Synthesis of MOFs and Characterization and Drug Loading Efficiency

Abstract

Asthma and allergic rhinitis (AR) stand as prevalent chronic ailments impacting children within the United States. It is approximated that as many as 40% of American children exhibit symptoms indicative of AR, a condition which, if inadequately managed, could potentially lead to the onset of additional illnesses such as asthma, rhinosinusitis, allergic conjunctivitis, and otitis media. We have devised a universal synthetic pathway to encapsulate small molecules of montelukast sodium within Metal–Organic Frameworks (MOFs) for the treatment of asthma and AR. Two distinct Cu-MOFs, namely single linker and mixed linker MOFs, were synthesized through the solvothermal method utilizing 1,4-benzenedioic acid (BDC) and 4,4′-dipyridile as linkers. The synthesized Cu-MOFs underwent thorough examination employing various analytical techniques including BET, SEM, FTIR, and PXRD. These MOFs hold promise as potential vehicles for drug delivery applications. Various proportions of Cu-MOF-1 and Cu-MOF-2 were dispersed alongside montelukast sodium. Notably, the 1:1 ratio of both MOFs exhibited enhanced drug absorption compared to other ratios. Furthermore, Cu-MOF-2 demonstrated superior drug absorption overall when contrasted with Cu-MOF-1. This investigation also delves into the drug release dynamics from different ratios of MOFs and the drug. The drug release analysis was conducted in a phosphate-buffered saline (PBS) solution with a pH of 7.4, and the absorbance values were measured using a UV-visible spectrometer at distinct time intervals. Drug molecules are effectively encapsulated within MOFs and demonstrate controlled release through the establishment of hydrogen bonding or π–π interactions between the drug molecules and MOFs. Despite notable advancements in the utilization of MOFs for biomedical purposes, additional enhancements are necessary before they can be considered viable therapeutic modalities.

1. Introduction

Asthma and AR are commonly occurring conditions with a high prevalence rate [1]. Since 1979, the US National Health Interview Survey (NHIS) has served as the principal means of monitoring the frequency and prevalence of asthma within the country [2]. As per the 1997 NHIS data, a total of 26 million individuals in the United States have received a diagnosis of asthma at some point in their lifetime [3]. Children under the age of 18 make up approximately one third of the total number of diagnosed asthma cases in the United States [4]. Asthma stands out as the most prevalent diagnosis among pediatric hospital admissions, indicating a significant rise in prevalence particularly among individuals younger than 20 years of age in recent times [5]. In recent years, there seems to be an increase in the prevalence of asthma among children with indications of heightened severity or both [6].

AR, characterized by inflammation of the nasal membrane and presenting symptoms such as nasal congestion, rhinorrhea, sneezing, nasal itching, and postnasal drainage, stands as the predominant form of rhinitis in the United States [7,8,9,10,11]. The majority of epidemiological investigations have assessed the prevalence of seasonal AR based on the presence of consistent seasonal symptoms [12]. Identifying perennial AR, which presents ongoing challenges, may involve overlapping symptoms with chronic sinusitis, recurrent respiratory infections, and vasomotor rhinitis [13]. Moreover, prevalence statistics for AR primarily rely on physician diagnoses, posing challenges in data interpretation and potentially excluding individuals who self-administer over-the-counter (OTC) remedies [14]. They may obtain prescription medications from friends or family members and/or refrain from seeking medical attention from a healthcare provider [15]. It is noteworthy that almost one third of individuals with AR have not sought medical consultation, highlighting an underestimation of AR prevalence [16].

MOFs represent an emerging class of materials comprising metal ions or clusters interconnected by multifunctional organic ligands [17], forming extended network structures [18]. Because of their ability to be adjusted structurally and functionally, their exceptional porosity, their high thermal and chemical stability, and their capacity for tailored structure, MOFs are appealing for numerous applications [19]. Extensive research has been conducted on MOFs for their potential utilization in catalytic processes, selective adsorption and separation techniques, as well as gas storage applications [20,21,22]. Recently, there has been exploration into the potential biomedical uses of MOFs across various domains, such as drug delivery, molecular imaging, and biological sensing [23,24,25]. The adaptable characteristics and gentle synthetic environments of MOFs enable the deliberate structural planning of numerous nanoscale MOFs (NMOFs), facilitating the integration of diverse functionalities, including targeted therapeutic biomolecules and imaging agents [26]. A growing body of research has employed NMOFs as carriers for drugs at the nanoscale and as probes for molecular imaging [27].

