A Review on Metal–Organic Frameworks as Technological Excipients: Synthesis, Characterization, Toxicity, and Application in Drug Delivery Systems

Abstract

Metal–organic frameworks (MOFs) are also known as porous coordination polymers. This kind of material is constructed with inorganic nodes (metal ions or clusters) with organic linkers and has emerged as a promising class of materials with several unique properties. Well-known applications of MOFs include their use as gas storage and in separation, catalysis, carbon dioxide capture, sensing, slender film gadgets, photodynamic therapy, malignancy biomarkers, treatment, and biomedical imaging. Over the past 15 years, an increasing amount of research has been directed to MOFs due to their advanced applications in fuel cells, supercapacitors, catalytic conversions, and drug delivery systems. Various synthesis methods have been proposed to achieve MOFs with nanometric size and increased surface area, controlled surface topology, and chemical activity for industrial use. In this context, the pharmaceutical industry has been watching the accelerated development of these materials with great attention. Thus, the objective of this work is to study the synthesis, characterization, and toxicity of MOFs as potential technological excipients for the development of drug carriers. This work highlights the use of MOFs not only as delivery systems (DDSs) but also in advanced diagnostics and therapies, such as photodynamic therapy and targeted delivery to tumors. Bibliometric analyses showed a growing interest in the topic, emphasizing its contemporary relevance.

1. Introduction

The technological development achieved in recent decades has allowed scientists to build materials that are even innovative and smart. Advances in the field of nanotechnology, in particular, have been and continue to be astonishing. Therefore, the biomedical sciences were abundantly rewarded [1]. Materials with a diverse range of applications were adapted, and they can now be used as platforms for modulated drug delivery [2]. Consequently, therapeutic compliance, drug efficiency, and safety improvements are positively influenced by the use of these materials.

Among the most promising of these materials, metal–organic frameworks (MOFs) stand out [3]. MOFs are hybrid, organic-inorganic materials that have promising properties for use as drug carriers, such as their bioavailability, biocompatibility, large surface area, high thermal stability, high capacity for the insertion of ionic species and small molecules, and the promotion of the modulated release of substances [3,4,5].

This class of materials consists of hybrid meso-, micro-, or ultraporous crystalline networks. They are formed by the coordination of organic linkers with metal ions or ion clusters (Figure 1), which allows for the tunability of the chemical composition and the arrangement of the components in space, providing materials with distinctive chemical behaviors and, therefore, comprising a series of different dimensions and topologies [6].

MOFs are therefore a subclass of coordination polymers, and because it is a polymeric matrix, it has a large pore network generating a large specific surface area. These spaces can be used for many purposes and will be covered throughout this work. This parameter is derived strictly from the chemical composition of the binders and may be chemically manipulated to obtain the desired characteristics of the materials [7]. Therefore, although porosity has been present in known materials for a long time, what makes MOFs peculiar is precisely how to control the synthetic conditions of organic chemistry and the geometric and compositional variation obtained with inorganic chemistry [8]. This structure becomes stable due to the coordinating interactions of Lewis acids and bases based on the donation of a pair of free electrons and reception by an atom with an empty orbital [9]. The large variety of MOF structures that use different organic linkers and metal ions (used as clusters) results in structures with different physicochemical properties and applicabilities, such as substance adsorption, substance exchange membrane [10,11], catalysis [12,13], separation and storage of gases and vapors [14], and drug delivery system (DDS) components [5,15,16,17,18].

The term MOF was first introduced in the scientific community in 1995 [19]. Seeking an alternative to microporous zeolites, the authors synthesized an organometallic network using benzene-1,3,5-tricarboxilic acid (BTC), cobalt nitrate (Co(NO₃)₂), and pyridine. Since 2009, the International Union of Pure and Applied Chemistry (IUPAC) has been developing a project for the harmonization of synthetic methods, terminologies, and nomenclatures in the field of coordination polymers. These authors generated a regulated system for naming and analyzing certain materials that later received the collaboration of the International Union of Crystallography. In 2014, this multinational research task force finally harmonized the concept of MOFs mentioned above, which is in line with the Commission on Metal–Organic Frameworks [9,20,21].

This adequacy of concepts and techniques is essential for the advancement of studies on MOFs given the applications of these materials in several emerging technological areas. For instance, Fang and coworkers [22] published a review on the utilization of MOFs as sensors. Due to their elevated surface area and pore size tunability, in addition to structural, chemical, and physical changes when receiving a guest molecule, MOFs present great potential in the monitoring of environmental contaminants. The same characteristics are responsible for the use of these coordination polymers in gas separation, contributing to the minimization of the greenhouse gas effect, toxic gas monitoring, and clean energy use [23]. Other studies have shown the applicability of these materials for catalysis in industrial processes [24]. For example, the reduction of alkynes to alkenes can be performed using NU-1000 (zirconium (Zr)-based) MOFs with more than 99% stereoselectivity [25,26].

An ideal MOF should have a high porosity and be thermally and chemically stable, in addition to having a sustainable production method. Thus, during synthesis, several factors must be considered, such as the cost and availability of the raw material, the synthesis conditions, processing procedures, high yield, high purity, and minimum use of toxic solvents. The synthesis parameters must be adjusted to control the size and shape of the crystal, such as the solvent, pH, metal cluster, concentration, and/or molar ratio of reagents [27,28]. Other factors, such as the reaction time, temperature, pressure, and heating source, can also influence the final structure obtained [29].

An example of the influence of the metal source on MOF structures is the difference in particle size when zinc nitrate and oxide are employed in the synthesis of MOF-5 (or IRMOF-1, an MOF composed of Zn₄O clusters and 1,4-benzo dicarboxylic acid as organic linkers) instead of zinc acetate. The crystal sizes obtained with the priors were greater than 100 μm, while those obtained with zinc acetate were less than 10 μm, with both presenting a cubic form [30]. Another study showed that the crystal size of MOF-5 was affected by temperature and sonication time, decreasing in size as the conditions increased [31].

The use of MOFs as adjuvants to DDSs has become more recent [32,33,34]. Pioneers in investigating the use of MOFs as drug carrier systems or DDSs, Férey and his collaborators used Materials of Institute Lavoisier (MIL), developed from trivalent metal centers and carboxylic acids as linkers, and this approach was highly promising due to its attractive features: large pores (25–34 Å), large surface areas (3100–5900 m²·g⁻¹), and the ability to incorporate functional groups into the structure through noncovalent interactions [8]. The authors synthesized two networks from 1,3,5-benzenetricarboxylic acid (BTC) and 1,4-dicarboxylic acid (BDC) as organic linkers and chromium(III) as the metal cluster (MIL-100 and MIL-101, respectively). Ibuprofen was the drug selected by the authors for use by the MOFs. The results showed that MIL-100 and MIL-101 could carry 0.35 g and 1.40 g of ibuprofen per gram of MOF, respectively, demonstrating that a small portion of material can be administered with a high dose of the drug. Furthermore, 3 and 6 days were needed for the material to release all the drugs from MIL-100 and MIL-101, respectively. Ultimately, the differences observed by the authors were attributed to the distinct structures and therefore surface areas of both materials [8].

In addition to the factors discussed above, toxicity must be considered when considering the biomedical applications of MOFs, especially when considering the choice of metal ions [35,36]. For this reason, the most commonly used clusters are composed of atoms of iron, zinc, and zirconium, while the most widely used organic ligands are those obtained or synthesized from natural compounds or endogenous ligands such as carboxylates, imidazolates, pyridyl, amines, and aspartate, aiming not to interfere with the physiological functions of the body or promote biocompatibility and relative safety in vivo [32,37].

In this context, this work aims to present and discuss important aspects of MOFs as pharmaceutical adjuvants, regarding the structure of these materials, their physical–chemical properties, toxicological compatibility, their applicability in drug delivery systems (DDS), and possibilities of using these materials in the healthcare industry.

