Advancing Drug Delivery with Metal-Organic Frameworks: Challenges, Synthesis and Application

With the rapid progress in materials science, considerable attention has been focused on the development of advanced nanoplatforms for the controlled and intelligent release of drugs, aiming to enhance therapeutic efficacy while minimizing unwanted side effects.^[1] Metal- Organic Frameworks (MOFs) have emerged as a promising class of hybrid materials, which are made up of metal ions or metal clusters bonded with organic linkers to form highly porous crystalline networks.^[2] Since their inception in 1989 by Hoskins and Robson, MOFs have attracted a great deal of interest because of their molecular-level tunability, ultrahigh porosity, and modular design^.[3] The Cambridge Structural Database currently has over 20,000 MOF structures, demonstrating the field's rapid expansion and the materials' promise for a range of uses, including drug delivery.^[4] MOFs are perfect for biomedical applications because of their special physicochemical characteristics, which include large surface area, tunable pore size, adjustable morphology, and the capacity to alter their hydrophilicity or hydrophobicity. In addition to medication delivery, MOFs have shown promise in a number of other areas, including gas storage, separations, imaging, catalysis, sensing, and energy storage^.[5] However, MOFs are especially promising for biomedical applications, where drug delivery has seen the quickest progress in recent years, due to their customisable porosity, functionalizability, and structural plasticity^.[6]

This review aims to explore the transformative potential of MOFs in DDSs, emphasizing their design, synthesis, characterization, and practical applications in disease treatment. As MOFs continue to evolve, their integration with emerging technologies, such as microrobotics and personalized medicine, promises to revolutionize the field of drug delivery, paving the way for next-generation therapeutic strategies.  In figure 2 data indicates the growing interest and research output related to Metal-Organic Frameworks (MOFs) over the years, as reflected in the number of publications or mentions. The significant increase from 2010 to 2025 showcases the rising importance of MOFs in various fields such as catalysis, gas storage, drug delivery, and more.

Metal-Organic Frameworks (MOFs) have gained significant attention in drug delivery systems (DDS) due to their tunable structures, biocompatibility, and biodegradability.^[15] The classification of MOFs for DDS is primarily based on the metal ions used in their synthesis, as these metals influence the framework's stability, drug loading capacity, and release profile. Refer figure 3. Below are some of the commonly studied MOFs based on their metal ions:

Classification by Metal Ions

Cr-MOFs (Chromium-based Metal-Organic Frameworks)

Chromium-based MOFs, such as MIL-100(Cr) and MIL-101(Cr), are constructed using chromium (III) ions coordinated with organic carboxylate linkers like 1,3,5- benzenetricarboxylic acid (BTC) and 1,4-benzenedicarboxylic acid (BDC).^[16] The frameworks feature octahedral metal clusters linked by these organic ligands, resulting in highly porous structures.^[17] The high surface area and porosity of these MOFs make them suitable for applications like drug delivery, where their ability to encapsulate large quantities of drugs is particularly beneficial. ^[12] For instance, MIL-101(Cr) has demonstrated a drug-loading capacity of up to 1.4 grams of ibuprofen (IBU) per gram of MOF. This property makes them ideal for delivering hydrophobic drugs in a controlled manner, potentially enhancing therapeutic effects while minimizing side effects. ^[7] Aside from drug delivery, Cr-MOFs have also been explored for gas storage, catalysis, and water treatment, benefiting from their large surface area and versatility.[15] However, the potential toxicity of chromium, especially in its hexavalent form (Cr(VI)), poses a significant limitation to their use in biomedical applications.[18] While Cr(III) is less toxic, concerns remain About the potential release of chromium ions from the MOF during degradation, which could be harmful to health.[19] This highlights the need for further research on the safety, biodegradability, and biocompatibility of Cr-based MOFs in living systems. Alternative materials or modifications may be necessary to address these toxicity concerns for broader biomedical.

Iron-based Metal-Organic Frameworks (Fe-MOFs), such as MIL-53(Fe), are highly versatile materials synthesized by coordinating Fe(III) ions with organic carboxylate ligands like terephthalic acid. ^[20] One of the key features of Fe-MOFs is their unique structural flexibility, which allows these frameworks to undergo reversible changes in response to external stimuli, such as temperature and pressure. ^[21] This flexibility makes Fe-MOFs ideal candidates for various applications in drug delivery, especially in environments where responsive behavior is crucial. ^[5]

Fe-MOFs have been shown to successfully load and deliver a variety of drugs, including anticancer agents like oridonin and retroviral drugs, owing to their high surface area and tunable pore structures. ^[7] Their ability to encapsulate drugs is enhanced by the presence of open metal sites, which facilitate the adsorption of therapeutic molecules. ^[22] This characteristic is particularly useful in controlled drug release applications, where the release profile can be tailored according to the needs of specific drugs or disease sites.