Since the initial investigation by Ferey et al. on iron-based MOFs for potential biomedical applications, an extensive body of research has emerged aimed at harnessing the significant potential of nanoparticulate MOFs (NMOFs) for diverse applications in healthcare [28,29].

MOFs present numerous benefits compared to existing drug delivery systems (DDSs), which frequently consist solely of organic or inorganic components [30]. Liposomes or polymers, while exhibiting greater biocompatibility, often have lower capacities for drug payloads. Conversely, materials like gold, iron, and silica nanoparticles, among others, can accommodate significantly higher drug loads but possess lower biocompatibility. Their slow degradation rates may lead to accumulation in organs such as the liver or spleen, potentially causing undesired side effects [31].

To address this significant challenge, we have recently developed a methodology that integrates targeted chemistry with structural computational modeling to produce mesoporous hybrids with large pores. This approach has led to the development of two novel MOFs synthesized using a cost-effective solvothermal synthesis method employing 1,4-benzenedicarboxylic acid (BDC) and 4,4′-bipyridine as organic linkers, along with a Cu(II) salt. The synthesized MOFs were utilized for the loading and targeted delivery of a drug molecule. Single linker and mixed linker MOFs exhibited distinct percentages of drug molecule loading and release content. They showcased large pores and exceptional surface areas, maintaining crystallinity without any loss after water clearing. In this study, we examine the adsorption and delivery of a model drug, montelukast sodium, by Cu-MOF-1 and Cu-MOF-2. As a component of our ongoing research program focused on porous materials and novel drug delivery systems aimed at regulating drug release, montelukast sodium was selected as a model drug for managing chronic asthma and AR due to its smaller size compared to Cu-MOF pores. The encapsulation of drug molecules is achieved through the establishment of hydrogen bonds between the drug molecules and Cu-MOF. Montelukast sodium was adsorbed onto the desiccated powdered materials from an ethanol solution, and the quantity adsorbed was determined using UV/Vis spectroscopy. The influence of material dehydration, montelukast sodium-to-material ratio, immersion duration, and the number of consecutive impregnations on the quantity of adsorbed drug was investigated. X-ray powder diffraction analysis conducted on the two materials confirmed that their structures remained intact following drug adsorption. Furthermore, N2 adsorption post-incorporation revealed minimal residual porosity. Thus, the drug completely occupies the pores or potentially obstructs the apertures of the cavities, resulting in nearly no available pore volume for nitrogen.

2. Materials and Methods

Chemicals including copper(II) nitrate trihydrate, benzene-1,4-dicarboxylic acid, and 2,2′-bipyridine were procured from Sigma Aldrich, while all solvents such as N,N-dimethylformamide (DMF), ethanol, methanol, and pyridine were obtained from Fluorochem. All chemicals were utilized as received without further purification.

2.1. Cu-MOF-1 Synthesis

In a Teflon cup, 25 mL of DMF and 2.5 mmol of benzene-1,4-dicarboxylic acid (BDC) were combined. The mixture was vigorously stirred for 30 min to ensure uniformity. Subsequently, 5 mmol of copper(II) nitrate trihydrate was added, which was followed by an additional 30 min of stirring. The Teflon cup was then placed inside a Teflon-wrapped iron jacket, and the autoclave was positioned in an oven set at 85 °C for 48 h. Upon completion, the autoclave was cooled to room temperature. After adding 5 mL of DMF, the mixture was stirred for 15 min and then filtered. Multiple washings with DMF were performed to eliminate any residual linker acid and unreacted metal ions. The resulting material was dried at 60 °C for 12 h to yield the blue Cu-MOF-1 crystals.