The results showed the contemporary relevance of the topic, presenting innovative synthesis techniques, such as sustainable synthesis methodologies, and the use of functionalized and nanostructured MOFs to improve therapeutic efficiency and reduce adverse effects. Furthermore, MOFs have been highlighted not only as drug carriers but also in advanced diagnostics and therapies, such as photodynamic therapy and targeted delivery to tumors.

2. Synthesis and Characterization of MOFs

MOFs play an important role as drug carriers since these materials exhibit remarkable porosity, high loading capacity, and great thermal and chemical stability. In this context, biocompatible zinc-, iron-, and zircon-based MOFs have been widely employed as adjuvants for DDSs. Therefore, in this regard, several concepts related to the structure, synthesis, and characterization of several specific MOFs will be discussed, such as Zeolite Imidazolate Frameworks (ZIFs), Materials of Institute Lavoisier-100/101 (MIL-100/101), and Universitetet i Oslo-66 (UiO-66), due to their previously mentioned characteristics [38,39,40].

ZIFs are formed by transition metal clusters (Ms) (cobalt, copper, or zinc), which are tetrahedrally coordinated and connected by imidazolate (IM) linkers. The imidazolate bridges (M-IM-Ms) have an angle of approximately 145°, which is similar to the angle found in many natural zeolites (Si-O-Si).

ZIF-8 is a sodalite-type structure formed by zinc ions and 2-methylimidazole (Hmim or 2-MIM) that contains a micropore located in the center of the material with a diameter of 11.6 Å; this micropore may be accessed through small cavities with a diameter of 3.4 Å [41]. The classical methods for synthesizing ZIF-8 include solvothermal [41] or hydrothermal [42] procedures. In these methodologies, ZIF-8 may be synthesized by using a zinc source, such as zinc nitrate or Hmim; variable temperatures (from room temperature to reflux temperature); or organic solvents (for instance, N,N-dimethylformamide, N-methylpyrrolidine, methanol, ethanol, or isopropanol), or water [39]. For example, Cravillon and coworkers [43] synthesized ZIF-8 by using Zn(NO₃)₂∙9H₂O as the zinc source and methanol as the solvent at room temperature for one hour (Figure 2).

Furthermore, to overcome some of the limitations of these traditional methods, ZIF-8 particles (Figure 3) have also been prepared by sonochemical [44], continuous flow [45], and mechanochemical methods [46], which are more efficient and sustainable processes. Although one strategy may be more efficient than the other, choosing the most appropriate synthetic method should rely on the desired form, size, and properties of ZIF-8 [39].

The frameworks of MIL-100(Fe) and MIL-101(Fe) were obtained by combining [Fe₃O(X)(H₂O)₂] (where X = OH-, F- or Cl-) clusters with trimesate and terephthalate linkers, respectively. These combinations led to the formation of porous trivalent iron carboxylates, whose topology provided two kinds of cavities for each MOF with the following diameters: 25 and 29 Å for MIL-100 and 29 and 34 Å for MIL-101. These cavities may be accessed through specific windows; in other words, the smaller cage and the larger cage are accessible for two types of windows with diameters of 5.5 and 8.6 Å for MIL-100 and 12 and 14.5 Å for MIL-101 [40,47].

Although MIL-100/101 contains a variety of metals (Cr, Sc, V, Al, and Mn), the low toxicity and good biodegradability attributed to iron-based MOFs make these materials important for DDS applications [48]. Moreover, MIL-100(Fe) has high stability in water, making it an excellent candidate for biomedical applications and industrial processes [49]. Hydrothermal methods using hydrofluoric acid as a crystallizing agent are the most traditional procedures for synthesizing MIL-100/101(M) [50,51,52]. However, other alternative synthetic methods, such as HF-free procedures (Figure 4a) [53], microwave-assisted procedures [54], and solvent-free protocols [55], have been proposed for safer and more efficient syntheses.

The combination of cationic Zr₆O₄(OH)₄ nodes and terephthalate linkers leads to the formation of UiO-66, one of the most commonly used Zr-based MOFs. This material has a face-centered cubic framework with octahedral and tetrahedral cages measuring approximately 11 and 8 Å, respectively, that may be accessed through 6 Å windows. UiO-66 is able to withstand temperatures between 400 and 540 °C and has demonstrated stability even in boiling water, several solvents, and acidic/basic aqueous solutions [40,56].

Solvothermal treatment is the most common methodology for synthesizing UiO-66. Normally, UiO-66 is obtained by combining terephthalic acid with Zr₆O₄(OH)₄, which is generated in situ by hydrolysis of ZrCl₄ by using dimethylformamide (DMF) as a solvent (Figure 4b) [56]. Again, among the alternative synthetic methods, mechanochemical assembly [57] and microwave heating stand out [58,59].

Table 1. Common types of MOFs cited in this study, their synthesis methods, and encapsulated substances in these structures described in recent research.

MOF	Synthesis Method	Encapsulated Substance/ MOF-Based System	Ref.
ZIF-8	room-temperature aqueous synthesis	interleukin 2 (Il2)/ Il2/ZIF-8@salmonella	[60]
		celastrol (CEL)/ CEL@ZIF-8@PEG-BIO	[61]
		apatinib/ apatinib/Ce6@ZIF-8@cytomembrane (ACZ@M)	[62]
		thymosin beta 10 (TMSB10)/ TMSB10@ZIF-8	[63]
	electrochemical	dichlorophene (2, 2-methylenebis (4-chlorophenol), Dcp) /ZIF-8@PEDOT:PSS	[64]
	hydrothermal	shell–ligand exchange reaction (SLER)/ ZIF-8-SLER-PLs	[65]
MIL-101 (Fe)	solvothermal (S)/electrochemical (E)	curcumin@MIL-101(Fe)-NH2—(S)/ curcumin@MIL-101(Fe)-NH2—(E)	[66]
	hydrothermal	doxorubicin hydrochloride (DOX)/ DOX@MIL-101(Fe)@molecularly imprinting polymer	[67]
		methotrexate (MTX)/ MTX@MIL-101(Fe)	[68]
	solvothermal (polar solvent) + hydrothermal	5-fluorouracil (5-Fu)/ (5-Fu)-loaded gold nanorods@MIL-101(Fe)–NH2 @carboxylatopillar [5] arene	[69]
ZIF-90	dissolution (polar solvent)	resveratrol (Res)/ Res@ZIF-90	[70]
	hydrothermal	metronidazole (MI)/ MI@ZIF-90	[71]
	solvothermal	porcine pancreatic lipase (PPL)/ PPL@ZIF-90	[72]
		doxorubicin (Dox)/ (poly(lactic-co-glycolic acid)@ZIF-90)@PLGA	[73]

shows three common types of MOFs mentioned in this work (ZIF-8, MIL-101 (Fe), and ZIF-90), methods used to synthesize them, as well as active substances that have been encapsulated in these structures to produce the respective MOF-based delivery system.

After synthesis, several features of the MOFs must be analyzed to characterize and validate the structure of the synthesized materials. In this way, the techniques and characteristics commonly analyzed are Brunauer-Emmett-Teller surface area analysis (BET—N₂ sorption–desorption isotherms—textural properties such as pore volume and surface area); X-ray diffraction (XRD—crystallinity); field-emission scanning electron microscopy (FESEM—size and shape); transmission electron microscope images (TEM—size); Near Infrared Spectroscopy (NIR); nuclear magnetic resonance (NMR—structural characterization); Fourier transform infrared (FTIR—surface functional characteristics); stability tests in water or a phosphate-based solution (water stability); thermal gravimetric analyses (TGA—thermal stability); zeta potential (stability before and after drug loading); differential scanning calorimeter (DSC—thermal behavior before and after drug loading); high-performance liquid chromatography (HPLC—to investigate the loading capacity of the MOFs and drug release); and UV-vis spectroscopy (to measure the maximum absorption wavelength of the drug in order to determine its concentration by using HPLC) [74,75,76,77,78,79].