In addition to their use in drug delivery, Fe-MOFs also possess significant potential in medical imaging, particularly in magnetic resonance imaging (MRI). This is due to the paramagnetic properties of Fe(III) ions, which can enhance the contrast in MRI scans ^[23]. This makes Fe-MOFs valuable not only as drug carriers but also as diagnostic tools in medical applications, especially for monitoring the distribution and release of drugs in vivo. ^[24] One of the most promising aspects of Fe-MOFs in drug delivery is their biodegradability and low toxicity. ^[25] These properties make them particularly suitable for biomedical applications, where the long-term accumulation of materials in the body could pose risks. Fe-MOFs are designed to degrade safely, which minimizes the chances of harmful side effects. ^[26] Moreover, they are able to respond to the acidic microenvironment of tumors, a characteristic that is highly advantageous in cancer therapies. The pH-responsive release mechanism allows for more targeted drug delivery, ensuring that the drug is released predominantly at the tumor site, where the environment is more acidic than in normal tissues. ^[27] The combination of these beneficial properties—flexibility, high drug loading capacity, potential for MRI applications, biodegradability, and pH-responsive release—makes Fe-MOFs an attractive option for use in drug delivery systems (DDS). ^[7] Their ability to deliver drugs in a controlled, targeted manner, especially in anticancer treatments, has been the focus of extensive research, with promising results in preclinical and clinical settings. ^[28] Given their biocompatibility and relatively low toxicity, Fe-MOFs are expected to play a significant role in the development of more effective and safer drug delivery systems in the future. ^[7]

Zinc-based MOFs (Zn-MOFs)

Zinc-based Metal-Organic Frameworks (Zn-MOFs), including structures like ZIF-8 and Zn- BDP_X, are composed of Zn(II) ions coordinated with organic ligands such as imidazolate or pyrazolate. These frameworks are highly stable in aqueous environments, which makes them particularly valuable for biomedical applications, especially for drug delivery systems. The inherent stability and tunability of Zn-MOFs allow for the efficient encapsulation and controlled release of therapeutic agents. ^[7] Zn-MOFs have demonstrated significant success in delivering a range of anticancer drugs, including mitoxantrone, 5-fluorouracil (5-FU), and curcumin. ^[29] This success can be attributed to their ability to encapsulate both hydrophilic and hydrophobic drugs, overcoming the typical limitations faced by conventional drug delivery systems. Hydrophobic drugs, which are often challenging to deliver, benefit from the ability of Zn-MOFs to improve their solubility, thus enhancing bioavailability. ^[30]

In addition to their drug encapsulation capabilities, Zn-MOFs exhibit pH-responsive release behavior, which makes them ideal for targeted drug delivery to acidic environments such as tumors.[31] The release of the drug can be triggered under acidic conditions, facilitating the precise delivery of the therapeutic agent to the tumor site, thereby reducing the systemic side effects typically associated with chemotherapy. ^[32] The stability, biodegradability, and targeted drug delivery potential of Zn-MOFs make them promising candidates for advanced cancer therapies. Their ability to encapsulate a wide range of drugs, improve solubility, and provide pH-responsive release properties positions them as highly effective carriers in the field of drug delivery systems^[31]. With ongoing research into their applications, Zn-MOFs hold significant promise in improving the efficacy and safety of drug treatments, particularly for cancer therapy.^[33]

Zirconium-based MOFs (Zr-MOFs)