2.2. Synthesis of Cu-MOF-2

A Teflon cup was charged with 2.5 mmol of biphenyl-4,4-dicarboxylic acid (BPDC) and 25 mL of DMF. The solution was stirred vigorously for 30 min to achieve a uniform mixture. Then, 5 mmol of copper(II) nitrate trihydrate was added, which was followed by an additional 30 min of stirring. The Teflon container was sealed within the iron jacket, and the autoclave was placed in an oven at 85 °C for 48 h. After cooling to room temperature, the autoclave was opened, and the mixture was recombined with 5 mL of DMF and stirred for 15 min. To remove any residual metal ions and BPDC molecules, the resulting material was filtered and washed several times with DMF. Cu-MOF-2 was obtained by drying the material at 60 °C for 12 h.

2.3. Activation of MOFs

Both Cu-MOF-1 and Cu-MOF-2 were synthesized utilizing N,N-dimethylformamide (DMF), which is a solvent with a high boiling point. Following synthesis and drying, DMF may become incorporated into the MOFs, resulting in reduced porosity, adsorption capacity, and drug-loading capability. To eliminate incorporated DMF molecules, the MOFs underwent activation through a solvent-exchange technique. The MOFs were stirred with ethanol for 24 h, which was followed by separation, drying, and subsequent stirring with trichloromethane for another 24 h. In this procedure, DMF migrates from regions of higher concentration to lower concentration, facilitating its removal from the MOFs. Both ethanol and trichloromethane are solvents with low boiling points, allowing for easy evaporation. Subsequently, drug loading was carried out on the MOFs.

2.4. Drugs Encapsulation and Release

2.4.1. Montelukast Sodium Is Enclosed on MOFs

Montelukast sodium was loaded onto the MOFs by dispersing the required amount of MOF into three distinct aqueous solutions, with ratios of 1:2, 1:1, and 2:1, respectively. The three reaction mixtures were stirred using a stirrer for 24 h at room temperature. The reaction mixtures were centrifuged at a speed of 3000 rpm for a duration of 30 min. Following centrifugation, the drug-loaded MOFs were collected and dried. UV-VIS spectroscopy of the supernatant, obtained through syringe collection, was utilized to quantify the quantity of medicine adsorbed onto the MOFs.

(1)$\%\mathrm{age}\mathrm{montelukast}\mathrm{sodium}\mathrm{loading}\mathrm{efficiency}={\displaystyle \frac{\mathrm{Weight}\mathrm{montelukast}\mathrm{sodium}\mathrm{in}\mathrm{MOF}}{\mathrm{Weight}\mathrm{of}\mathrm{MOF}}}\times 100$

2.4.2. Drug Release from MOFs

The drug-loaded MOFs were immersed in a 10 mL phosphate-buffered saline (PBS) solution at pH values of 7.4, 2.6, and 3.5, and stirred using a magnetic stirrer at 37 °C. At specified time intervals, 1 mL of the PBS solution was replaced with an equivalent volume of fresh PBS solution to enable the determination of the released medicine concentration. The quantity of montelukast sodium released was assessed using UV-VIS spectroscopy.

3. Result and Discussion

3.1. Characterization of MOFs

3.1.1. BET Study

BET Study of Cu-MOF-1

The permanent porosity of Cu-MOF-1 and Cu-MOF-2 was determined using the N2 sorption isotherm at −196.15 °C. For both materials, activation involved soaking in methanol for three days, followed by immersion in dichloromethane for three days, and finally standing at room temperature for one hour.

Cu-MOF-1 exhibited a type-IV N2 sorption isotherm with mesopores, showing a maximum nitrogen uptake indicating a pore size of 17.7059 nm, BET surface area of 9.9267 m²/g, Langmuir surface area of 8.6233 m²/g, and a pore volume of 0.0490593 cm³/g (equivalent to 31.71 cm³/g) (Figure 1).