These techniques are also widely used to support the development of DDSs because they involve very complex coordination polymers. XRD analysis is an important tool for identifying the physical properties of these materials, as well as their phase purity. The crystallinity is reflected by a characteristic region called the fingerprint in the diffraction pattern. Due to the specificity of the fingerprint, crystallinity can be identified separately by the crystallinity of the carrier. The diffraction pattern is based on Bragg’s equation and is capable of determining the basal spacing between MOF dimensional lamellae; therefore, the diffraction pattern can be used as a determining parameter in the adsorption of materials [80,81,82,83].

The analysis of a diffractogram might corroborate the results of other analyses, such as particle size, surface area, pore size, and volume. For example, the Scherer formula can be used to measure the particle size of materials, an important parameter for determining the size scale of MOFs and monitoring their changes during the process of obtaining systems. They are also important characterization tools for drugs that have polymorphisms, aiming to investigate possible changes in metastable and stable forms of drugs in the DDS production chain [81,84].

BET analysis can also be used for these purposes. From the sorption and desorption of N₂ isotherms, it is possible to obtain reliable results for surface area, pore size, and volume; additionally, these results not only characterize the material but also indicate whether there was in fact adsorption of drugs in the polymeric network of the coordination polymer [81,83]. The analysis of the zeta potential is also important for determining the polydispersity index since MOFs have very low solubility in water and organic solvents, and a large part of DDS development occurs through the coprecipitation method [85].

Imaging techniques are also of paramount importance for the analysis of elementary composition, as well as for the visualization of important and definitive physical characteristics to confirm system formation. TEM, SEM, atomic force microscopy (AFM), FESEM, and NMR are examples of the most commonly used techniques for this purpose. NMR is also often used to identify host interactions and determine the linker-to-ligand ratio, providing important information for subsequent studies on drug release [80,82,85].

In vitro dissolution studies and dialysis assays were carried out to analyze the kinetics of drug release from the MOF. In this context, different dissolution media can be used to verify the behavior of this release at different pH values, an important factor to be evaluated in MOFs that usually have a pH-responsive profile [80,82,85,86,87].

Thermal analysis techniques, mainly TGA and DSC, can be used to investigate the thermal profile of the materials obtained and to confirm drug conjugation to the MOF network. Important information about crystallinity, the amorphous state, and the temperature related to the melting and degradation of materials are essential not only for investigating the stability of active pharmaceutical ingredients but also for conducting compatibility studies to investigate possible physical and chemical interactions with other excipients in a dosage form, which could perhaps prevent the development of a certain formulation [82,88]. These results can also be used to predict the stability of pharmaceutical products and should subsequently be validated with accelerated and long-term stability studies carried out with the finished pharmaceutical product [84,85,89].

Moreover, quantification methods can be validated to support drug-loading studies. In this context, equipment of greater sensitivity that is capable of developing and reproducing specific methods for the determination of drug loading efficiency (DEL) should be used. Among the most commonly used techniques, the following stand out: FTIR, NIR, UV-vis, HPLC, and elemental analysis [82]. The quantification of drugs adsorbed or trapped in the structure of MOFs is usually easily determined through the indirect method, whose determination is made after successive washes of the material obtained for the quantification of free drugs [57], $\%DEL={\displaystyle \frac{Ci-Cf}{Ci}}\times 100$, where C_i is the amount of drug added, and C_f is the amount of free drug.

Although there is no harmonization of which techniques are necessary for characterization, it is important that the researcher perform a detailed study and use as many assays as possible to provide clear and concise results on the physical and chemical parameters of the materials.

3. Toxicological Compatibility of MOFs for Biological Applications

MOF geometry, porosity, and pore size have led to the use of these materials as drug carrier adjuvants. However, the inorganic moiety of these hybrid molecules might have high toxicity, which makes their in vivo applications difficult. Therefore, knowledge about the safety of the materials used as a DDS is highly important [90].

Many authors use the concept of tolerable ingestion for nontoxic metals or for those that are already found in significant quantities in the body, such as calcium (Ca⁺²), copper (Cu⁺²), manganese (Mn⁺²), magnesium (Mg⁺²), zinc (Zn⁺²), iron (Fe⁺²), titanium (Ti⁺⁴), or zirconium (Zr⁺⁴). For instance, iron is an important component of hemoglobin. The estimated toxicity rates by oral lethal dose and 50% (LD50) of these elements are described in

Table 2. Oral lethal dose, 50% (LD50), of the most common metal clusters in MOFs [90,91].

Metal Ion	LD50 (g·kg−1)
Ca+2	1
Cu+2	0.25
Mn+2	1.5
Mg+2	8.1
Zn+2	0.35
Fe+2	30
Ti+4	25
Zr+4	4.1

[90,91].

Thus, DDSs should be formulated in a manner in which the systemic concentrations of these metals are kept below the limits [32]. The in vitro and in vivo toxic effects of iron-containing MOFs, for example, were investigated regarding acute and subacute exposure to highly elevated doses of iron (up to 220 mg·kg⁻¹). Three different MOFs containing iron carboxylates administered intravenously to rats showed no toxic effects [51,92].

The iron released by structural erosion is rapidly captured by the liver and spleen, where it is biodegraded and then excreted via renal or fecal pathways, with no harm to the body. Toxicological studies of MIL-101(Fe) and MIL-88(Fe) MOFs in rats have shown similar results, with no deleterious effects observed even after months of chronic exposure [51,92].

The toxic effects of zinc-containing MOFs have also been studied. Zinc is one of the main transition metals that controls the homeostasis of the central nervous system. However, it has a dose-dependent effect and is an important neuromodulator at low doses and a neuronal death-causing agent at elevated doses [7,93,94].

Kao and coworkers [95] demonstrated the endocytosis of zinc oxide molecules, which can enter neurons and dissociate at low pH, releasing zinc ions into the cytosol and contributing even more to the toxic effects of these materials. Thus, these potential zinc-based materials can be assumed to be able to be endocytosed, increasing zinc levels to deleterious concentrations.

This fact led Ren and coworkers [7] to evaluate the cytotoxic potential of zinc-based materials. The authors analyzed the toxic effect of the nanoscale isoreticular MOF (IRMOF) composed of zinc ions (IRMOF-3) on PC-12 cells—rat pheochromocytoma—which behave like neuronal cells when exposed to nervous growth factor (NGF). The study was performed with IRMOF-3 at concentrations of 25, 100, and 400 μg·mL⁻¹, and the toxicity was evaluated by the MTT cell viability assay. The results showed that the 25 μg·mL⁻¹ dose did not affect cell viability, while the 400 μg·mL⁻¹ dose strongly promoted toxicity, decreasing cell viability to 33.79% after 48 h of the experiment. The authors also observed cell wall damage after the administration of the 100 μg·mL⁻¹ dose, during which a small portion of the IRMOF-3 was internalized [7].

The same study compared the toxicity of zinc ions—the toxic products of IRMOF-3 after degradation—with that of the MOF itself. The authors found that the toxic effect of IRMOF-3 was mild compared to that caused by zinc ions alone. At 25 μg·mL⁻¹, IRMOF-3 presented normal cell differentiation compared with that of PC-12 cells. At 400 μg·mL⁻¹, drastic alterations were observed in the induction of differentiation in these cells. Zinc ions demonstrated significant toxicity toward PC-12 cells, considerably inhibiting their inductive potential to a greater extent than the corresponding IRMOF-3 dose. At doses of 100 and 400 μg·mL⁻¹, actin and tubulin filaments, which are responsible for the maintenance of the cell cytoskeleton, respectively, were still reduced, which in turn can cause a reduction in the number of cell contacts on the surface [7]. The authors suggested, therefore, that the use of this material cannot exceed 25 μg·mL⁻¹; hence, this concentration is enough to promote drug delivery.

