on the crystal surface, which was not observed on the PXRD pattern.

Figure 4. SEM images of (A) MIL-101(Fe) before, (B) after MTR loading

In vitro Release:

The release rate of MTR@MIL-101(Fe) is different in three different fluids. The complete release of MTR in artificial saliva ends after 7.5 h and in blood serum after 9 h. In deionised water the release of the drug ends after 30.5 h. The maximum cumulative release was 92.74±2.04% in artificial saliva, 80.36±1.57% in blood serum and 7.34±0.12% in deionised water (Figure 5).

Figure 5: The release of MTR from MTR@MIL-101(Fe) at the three fluids.

The samples did not dissolve after the experiment, so there was a PXRD which showed the preservation of the crystal structure of the MOF after exposure to deionized water, which correlates with a low value of metronidazole release. However, samples remaining in saliva and blood serum after release were found to be largely amorphous. This phenomenon is associated with the destruction of MIL-101(Fe) under the action of phosphate ions, which also correlates with an increase in MTR concentration in these fluids ⁷¹. It is interesting to note that the release of MTR in serum did not lead to complete recovery in solution. We suggest that this is due to a lower phosphate content in blood serum than in saliva, leading to incomplete degradation of MOF and pore clogging on crystal surface.

Figure 6. PXRD patterns MTR@MIL-101(Fe) after release.

CONCLUSION:

In this work, the kinetics of release MTR as an antibacterial drug from MIL-101(Fe) was investigated. MTR is applicable in stomatology, therefore it is important to know the kinetics of release of MTR from MIL-101(Fe) in biological fluids such as blood serum and saliva. This type of MOF was chosen because of the low toxicity of its components, high surface area, large pore size and ease of preparation. The results obtained confirmed that MIL-101 (Fe) structure is not affected upon MTR loading.

The data obtained showed that the release occurred selectively during the transition from water to human biological fluids. MTR@MIL-101(Fe) did not dissolve completely when treated with saliva and serum, but degradation of the support occurred under the action of phosphates. At the same time, there was almost complete release of MTR from the MOF in saliva and incomplete release in blood serum. On the contrary, the crystal structure of MTR@MIL-101(Fe) is preserved after treatment with deionised water and a slight release of MTR occurs, presumably under the action of desorption of the drug from the crystal surface. The selective release data obtained may be useful for using this composite for targeted delivery and prolonged release.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The work was performed under the financial support of the Russian Science Foundation, project 24-23-00162.

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Received on 24.07.2024 Revised on 21.11.2024

Accepted on 03.01.2025 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1317-1323.

DOI: 10.52711/0974-360X.2025.00191

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