3.1.2. Analysis of Cu-MOF-2 by BET

In contrast, Cu-MOF-2 displayed a type-II N2 sorption isotherm with mesopores indicating a maximum nitrogen uptake of 131.67 cm³/g. It exhibited a smaller pore diameter of 2.1322 nm, BET surface area of 382.08 m²/g, Langmuir surface area of 400.26 m²/g, and a pore volume of 0.203667 cm³/g (Figure 2).

3.2. SEM Analysis

SEM of Cu-MOF-1 and Cu-MOF-2

The morphology of Cu-MOF-1 and Cu-MOF-2 was examined using SEM. As seen in Figure 3, Cu-MOF-1 showed a cubic shape, while Cu-MOF-2 displayed a nanorod-like morphology with interconnected structures. The 3D arrangement of the nanorods in Cu-MOF-2 improved its electrocatalytic activity compared to the purely cubic-shaped Cu-MOF-1, which lacked interconnection. Particle sizes for Cu-MOF-1 ranged from 20 to 190 nm, and for Cu-MOF-2 from 20 to 100 nm, with the smaller particle size enhancing the potential for oxygen evolution reactions (OERs).

3.3. FTIR Analysis

3.3.1. FTIR of Cu-MOF-1

In the FTIR spectra of Cu-MOF-1, two predominant peaks were observed at 1603 cm⁻¹ (antisymmetric stretching) and 1388 cm⁻¹ (symmetric stretching), corresponding to stretching vibrations of the carboxylate ion groups within the range of 1630–1500 cm⁻¹ and 1400–1310 cm⁻¹, respectively. Notably, the observed values were lower than the carbonyl stretching vibration detected in the free COOH group at 1745 cm⁻¹ (within the range of 1760–1690 cm⁻¹). These two peaks are attributed to the stretching vibration of the carboxylate anion. The absence of strong absorption bands at 2926 cm⁻¹ indicates the complete deprotonation of carboxylic groups in Cu-MOF-1, supporting the coordination between Cu(II) and the ligand upon reaction with the metal ions (Figure 4). A bond between the metal and ligand is observed at 565 cm⁻¹ (Cu-O). Bands below 900 cm⁻¹ correspond to various bending vibrations of C-H bonds and deformation bands of C=C-H in the aromatic ring.

3.3.2. FTIR of Cu-MOF-2

Cu-MOF-2 exhibits two prominent peaks at 1602 cm⁻¹ (antisymmetric stretching) and 1385 cm⁻¹ (symmetric stretching), corresponding to the stretching vibrations of the carboxylate ion groups within the ranges of 1630–1500 cm⁻¹ and 1400–1310 cm⁻¹, respectively. These values are lower than those observed for the stretching vibration of the carbonyl group in the free COOH group (1760–1690 cm⁻¹). These two peaks are attributed to the stretching vibration of the carboxylate anion. The absence of strong absorption bands between 2500 and 3000 cm⁻¹ indicates the complete deprotonation of carboxylic groups in Cu-MOF-2, supporting the coordination between Cu(II) and ligands upon reaction with the metal ions (Figure 4). Peaks corresponding to metal–ligand bonds are observed at 745 cm⁻¹ (Cu-N) and 567 cm⁻¹ (Cu-O). Several bending vibrations of C-H bonds and deformation bands of the aromatic ring are observed below 900 cm⁻¹.

3.4. PXRD Analysis

PXRD Analysis on Cu-MOF-1 and Cu-MOF-2

The crystallinity and phase purity of Cu-MOF-1 and Cu-MOF-2 were analyzed using PXRD (Figure 5). Cu-MOF-1 showed prominent peaks at 2-theta values ranging from 10.24° to 73.62°, indicating a crystalline structure. Cu-MOF-2 exhibited distinct sharp peaks with major diffraction patterns occurring between 6.0° and 73°. The average crystallite sizes were 62 nm for Cu-MOF-1 and 39 nm for Cu-MOF-2 with smaller crystallite sizes corresponding to increased peak broadening.