Organic linkers can be categorized into two classes: exogen and endogen linkers. The most common linkers are exogens, which are molecules synthesized from natural compounds and are not found in the biochemical routes of the body. The exogen linkers used in MOFs for drug delivery include polycarboxylates, imidazolates, pyridil, and amides, among others. The toxicity data (provided from LD50) for a few of the organic linkers used were 5.0 g·kg⁻¹ (terephthalic acid), 8.4 g·kg⁻¹ (trimesic acid), 5.0 g·kg⁻¹ (2,6-napthalenedicarboxylic acid), 1.13 g·kg⁻¹ (1-methylimidazole), 1.4 g·kg⁻¹ (2-methylimidazole), 5.0 g·kg⁻¹ (isonicotinic acid), and 1.6 g·kg⁻¹ (5-aminoisophthalic acid), indicating that their toxicity is acceptable for bioapplication [32].

Another option is the use of endogen organic linkers, whose molecules are found in the body. These could be the more appropriate ligands used to construct MOFs for drug delivery systems during dosage form development. To date, many MOFs based on endogen linkers have been synthesized as built from amino acids [32] and 3D MOFs based on nucleobases [96]. Saccharide MOFs were not exploited extensively, but a symmetric oligosaccharide, g-cyclodextrine (g-CD), was employed as an organic linker [97].

Finally, it is important to discuss MOF stability, an essential characteristic in the development of drug delivery systems since toxicity evaluation of the material and its degradation products is needed. The degradable character of MOFs could facilitate drug release from the matrix, increasing their efficiency in vectorization or enhancing some physicochemical properties, such as aqueous solubility, although this performance is also influenced by host–guest interactions, pore size, and hydrophobic/hydrophilic properties [48].

Until now, little information has been collected about MOF stability in real body fluids, although under simulated physiological conditions, the stabilities of some MOFs, such as MIL-100(Cr), MIL-101(Cr), MIL-53(Cr), and ZIF-8(Zn), have been researched. MIL-100(Cr) has a 3D mesoporous system based on a trimeric metal (octahedrally coordinated) and 1,3,5-benzenetricarboxilic acid (BTC). Its degradation was greater after 3 days in simulated body fluid (SBF). MIL-101(Cr), obtained with the same trimeric metal but with 1,4-bicarboxylic acid (terephthalic acid), was degraded after 7 days in SBF at 37 °C [8]. ZIF-8 exhibited high hydrothermal stability and remained intact after 7 days in phosphate buffer solution (PBS) (pH 7.4) at 37 °C [98]. However, it is less stable in acetate buffer (pH 5.0, simulated fluid of tumor tissues), and rapid degradation was observed within a few minutes in this buffer. This can be explained by the protonation of the imidazolate anion, which occurs easily at acidic pH values, decreasing the complexation power of the linker for the metal ion [32]. Ultimately, it is clear that MOFs that contain iron and zinc as transition metals are more biocompatible than the other materials because they have low toxicity and, consequently, are the favorites when this material is expected to have therapeutic potential. Therefore, MOFs have been investigated further for their toxicity to the body.

4. Applications of MOFs as Drug Delivery Systems

The medicines used are mainly used in continuous oral dosage forms and, in turn, have two release mechanisms (conventional and modulatory). A modulated (modified or programmed) one provides a “controlled” release, promoting the delay or prolongation of the dissolution process [99]. This type of system has many advantages over conventional systems.

The development of drug delivery systems (DDSs) occurs due to the chemical interaction between the drug and the carrier. In terms of this interaction, examples of bonds between drugs and carriers include van der Waals forces, hydrogen bonds, π–π stacking bonds, ionic bonds, and even covalent bonds. Among these, the electrostatic bond between ionized drugs and ionized MOFs is of particular interest because drug release can be modulated through ion exchange [100,101].

Polymers act as carriers of drugs via different mechanisms, such as erosion, diffusion, and solvent activation; these events can occur simultaneously [102]. To date, several strategies, such as organic polymers and porous inorganic materials, have been studied for biological applications. However, its applications are limited by a lower load capacity or uncontrolled release. Therefore, the use of MOFs has emerged as one of the most promising strategies for developing DDSs [32]. One of the justifications for the rational development of a DDS is to obtain prolonged release. These interactions control delivery and drug release through MOFs.

In fact, Figure 5 shows the temporal evolution (2009–2023) of the number of scientific publications in the literature related to the descriptors “MOFs” and “drug delivery”. It is possible to note a significant increase in the number of works on the subject in the last 10 years. For information, the number of publications in 2024 (409 studies up to now) already exceeds that of the previous year, indicating that the area of research on MOFs as drug carriers remains on the rise, as an open field of research. The bibliometric research also revealed that the main fields of research working on the topic involve: chemistry; materials science; engineering; biochemistry, genetics, and molecular biology; and pharmacology, toxicology, and pharmaceutics.

4.1. MOFs Used for Prolonged Release

Although it is not possible to standardize what is a prolonged or extended release, it is expected that (1) there is a release of 20–30% of the labeled content of the drug in up to 2 h (preventing the immediate release and the burst effect of conventional releases); (2) then, the release must reach a constant dissolution pattern until 50% of the labeled content is dissolved; and (3) the target of at least 80% of the content dissolved in less than 24 h must be achieved.

Organometallic compound structures are classified as flexible or rigid. Rigid materials have permanent porosity and robust porous structures similar to those of porous inorganic materials. Flexible materials have dynamic porosities and respond to external factors, such as guest molecules, temperature, pressure, and pH. Such structural flexibility is sometimes defined as a breathing phenomenon. This phenomenon generates real exit gates for the adsorbed substances, mainly in acidic media. ZIF-8, for example, dissociates from the coordination network at pH values between 5.0 and 6.0, which can promote “breathing” and vectorized release of the drug in environments at this pH [98,103,104].

Therefore, ZIF-8 is one of the most common MOFs used in the development of DDSs. The pioneers of using ZIF-8 as a pH-sensitive drug delivery system were Sun and coworkers [98]. The authors impregnated 5-fluouracil (5-FU) onto ZIF-8 and performed release studies in PBS (pH 7.4) and acetate buffer (pH 5.0). They found that at pH 7.4 (in PBS), approximately 50% of the loaded drug was released at the early stage, followed by a more stable release of a smaller dosage for 7 days. However, when evaluating the release in an acidic medium (acetate buffer pH 5.0), more than 45% of the loaded drug was released within one hour of the experiment, whereas only 17% was released in PBS at the same time interval. After 12 h of the experiment, a plateau was achieved, with 85% of the loaded drug released.

Several authors have followed this trend and used the pH sensitivity property of ZIF-8 to meet their needs. Liédana and coworkers [5] developed a system based on caffeine and ZIF-8 (CAF@ZIF-8), which presented controlled release for 27 days. Doxorubicin (DOX) was successfully incorporated into ZIF-8, and its release rate was greater at acidic pH values than at other pH values [105,106]. Additionally, a system with DOX and ZIF-8 was developed, and greater release of the drug at acidic pH and greater cytotoxic activity were observed.

A system based on curcumin and ZIF-8 was investigated in 2017, and the results showed that at pH 5.0, the percentage release of curcumin was three times greater than that at pH 7.4 [107]. Liang and coworkers [108] also worked with DOX and ZIF-8 using biocompatible bovine serum albumin (BSA) in the preparation of nanoparticles (DOX/BSA). The developed BSA/DOX@ZIF system demonstrated DOX pH-sensitive release and cytotoxic activity on a breast cancer cell line, an interesting finding given that cancer cells have a more acidic pH; therefore, this system can be used to target drug release and reduce potential side effects of conventional chemotherapy, including the low selectivity of these drugs.

Recently, a system formed by ZIF-8 and arsenic trioxide (As) (As@ZIF-8) was studied, and the results demonstrated that more As was released at acidic pH, which could have cytotoxic effects on cell lines with atypical rhabdoid tumors [109]. In the studies previously mentioned, the authors found that the use of ZIF-8 as a nanocarrier allows for the slow release of each substance; however, a greater release at acidic pH, which is considered ideal for evaluating pharmacological activity, was obtained.

In the same year, Sava Gallis and coworkers [110] investigated a system with ceftazidime and ZIF-8 (ceftazidime@ZIF-8), in which a slow release of ceftazidime was observed, with an effect on Gram-negative bacteria. Another study developed a system with antibacterial action using vancomycin and ZIF-8. Interestingly, in this work, a controlled release of vancomycin was achieved, reaching a concentration of 77% after 48 h at pH 5.4 [111].

Cheng and coworkers [112] evaluated a nanocomposite formed from Fe₃O₄-ZIF-8 capable of promoting the release of doxorubicin (DOX), a cytotoxic agent used as an anticancer agent. The system promoted the slow and sustained release of DOX and was found to have a better cytotoxic effect on the hepatocellular carcinoma cell line. In addition to ZIF-8, other MOFs also have the ability to control the release of drugs eventually incorporated. Thus, we will present these processes and describe the procedures for preparing these systems.

In this context, a system composed of two anticancer drugs (doxorubicin and 5-fluouracil) and composed of NMOF (ZIF-90) was studied [113]. ZIF-90 was added to a methanolic solution of doxorubicin (DOX), and the mixture was agitated for 48 h. At the end of the agitation step, the mixture was centrifuged and washed, yielding ZIF-90-DOX. The obtained material was added to PBS containing 5-fluoruracil (5-FU), and at the end of the procedure, a mixture of the three components (5-FU@ZIF-90-DOX) was obtained. The drug release profiles were assessed in PBS at two different pH values (7.4 and 5.5). The samples (DOX, 5-FU, and 5-FU@ZIF-90-DOX) were dispersed in dissolution media and agitated at 100 rpm and 37 °C. Aliquots were collected at predefined time intervals and analyzed via UV-vis spectrophotometry at 481 and 262 nm for DOX and 5-FU, respectively.

At pH 7.4, almost 90% of the 5-FU was released after 7 h of treatment when the drug was evaluated alone. However, when evaluating 5-FU@ZIF-90-DOX, approximately 25% of the 5-FU was rapidly released in the first 3 h. Afterward, the release profile became much slower, with 44% of the 5-FU released after 25 h of the experiment. In turn, 95% of the DOX was released after 4 h of treatment when the drug was evaluated alone, and 20% was released after 20 h when 5-FU@ZIF-90-DOX was evaluated. The release profile was also assessed at pH 5.5 since the drugs target tumor tissues. After 15 h, approximately 95% of the 5-FU was released from 5-FU@ZIF-90-DOX. It took 25 h for 91% of the DOX to be released from the matrix. Considering the results obtained, the authors stated that ZIF-90 can transport drugs toward cancer cells with very little loss of drug during the process and release them around the cells, showing that in addition to the pH-controlled release, MOFs can also target cancer cells.

Another study involving ZIF-90 and DOX was developed to obtain additional information regarding the use of this MOF in therapeutic systems for the treatment of cancer involving the addition of the Y1 linker to the surface of the DOX@ZIF-90 system, which is useful for identifying breast cancer cells [114].

The researchers synthesized DOX@ZIF-90 by a self-assembly process using 2-imidazolecarboxyaldehyde (2-ICA) in dimethyl sulfoxide (DMSO) solution and zinc acetate (Zn(CH₃COO)₂) in dimethylformamide (DMF) solution. Both solutions were mixed and agitated for 30 min. The solid obtained was washed three times with ethanol and then dried under vacuum for 24 h. After this procedure, the AP linker was incorporated into the surface of DOX@ZIF-90 through a Mannich reaction, yielding the final system AP-DOX@ZIF-90. The in vitro release profiles were assessed using a dialysis sack. A total of 1 milliliter of AP-DOX@ZIF-90 (10 mg/mL in PBS) was added to a dialysis mixture containing 49 mL of PBS in an oscillating incubator at 100 rpm and 37 °C containing the same dissolution media as the sack. Aliquots were collected at predefined time intervals, and the drugs were quantified via UV-vis spectrophotometry.

The results showed that only 1.7% of the DOX was released from AP-DOX@ZIF-90 within 2 h at pH 7.4, a value smaller than that expected considering the data survey performed by the researchers. After the same pH was reached but ATP was added to the release media (0.5 mM final concentration), the release increased, reaching 19.8%. In an acidic medium (pH 5.0 and pH 5.0 with 0.5 mM ATP), DOX release from AP-DOX@ZIF-90 was faster, reaching approximately 21.7% and 70.2% within 2 h in PBS and PBS with ATP, respectively. The increase in drug release in a medium containing 0.5 mM ATP is justified by the fact that ATP is coordinated more strongly to zinc ions than to imidazole itself, as the MOF is destabilized, resulting in DOX release. As discussed before, the authors concluded that the release profile of the system based on ZIF-90 protects against DOX release at physiological pH but promotes its rapid release in the tumoral microenvironment or in tumor cells at lower pH. They also concluded that this release would be greater in cell structures with high ATP levels.

Materials from the Institute Lavoisier (MILs) family were also exploited as drug carriers. Férey’s group was the first to demonstrate the ability of MIL-100(Fe) and MIL-101(Cr) frameworks to carry a drug, with ibuprofen being the chosen drug for developing a system based on aspirin (ASA) and MIL-100(Fe) [115,116]. MIL-100 was obtained from a solution of iron, trimesic acid, hydrofluoric acid, nitric acid, and water. The system was characterized by XRD, SEM, UV-vis, NMR, TGA, and TOF-MS. Aspirin was added to the MIL-100 nanomaterial at a ratio of 1 mg of MOF:200 µL of ASA solution. The data obtained showed a high loading efficiency (181%), which was attributed to the π–π stacking interactions between aromatic rings (aspirin and trimesic acid linker). In summary, the work demonstrated good loading efficiency, and approximately 14 days were required for the drug to be released in phosphate-buffered saline at 37 °C.

More recently, the potential of MIL-101(Fe) for loading and sustained release of curcumin (CCM) by different pH stimuli was investigated. This MOF promotes pH-sensitive release with a high drug-loading content (56.3%) and sustained drug release over 22 days [117]. Moreover, microporous MIL-53(Fe) and mesoporous MIL-101 are flexible materials that have been used as matrices for adsorption and in vitro drug delivery. Specifically, regarding MIL-53(Fe), the results demonstrated that the amount of each drug that was incorporated within the microporous channels was slowly controlled by diffusion [118].

A system based on nanoparticles of Fe₃O₄@MIL-100(Fe) composites (prepared by a one-pot in situ crystallization technique) was also the target of these studies. These composites were loaded with DOX. The system was characterized by XRD, TEM, FESEM, TGA, and zeta potential analysis. The results proved that the system was successful and that the loading rate was 19%. The authors showed that the drug release patterns of all the composites were well controlled and sustained for more than 20 days without premature release of DOX [119].

UiO-66(Zr) is also a type of MOF used in the development of DDSs. Zhu and coworkers [120] developed a system based on alendronate (AL) and UiO-66 nanoparticles (NPs). The system was characterized by XRD, FTIR, SEM, and TEM, and the release profile was assessed from the dialysis bag. The data demonstrated that 88.1% of the AL was released from UiO-66 after 108 h at pH 7.4, while at pH 5.5, the amount of AL released was less than 76% within the same period of time.

4.2. Solubility Increase

The low aqueous solubility of these drugs is one of the main problems in the development of dosage forms. This is because most of the molecules of interest are part of class II or III of the biopharmaceutical classification system (BCS) [81]. In addition, the appropriate dosage must promote a favorable environment to prevent saturation followed by precipitation of the drug, which will have a negative impact on bioavailability.