Powder X-ray diffraction (PXRD) was utilized to evaluate the crystallinity and phase purity of Cu-MOF-2 materials. The material exhibited crystallinity in phase, as evidenced by the presence of strong peaks in the PXRD pattern. The crystallinity of Cu-MOF-2 was characterized by sharp and distinct peaks. In the Cu-MOF-2 pattern, six prominent strong peaks were observed at 2-theta values of 6.0°, 8.94°, 12.08°, 12.82°, 15.20°, 16.87°, 17.98°, 25.71°, 27.0°, 27.92°, 31.95°, 36.41°, 42.5°, 61.62°, and 73°. The average crystallite sizes of Cu-MOF-1 and Cu-MOF-2 were determined to be 62 nm and 39 nm, respectively, using the Debye–Scherer relationship (D = 0.9/Δcosθ), where Δcosθ represents the broadening of the peaks. The crystallite size of Cu-MOF-2 was found to be smaller than that of Cu-MOF-1, owing to the inverse relationship between crystallite size and peak broadening, as assessed from full width at half maximum (FWHM).

3.5. Drug Loading and Release

Drug encapsulation and release were studied using UV-Visible spectroscopy, monitoring the absorbance of ibuprofen and montelukast sodium loaded into single linker and mixed linker MOFs. Absorbance values at specific wavelengths for each drug indicated successful encapsulation.

3.6. Loading Montelukast Sodium into MOFs

Montelukast sodium solutions (2.5 mg/mL and 5 mg/mL) were mixed with different MOF-to-drug ratios (2:1, 1:1, 1:2) and stirred for 24 h. Absorbance values after separation showed loading differences between Cu-MOF-1 and Cu-MOF-2, as summarized in Table 1 and Figure 6.

3.7. Drug Release

The Liberation of Montelukast Sodium from Cu-MOF-1

Both Cu-MOF-1 and Cu-MOF-2 displayed biphasic drug release kinetics in phosphate-buffered saline (PBS) at pH 7.4 and 37 °C. An initial burst release occurred within the first 30–60 min, which was followed by a slower release phase.

For Cu-MOF-1, the percentage release of montelukast sodium was higher at the 1:2 ratio, reaching approximately 66.61% after 60 min. Lower amounts were released for the 1:1 (25.85%) and 2:1 (58.59%) ratios.

Cu-MOF-2 showed the highest release at the 1:1 ratio (57.67%), which was followed by 1:2 (41.30%) and 2:1 (10.58%). These results are depicted in Figure 7.

3.8. The Liberation of Montelukast Sodium from Cu-MOF-2

Cu-MOF-2 loaded with a combination of MOF and drug at ratios of 2:1, 1:1, and 1:2 were individually immersed in 10 mL of phosphate-buffered saline (PBS) solution with a pH of 7.4 at 37 °C. At intervals of 2, 5, 15, 30, 60, 120, 240, and 480 min, 1 mL of the PBS solution was replaced with fresh PBS solution from each sample. The release of montelukast sodium from Cu-MOF-2 followed biphasic kinetics, which were characterized by an initial burst release within the first 30–60 min followed by a slower release phase. The peak release of the drug occurred after 60 min. The released quantity of montelukast sodium was analyzed to evaluate the percentage release efficiency of Cu-MOF-2 across various MOF and drug ratios. Approximately 10.58%, 57.67%, and 41.30% of ibuprofen were released from Cu-MOF-2 at ratios of 2:1, 1:1, and 1:2, respectively, after 60 min. The percentage release of the drug (montelukast sodium) at different time intervals for different ratios of Cu-MOF-2 and the drug is illustrated in Figure 7.

3.9. Comparison of Drug Release

The Liberation of Montelukast Sodium from Cu-MOF-1

Drug release behavior differed between the two MOFs, which was influenced by the ratio of MOF to drug and the structural characteristics of the MOFs. For Cu-MOF-1, nearly complete release was observed within one hour for the 1:2 ratios (Figure 8), while Cu-MOF-2 reached maximum release at the 1:1 ratio.

Factors affecting the drug release included the nature of the drug, MOF–drug ratio, and the structural characteristics of the MOF used.