Although solubility is an intrinsic characteristic, dissolution rates can change. Dissolution is associated with the formation of a dynamic equilibrium composed of a diffuse layer that controls the amount of drug that is dissolved and absorbed by the mucosa of the gastrointestinal tract when the drug is taken orally, for example. The rate of dissolution of a drug can be represented by the Noyes–Whitney equation [81], ${\displaystyle \frac{dm}{dt}}=kA(C_s-C)$, where the dm/dt ratio represents the dissolution rate, k is the dissolution rate constant, A is the surface area of the dissolving solid, C_S is the solubility of the drug, and C is the concentration of the drug in the dissolution medium at time t.

This equation shows that it is possible to increase the dissolution rate of a drug and consequently increase its concentration in the diffuse layer. This can be achieved by increasing the surface area (A), reducing the particle size, or bonding the particles to the surface of porous materials.

Thus, instead of synthesizing new entities and promoting chemical substitution to increase the aqueous solubility of the pharmaceutical ingredient, it is possible to use a series of techniques using pharmaceutical technology to overcome these barriers. Among the options, we can highlight the following: micronization, soluble salt use, cocrystallization, incorporation into polymers, nanoencapsulation, and, with the development of MOFs, a new approach appears to enhance the aqueous solubility of these molecules [101].

Given the high surface area of MOFs, drugs are dispersed within their structure, pores, and surface, drastically reducing their particle size and increasing their surface area. Then, they can act as drug carriers, inhibiting crystallization once the drug molecules are confined within the MOF nanometric pores. In addition, MOFs suffer rapid hydrolytic decomposition in simulated gastric medium and in PBS, leading to the immediate release of the drug in its amorphous state (Figure 6).

Suresh and Matzeger [121] used MOF-5 to increase the solubilities of curcumin (CUR), sulindac (SUL), and trimethylenone (TAT). The drugs were incorporated into MOF-5 after synthesis, which reached 7.7% (w/w) drug loading for CUR, 22.4% (w/w) for SUL, and 34.0% (w/w) for TAT. The immediate release of CUR molecules from CUR@MOF-5 through MOF hydrolytic decomposition leads to rapid dissolution, which generates a high supersaturation rate within the first 60 min, releasing almost all the drug within 4 h. SUL@MOF-5 also immediately releases the drug (SUL), yielding high supersaturation in the first 60 min of dissolution, with a maximum concentration of 50.7 mg/mL.

As the dissolution test proceeds, the SUL concentration slowly decreases due to SUL precipitation once the acid and medium pH are decreased by the decomposition of MOF-5. The immediate release of TAT from TAT@MOF-5 occurred within the first 20 min when the maximum concentration reached 55.5 mg/mL, after which the release decreased slightly as the concentration became constant until 4 h of the experiment.

These three systems developed with MOF-5 presented greater dissolution than the isolated drugs, rapidly promoting supersaturation of the dissolution medium. In biological terms, this rapid dissolution of the drug into its amorphous form facilitates the absorption process, allowing the initiation of therapeutic activity.

In this sense, a MOF composed of γ-CD and potassium hydroxide (CD-MOF) proved to be an interesting system for increasing the solubility of drugs. He and coworkers [122] used CD-MOF as a vehicle to increase the solubility and bioavailability of azilsartan (AZL). This MOF was synthesized using γ-CD and potassium hydroxide dissolved in a mixture of water and methanol. The mean size of the MOF crystals ranged between 300 and 500 nm. AZL was incorporated into CD-MOF under magnetic stirring in an ethanolic solution for 24 h. The precipitates were collected by centrifugation and dried under vacuum, yielding AZL/CD-MOF.

A solubility study of the AZL/CD-MOF system was performed in different dissolution media (pH 1.2, hydrochloric acid; pH 4.5, acetate buffer; pH 6.8, phosphate buffer; and distilled water). Samples of isolated AZL, AZL/CD-MOF, and the inclusion complex γ-CD and AZL in excess were dispersed in 5 mL of dissolution medium, subjected to mechanical agitation at 25 °C for 72 h, filtered, and analyzed via high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD).

Interesting results of increased solubility have also been demonstrated in vivo. In addition to the solubility study, a pharmacokinetic study was also performed in which male Sprague-Dawley rats were divided into three groups of six rats each; the groups were orally administered AZL, AZL/CD-MOF, or the inclusion complex γ-CD and AZL at a dose of 1 mg/kg. Blood samples were collected at predefined time intervals and analyzed via HPLC-MS/MS.

Cyclodextrin (CD) inclusion complexes are already widely used as alternatives to increase the solubility of drugs, and the results demonstrated that the inclusion complex γ-CD:AZL promoted an increase in AZL solubility by 9.4 times. However, the AZL/CD-MOF system demonstrated an even better result, in which the AZL solubility was 340 times greater than that of the AZL bulk form. While less than 10% of the AZL was released within 60 min from the bulk form in all dissolution media, the AZL dissolution rate from AZL/CD-MOF reached 90% within 3 min in phosphate buffer and distilled water and 45% within 60 min in acetate buffer. Therefore, the bioavailability of AZL from AZL/CD-MOF was 9.7 times greater than that of isolated AZL and 1.5 times greater than that of γ-CD:AZL. Thus, this work showed that the system developed using a MOF composed of γ-CD and sodium hydroxide was able to increase the solubility, resulting in an increase in the dissolution rate and bioavailability of AZL. Remarkably, the preparation of multicomponent systems by using γ-CD as a component of MOF synthesis is very interesting since cyclodextrins are already used to increase the solubility of drugs with low water solubility.

Zhang and coworkers [79] studied a CD-MOF as an alternative to increase the solubility of valsartan (VAL). The drug was incorporated into CD-MOF in an ethanolic solution under magnetic stirring (400 rpm) for 30 min at 40 °C. VAL@CD-MOF and VAL@γ-CD (inclusion complex) were subjected to an investigation of apparent solubility, where both DDSs were dispersed in a supersaturated aqueous solution and kept under agitation at 25 °C for 3 days. Furthermore, an in vitro dissolution study was executed using hard gelatinous capsules containing VAL alone, VAL@CD-MOF, and VAL@γ-CD. The capsules were placed in dissolution media (pH 1.2 hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water) and kept at 37 °C. An aliquot of 5 mL was collected in predefined periods and subjected to drug quantification by UV spectroscopy (λ = 250 nm).

A pharmacokinetic study was performed on beagle dogs previously treated with commercial VAL (Diovan^®), VAL@CD-MOF, or VAL@ γ-CD at a dose of 80 mg. Blood samples were collected at predefined time intervals ranging from 0 to 24 h, and the drug concentration was quantified via high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). At pH 6.8, all the samples were able to release all the VAL within 2 h, with VAL@CD-MOF and VAL@ γ-CD having smaller T(max) values. With water as the dissolution medium, VAL@CD-MOF and VAL@ γ-CD released 100% of the VAL within 2 h, whereas isolated VAL released less than 20% of the VAL within the same time interval. At pH 4.5, VAL released from the raw material reached approximately 40% within 2 h, whereas VAL@CD-MOF and VAL@ γ-CD released almost 100% of its VAL content. The worst result was observed for the VAL raw materials at pH 1.2, where less than 5% of the drug was dissolved within a 2 h interval. The VAL@CD-MOF and VAL@ γ-CD systems also exhibited less dissolution than the other pH groups, for which dissolution rates were approximately 80%.

Although the dissolution rates of VAL@CD-MOF and VAL@γ-CD are very similar, a pharmacokinetic study showed that the bioavailability of VAL was greater when VAL was transported by CD-MOF at a concentration of 10.38 μg·mL⁻¹·h⁻¹, whereas the bioavailability of VAL@γ-CD was 7.14 μg·mL⁻¹·h⁻¹, while that of the commercially available Diovan^® was 5.52 μg·mL⁻¹·h⁻¹.

Thus, the study concluded that VAL@CD-MOF and VAL@γ-CD have very similar dissolution rates, but VAL bioavailability is optimized when VAL is released from a system based on a MOF (CD-MOF). This study draws attention to the observation that systems with very similar dissolution rates may exhibit different performances in vivo, affecting the bioavailability of the drug.