In the context of montelukast sodium release from Cu-MOF-2, nearly all of the drug was released within one hour for the 1:1 ratio, while complete drug release was observed after two hours for both the 1:2 and 2:1 ratio. A higher quantity of drug was released in the 2:1 ratio compared to the other ratios. The ascending order of drug release rates for the different ratios is presented as follows: 1:2 > 1:1 > 2:1.

4. Conclusions

The distinctive characteristics of (MOFs) suggest their potential as promising materials in diverse applications with an expanding body of research focusing on their synthesis and utilization. MOFs are currently pivotal in domains such as gas storage, gas separations, and catalysis, which represent the most developed areas of MOF application. The exploration of MOFs for drug delivery applications is rapidly advancing with this emerging porous material class anticipated to supplant conventional nanoporous materials in drug delivery and storage in forthcoming years. However, the dearth of comprehensive data regarding crucial aspects such as MOF stability in humid conditions, toxicological profiles, and level of biocompatibility might impede the integration of MOFs into medicinal practices. Initial investigations into the toxicological aspects of (MOFs) show promising results, suggesting their potential suitability for expanded trials in various medical applications. Moreover, significant advancements have been made by the MOF research community over the past decade, indicating a promising future for the field with emerging opportunities for MOF utilization. In the present research investigation, Cu-MOF-1 and Cu-MOF-2 were successfully synthesized via the solvothermal method and characterized utilizing various analytical techniques including BET, SEM, FTIR, and PXRD. The encapsulation and subsequent release kinetics of commonly employed drugs, namely montelukast sodium, were assessed through UV-VIS spectroscopy. Notably, for both ibuprofen and montelukast sodium, the 1:1 ratio of MOFs exhibited superior drug loading capacity compared to the 2:1 and 1:2 ratios. However, the release kinetics of drugs from different ratios were contingent upon several factors including the specific MOF utilized, the chemical nature of the drugs, and the ratio of MOF to drug.

Author Contributions

Conceptualization, C.W. resources, supervision, funding acquisition, data curation. H.Y.M.A., writing—original draft preparation, visualization, investigation, formal analysis, methodology. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

The data presented in this study are available in the article.

Conflicts of Interest

Author Chuang Wu was employed by Nantong Fuleda Vehicle Accessory Component Co., Ltd. and Jiangsu Tongshun Power Technology Co., Ltd.. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

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Figures and Table

Figure 1 BET analysis of Cu-MOF-1.

Figure 2 BET analysis of Cu-MOF-2.

Figure 3 SEM images of Cu-MOF-1 were taken at magnifications of (A) 20 µm, (B) 190 µm, (C) 20 µm, and (D) 100 µm. Additionally, SEM images of Cu-MOF-1 were captured at magnifications of 20 µm and 100 µm.

Figure 4 The FTIR spectra of benzene-1,4-dicarboxylic acid (BDC) are depicted by the blue-colored spectra in (a,b). Specifically, (a) corresponds to the FTIR spectra of Cu-MOF-1, while (b) corresponds to the FTIR spectra of Cu-MOF-2.

Figure 5 PXRD patterns were acquired for (a) Cu-MOF-1 and (b) Cu-MOF-2.

Figure 6 The percentage of montelukast sodium successfully loaded onto the MOFs.

Figure 7 (a) The percentage release of the drug from Cu-MOF-1 across various ratios, and (b) the percentage release of the drug from Cu-MOF-2 across different ratios.

Figure 8 Drug liberation from (a) Cu-MOF-1 and (b) Cu-MOF-2 respectively across various ratios.

Table 1

MOF loading effectiveness for montelukast sodium in percent (percent).

Sr. No.	MOFs	Ratios of MOF and Drugs	Percentage (%) Loading Effectiveness
1.	Cu-MOF-2	2:1	21.24%
2.	Cu-MOF-2	1:1	36.75%
3.	Cu-MOF-2	1:2	48.01%
4.	Cu-MOF-1	2:1	24.03%
5.	Cu-MOF-1	1:1	35.27%
6.	Cu-MOF-1	1:2	46.50%

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