Gordon and coworkers [118] synthesized MIL-53(Fe) by using ferric chloride hexahydrate and 1,4-benzenedicarboxylic acid in 25 mL of DMF. This mixture was subjected to ultrasonic irradiation, after which the obtained product was centrifuged and dried. Before drug incorporation, the following activation steps were needed: (1) remove the DMF, starting by heating it at 150 °C for 24 h in an oven and then cooling it down; (2) put the obtained powder into deionized water and stir the mixture; and (3) remove the water from the pores by heating at 150 °C for 24 h.

In the same study, MIL-101 was hydrothermally synthesized from a mixture of anhydrous chromium nitrate, 1,4-benzenedicarboxylic acid, hydrofluoric acid, and water. Once the MOFs were ready, the stavudine and acetaminophen drugs were incorporated into the mixture through the humidity impregnation method, where the concentrated solution of each of the drugs was added to the MOF powder used to make the system mixed with a spatula until it was dry. The mixture was subsequently placed in a vacuum oven at 70 °C for 24 h.

In vitro release from the obtained systems was performed. The samples were placed in PBS and subjected to agitation (100 rpm) in a water bath at 37 °C. Aliquots were collected at predefined time intervals and filtered, and the amount of drug released into the medium was quantified through UV spectrophotometry. It was possible to observe that for all the systems obtained with MIL-101 and MIL-53, there were two phases of release: the first was a burst effect, where the majority of the loaded drug was released, and in the second phase, the drug was gradually released. Within 30 min, all the systems released approximately 90% of the drug that was loaded into the system. These two phases can be explained as follows: In the first phase, the release of the molecules that were adsorbed on the MOF surface occurred, and therefore, the MOF had a weaker bond. In the second phase, the molecules with stronger bonds to the MOF are released, which are the molecules that are incorporated into the pores and cavities of the material.

4.3. NanoMOFs

When MOF structures are reduced to the nanoscale (nMOFs), they promise to be an even more powerful method of drug delivery and controlled release due to their similarity to biological structures. In addition to all the improvements in the characteristics inherent to MOFs (such as a high surface area and the presence of pores and cavities in diverse dimensions and topologies), these materials might be functionalized for a diverse range of biomedical applications (therapeutic, diagnostic, and theranostic), such as chemo–photothermal therapy, imaging, and DDS development [100,123,124].

Although several aspects of MOF synthesis have been discussed previously, in this topic, we will present important details regarding the reaction conditions used to synthesize nMOFs.

Studies have been carried out to determine the design of these materials that meet the strict requirements of biological systems, such as metal and organic linker biocompatibility, nMOF stability in the biological environment, and modulated release of the drug into the target. One of the pioneering works on the synthesis and characterization of a nanoscale MOF was reported by Cravillon and coworkers, who synthesized nanozeolitic imidazolate framework-8 (nZIF-8) in a simple way compared with carboxylate-based nMOF synthesis, which was accomplished in previous works [43]. These nZIF-8 materials are formed by the binding of bivalent zinc ions to the Hmim linker in a 1:2 stoichiometric ratio. Moreover, the control of the input variables favors the achievement of several different crystal sizes. Some of these parameters are described below.

The simple synthetic procedure did not require any activation method or auxiliary stabilizing agents to furnish well-modeled nZIF-8 as stable colloidal dispersions or powders. In this methodology, a methanolic solution of Zn(NO₃)₂∙6H₂O at room temperature was added to a methanolic solution of Hmim. In contrast to the results of previous works, 2-methylimidazole was added in excess of the zinc source to obtain large microcrystals, and the ratio that led to the best results was 1:8:700 [Zn(NO₃)₂∙6H₂O:Hmim:methanol]. The process of crystal formation occurs in three phases: nucleation, crystal growth, and the stationary phase. A mean particle diameter of 46 nm was estimated from the XRD patterns, and secondary electronic micrographs revealed that the product obtained consisted of isometric nanoparticles with sharp edges and a narrow size distribution [125].

Similarly, Nune and coworkers [126] reported the synthesis of a selective nZIF-8 by using the stabilizer poly(diallyldimethylammonium), which plays a critical role in its morphology, leaving it hexagonal in shape with a mean diameter of 57 ± 7 nm and a thickness of 42 nm. In addition, through XRD analysis, it was possible to determine its crystalline structure with an identical topology to its microscale counterpart. It was also verified that the material possesses thermal stability up to approximately 400–500 °C (where the decomposition of the organic linker occurs and above this temperature, inorganic decomposition also occurs), 1264 m²·g⁻¹ for surface area, and pore size and volume of 5–20 Å and 0.51 cm³·g⁻¹, respectively. The pore size and volume results were similar to those presented by Soltani and coworkers [127] and Schejn and coworkers [128], but the particle diameter was approximately 200 nm.

The synthesis of nZIF-8 may occur by employing different temperatures, solvents, and additives, which contribute individually to obtaining structures with different dimensions. From a synthesis in methanol, by changing the temperature from −15 °C to 60 °C, it was found that the mean size of the nanoparticles decreased from 78 nm to 26 nm, with a consequent increase in the external area of the nanoparticles from 220 m²·g⁻¹ to 336 m²·g⁻¹. nZIF-8 can also be obtained from different zinc sources, such as Zn(acac)₂, Zn(NO₃)₂, ZnSO₄, or Zn(ClO₄)₂, yielding particles with diverse sizes ranging from 85 to 1160 nm [125,128].

The nZIF-8 is pH sensitive (it decomposes under acidic conditions and stays integers under alkaline conditions); an interesting characteristic for drug delivery is that once the pH is acidic, the drug can be released rapidly, whereas, at alkaline pH, it can prolong release. It shows excellent biocompatibility due to the low toxicity of zinc ions, as indicated by a study reporting a cell viability above 80% for nZIF-8 at concentrations less than 30 µg/mL in foreskin fibroblasts from Caucasian human fetuses (HFFF-2) and an effective maximal concentration (EC50) of 52.7 µg/mL. Another study showed cell viability above 70% for nZIF-8 at concentrations less than 50 µg·mL⁻¹ in a human epithelial carcinoma cell line (HeLa) with an EC50 of 63.8 µg·mL⁻¹, indicating that nZIF-8 may be used as a safe drug nanocarrier [127,129,130].

Many studies have shown the ability of nZIF-8 to serve as a hydrophilic and hydrophobic drug nanocarrier with high drug loading capacity. Among the drugs encapsulated in nZIF-8 were 5-fluoruracil (DLE = 68%), curcumin (DLE = 88.2%), and antibiotics such as ciprofloxacin (DLE = 21%) and gentamicin (DLE = 19%). In addition to these abovementioned methods, Tian and coworkers (2017) encapsulated fluorescein into nZIF-8 functionalized with graphene oxide (GO), which exhibited pH-controlled release due to the decomposition of nZIF-8; this process is sensitive to the photothermal effect of near-infrared radiation (λ = 808 nm), which aims to effectively kill cancer cells generated by OG [124,127,129,131].

A zirconium nMOF, UiO-66 (NH₂), was synthesized under the surface of an upward-converting nanoparticle (UCPN) for drug delivery, which was mediated through pH variation. The obtained structures had a particle size of approximately 170 ± 10 nm, a large surface area of 932 m²·g⁻¹ after conjugation with folic acid to target the system, and low cytotoxicity in the MDA-MB-468 and NIH3T3 cell lines (for which the cell viability was greater than 80%) [123].

Some MILs, such as MIL-100 (built from a hydrophilic aromatic linker, trimester), have been adapted for nanoscale synthesis, and the material obtained presented very low in vivo acute toxicity after intravenous administration to female Winstar rats (200 mg·kg⁻¹ dose), no cytotoxicity toward human leukemia and multiple myeloma cell lines, and high drug loading capacity; additionally, MIL-100 is being evaluated for its ability to act as a contrast agent for imaging exams [100].

Studies have been performed conjugating nMOFs with antineoplastic drugs such as doxorubicin (UiO-66), cisplatin (UiO), and camptothecin (nZIF-8). The obtained DDS showed a high DLE, improved aqueous solubility, reduced cytotoxicity, and, in a few cases, targeted drug delivery. These results are very stimulating because they can improve the quality of life of cancer patients, decreasing the toxic effects caused by antineoplastic drugs, which is a great problem in cancer therapy [123,132,133].

The biomedical use of nMOFs based on Fe²⁺, Zn²⁺, and Zr⁴⁺ as metal clusters has been promoted due to the low toxicity and biodegradability of these materials, whereas other nMOFs based on chrome, nickel, and cobalt are not usually indicated for this purpose because of their toxicity [100,134]. These materials may have structural particularities depending on factors such as the method of synthesis (hydrothermal, solvothermal, electrochemical, ionothermal, microwave-assisted, or sonochemical), organic linker and inorganic sources, solvent type, temperature, drying method, and functionalizing additives [135,136].

Lakshmi and Kim [135] reported the coordination and self-assembly of metals and organic linkers, where diverse kinds of bonds, such as electrostatic interactions, hydrogen bonding, metal coordination, and π–π stacking, may be found in nMOF crystals. It allows a wide variety of applications because of its characteristic advantages, attracting researchers from different areas.

5. Possibilities for MOF Applications in the Healthcare Industry

As porous coordination polymers, MOFs have emerged as promising materials with several unique properties and are becoming a target for the health products industry [137,138]. The biomedical applications of MOFs have mainly focused on the development of drug delivery systems, followed by use in photodynamic/radiotherapies, and medical imaging technologies.

A search of patent databases such as Espacenet, the WIPO Patentscope, and Lens revealed some patents filed in recent years that reported the research and development of MOFs related to the health industry (including the treatment or diagnosis of some prevalent diseases). Several types of MOFs have been explored for healthcare applications. However, some of them are more commonly reported than others. One reason for this difference is the low cost of starting reagents for synthesizing frameworks such as ZIF-8, NU-1000, MIL-100, and PCN-224 [139].

Some patents introduced inventions with ZIF-8 for either chemotherapy or diagnosis of cancer, as well as for cytotoxic agents [140,141,142]. The DDS formed by the loading of rhodamine 6G in ZIF-8, called R6G@ZIF-8, was patented by Chia-Kuang and coworkers [140]. Rhodamine (HR) is fluorescent, and dyes of this class are commonly used in biotechnological applications, such as fluorescence microscopy, flow cytometry, fluorescence correlation spectroscopy, and ELISA [143,144].

Another patented application containing ZIF-8 as a drug carrier is described in the patent filed by He and coworkers [141]. This invention involves the preparation of a photothermal and pH-sensitive therapeutic probe in which the substance IR-780 can be directly incorporated into the ZIF-8 framework. The invention has broad prospects for application in the treatment and diagnosis of cancer, as it is a nanobiomedical material. IR-780 is a good diagnostic material due to its strong absorption at wavelengths in the near-infrared region, and it is also a good anticancer agent due to its affinity for several tumor tissues.

Other areas, such as the development of therapeutic alternatives for neglected tropical diseases, have also attracted the attention of researchers. Ferraz and collaborators [115] developed a novel BNZ@ZIF-8-based DDS aimed at modulated release and potential antichagasic vectorization. In the filed patent [145], the researchers obtained in vitro pH-sensitive drug delivery data, demonstrating the efficiency of ZIF-8 as an intelligent carrier that is capable of generating safer products by increasing the aqueous solubility of the drug. An investigation of these findings via in vivo assays may support obtaining a drug capable of maintaining tolerable levels of BNZ within a therapeutic window, which may increase its bioavailability, reduce the incidence of adverse effects, and in turn increase the therapeutic success and compliance of the antichagasic drug.

The same research group also showed the applicability of ZIF-8 as an adjuvant capable of increasing the stability of active pharmaceutical ingredients [146] filed at the National Institute of Industrial Property (INPI—Brazil). Rolim-Neto and collaborators reported the thermal protection afforded by carbamazepine, a drug used to treat epilepsy and neuropathic pain. Through different analytical techniques, mainly thermal analysis, researchers were able to corroborate the formation of a system capable of delaying the degradation of the isolated molecule, contributing to an increase in thermal stability, an important characteristic considered in pharmaceutical industrial operations involving temperatures, such as granulation and drying processes.

The molecules of natural products were also used to develop systems with ZIF-8, as in the case of ellagic acid, patented by Wang and coworkers [147]. In addition to ZIF-8, other zeolite materials, such as ZIF-67 and HKUST-1, were mentioned in this same patent for assessing cytotoxic activity via the MTT test for the mouse JAWSII cell line. For all the developed systems, cell growth inhibition percentages greater than 85% were observed.

MOFs are expected as potential materials for the next generation of cancer therapeutics. The patent filed by Fairen-Jimenez and coworkers [148] refers to MOF-based compositions for the delivery of interfering RNA (RNAi) molecules with the aim of causing the mutation of cancerous genes. The mentioned patent refers to the use of NU-1000 (based on Zr⁺⁶) with RNAi, which can be short interfering RNA (siRNA), microRNA (miRNA), or an endosome release factor and is a peptide capable of facilitating the cellular penetration of MOFs. The invention allows RNAi molecules to be delivered to cells so that these molecules can interact directly with their target after being released into the cytosol [148].

Similarly, observing the perspective of drug delivery in MOFs for anticancer treatment, the patent filed by Wang and coworkers [147] sought to address the solubility problem. The results showed that both lipophilic and hydrophilic drugs were present in the same structure, with hydrophilic drugs being carried within MIL-100(Fe) and hydrophobic drugs being carried within the lipid bilayer of the DOPC liposome. DOPC liposomes carry paclitaxel, and MIL-100 carries gemcitabine, both of which are chemotherapeutic drugs, such that the combined effect of these two molecules is achieved, bypassing the impossibility of delivering them in the same therapeutic system [147].

Following the patent analysis of MOFs with anticancer effects, the patent filed by Nie and coworkers [149] refers to nanoparticles of MOF–manganese dioxide with a core–shell structure. The interior (core) is composed of PCN-224, an MOF based on zirconium, and the exterior (shell) is coated with manganese dioxide. This material has been described as being able to recognize tumor tissues and remain in them, facilitating drug delivery [149].

Some MOFs are currently used in photodynamic therapy (PDT) for the treatment of some cancers and in nonneoplastic dermatoses, as is the case for alterations related to photoaging [141]. The PDT can be considered a special form of photochemotherapy that involves the use of a photosensitizer, light, and oxygen. The layer of manganese dioxide that covers the surface of the MOF particle mentioned above can catalyze the decomposition of hydrogen peroxide present in cells to generate the oxygen needed for PDT, which consequently causes the death of tumor cells [149].

6. Conclusions

Over the past two decades, the wide range of applications of MOFs (gas storage, separation, catalysis, CO₂ capture, drug delivery, sensing, slender film devices, photodynamic therapy, malignancy biomarkers, treatment, and biomedical imaging) has encouraged the development of new synthetic methodologies to obtain MOF and MOF systems with different shapes, sizes, and functionalities. Moreover, the features of these materials are characterized by using many analytical techniques, such as BET analysis, XRD, FESEM, TEM, NIR, NMR, FTIR, UV-vis, TGA, DSC, and zeta potential.

In the field of pharmaceutical science, the use of MOFs as a novel class of drug carrier has been extensively explored, and consequently, many of these materials have emerged as potential adjuvants for DDSs, mainly biocompatible zinc- (ZIF-8), iron- (MIL), and zircon-based (UiO) MOFs. Among the most commonly used MOFs, ZIF-8 is widely encountered in many papers and patents, demonstrating its potential for the development of new pharmaceutical products.