Zirconium-based Metal-Organic Frameworks (Zr-MOFs), such as UiO-66, are synthesized using Zr(IV) ions that coordinate with carboxylate ligands, which contribute to their exceptional stability.^[34] These frameworks are renowned for their ability to withstand harsh environmental conditions, including high temperatures and acidic environments, making them highly suitable for challenging biomedical applications.^[35] The robustness of Zr-MOFs is one of their key advantages, particularly in drug delivery systems that require durability under physiological conditions.^[22] Zr-MOFs, including UiO-66, have shown great potential in drug delivery, especially in co- delivery systems where multiple drugs can be delivered simultaneously.^[36] This ability to deliver diverse therapeutic agents allows for more comprehensive treatment strategies, such as combination therapies for cancer. For instance, UiO-66 has been utilized to deliver anticancer drugs like 5-fluorouracil (5-FU) and dichloroacetate, demonstrating controlled release profiles.^[37] This capability is especially important for improving the efficacy of cancer treatments, as controlled release minimizes side effects and enhances therapeutic outcomes.^[28] Another significant advantage of Zr-MOFs is their versatility in drug loading. These frameworks can load both hydrophilic and hydrophobic drugs, which expands their applicability to a broad range of drug types^.[5] This makes them particularly useful in targeted cancer therapies, where long-term drug release and precise targeting of tumor cells are crucial.[^38] The ability to tailor the release profiles of drugs through the structural properties of Zr-MOFs further enhances their suitability for therapeutic applications.^[5] Moreover, the low toxicity, excellent stability, and biodegradability of Zr-MOFs make them strong candidates for therapeutic and diagnostic applications.^[39] Their properties enable them to be used not only for delivering cancer drugs but also for potential imaging and diagnostic purposes, where stability and biocompatibility are paramount. As research on Zr-MOFs continues to advance, their role in drug delivery systems, especially for cancer therapy, is expected to expand, offering promising outcomes for improved patient care.^[40]

Cyclodextrin-based MOFs (CD-MOFs)

Cyclodextrin-based Metal-Organic Frameworks (CD-MOFs) are a subclass of potassium- based MOFs in which potassium ions are coordinated with cyclodextrin (CD) linkers.^[41]These frameworks are particularly valued for their water solubility and biodegradability. CD-MOFs are highly effective for the delivery of poorly soluble drugs, such as azilsartan and lansoprazole, because the cyclodextrin units enhance the solubility of hydrophobic drugs. ^[42] This makes CD-MOFs ideal candidates for facilitating drug delivery through various routes, including oral, intravenous, and pulmonary administration.^[7] In addition to improving solubility, CD-MOFs are also beneficial in providing sustained drug release, allowing for the maintenance of therapeutic drug levels over extended periods.^[43] This property is especially useful for oral drug delivery, where enhancing the bioavailability of drugs is critical. The non-toxic, biodegradable, and water-soluble nature of CD-MOFs further contributes to their suitability for clinical applications, particularly in drug delivery systems that aim to improve the therapeutic outcomes of poorly soluble drugs.^[7] Their ability to enhance drug solubility and release profiles positions CD-MOFs as promising materials for improving the efficacy and safety of drug therapies.^[44]

Copper-based MOFs (Cu-MOFs)

Copper-based Metal-Organic Frameworks (Cu-MOFs) are an important subclass of MOFs that utilize copper ions as metal centers, typically coordinated with organic carboxylate ligands like benzene-1,4-dicarboxylic acid (BDC).^[45] These frameworks can also incorporate functionalized organic linkers to further enhance their drug-loading capabilities. The high surface areas and uncoordinated metal sites in Cu-MOFs allow for efficient drug adsorption and controlled release, making them highly effective for drug delivery applications. Cu-MOFs have been shown to successfully load a variety of therapeutic agents, including anti- inflammatory drugs like ibuprofen (IBU), anticancer agents such as doxorubicin, and other pharmaceutical compounds. The ability to control the release of these drugs makes Cu-MOFs particularly useful in addressing chronic conditions, where sustained drug delivery is crucial for therapeutic success. In addition to their use in cancer therapies, Cu-MOFs are valuable in antibacterial drug delivery. Their strong binding to drug molecules, coupled with the flexibility to release drugs in a controlled manner, makes them ideal for antibacterial treatments. Cu-MOFs are also being explored in dual-drug delivery systems, where two therapeutic agents can be delivered simultaneously, offering synergistic effects for more effective treatment outcomes. ^[7] Due to their stability, versatility in loading different drug types, and efficient drug release mechanisms, Cu-MOFs are proving to be highly promising candidates for a broad range of therapeutic applications, including both antibacterial and anticancer treatments. These features position Cu-MOFs as potential game-changers in the development of more effective and targeted drug delivery systems.^[46]

Synthesis Of MOFS

The synthesis of Metal-Organic Frameworks (MOFs) can be carried out using several methods, each offering distinct advantages for controlling the properties and functionality of the resulting structures.^[47] Refer Figure 4. The following are some commonly used methods for synthesizing MOFs, along with detailed explanations:

Hydrothermal/ solvothermal synthesis

The hydrothermal or solvothermal synthesis method is one of the most widely employed approaches for the preparation of MOFs due to its versatility and effectiveness. In this technique, metal precursors and organic ligands are dissolved in a solvent or a mixture of solvents. Common solvents include water, alcohols, or other organic solvents like DMF (dimethylformamide) or DEF (diethylformamide).^[48] The prepared solution is then transferred to a sealed reaction vessel, typically an autoclave, where it is subjected to high temperatures and pressures for a specified duration. These elevated conditions facilitate the formation and crystallization of MOF structures, driven by the slow reaction kinetics and stable environment provided by the autoclave.^[49] The solvent used in this process plays a dual role. It not only dissolves the reactants but also contributes to stabilizing the coordination between metal ions and organic linkers during the crystallization process.^[50] Adjusting the temperature, pressure, reaction time, and choice of solvent allows researchers to control critical aspects of the MOF, such as its porosity, particle size, and morphology. For example, variations in temperature can influence the nucleation and growth rate of crystals, which in turn affects their size and uniformity. Similarly, the choice of solvent can dictate the solubility of the precursors and the resulting framework structure.^[51] The hydrothermal/solvothermal method is particularly advantageous for producing highly crystalline MOFs with well-defined structures and tunable properties. By carefully optimizing the reaction parameters, it is possible to synthesize MOFs with specific pore sizes, surface areas, and functionalities tailored for various applications, such as gas storage, catalysis, or drug delivery ^[51]. Moreover, this method is relatively straightforward and does not require highly specialized equipment, making it accessible for both laboratory and industrial-scale production^.[52]

A notable example of this method is the synthesis of UiO-66, a zirconium-based MOF known for its exceptional stability and porosity. UiO-66 is typically prepared using zirconium chloride or zirconium oxynitrate as the metal source and terephthalic acid as the organic linker in a solvent mixture of DMF and water^.[53] The reaction is conducted at elevated temperatures (120– 200°C) for several hours, resulting in a highly crystalline product. Similarly, MIL-101, an iron or chromium-based MOF, is synthesized using hydrothermal or solvothermal conditions, often employing water or DMF as the solvent. The temperature and solvent conditions can be varied to produce MIL-101 with different particle sizes and morphologies, depending on the intended application.^[54]

The solvent-assisted ligand exchange (SALE) method is a post-synthetic modification approach used to tailor the properties of pre-synthesized MOFs. In this process, an existing MOF is exposed to a solution containing a new ligand that can partially or completely replace the original ligand(s) coordinated to the metal nodes.^[55] This exchange occurs under mild conditions, making it possible to modify the functionality of the MOF without compromising its structural integrity. SALE is particularly valuable for enhancing the performance of MOFs by improving their stability, catalytic activity, pore structure, or selectivity toward specific guest molecules.^[56] The mechanism of SALE typically involves the new ligand diffusing into the MOF's pores, where it competes with the existing ligand for coordination with the metal centers.^[57] The success and extent of ligand exchange depend on several factors, including the affinity of the new ligand for the metal center, the structural flexibility of the MOF, the solvent used, and the reaction time. For instance, solvents that solubilize the new ligand effectively while promoting ligand mobility within the MOF framework are essential for efficient exchange.^[58] SALE has been widely applied to modify MOFs like MIL-101, a chromium-based framework. By exchanging its original terephthalate or trimesate linkers with ligands containing functional groups such as amines, sulfonates, or phosphonates, researchers have enhanced MIL-101's stability under acidic or basic conditions. Additionally, SALE has been used to fine-tune the pore size and chemical environment of MIL-101 to improve its capacity for gas storage, drug delivery, or catalysis. For example, replacing some of the original ligands with functionalized ones has resulted in MIL-101 variants with improved guest-host interactions, thereby increasing their adsorption capacity and selectivity for specific molecules. This method is not limited to MIL-101; SALE has also been employed with other MOFs, including those based on zirconium, iron, and copper, to introduce functionalities such as hydrophobicity, chirality, or catalytic activity. By retaining the MOF’s core structure while selectively modifying its properties, SALE has emerged as a versatile and practical approach to expand the application scope of MOFs in various fields, including environmental remediation, drug delivery, and heterogeneous catalysis. ^[59]

Mechanochemical synthesis

Mechanochemical synthesis is an efficient and environmentally friendly method for producing MOFs. This technique involves solid-state reactions where mechanical force—such as grinding or milling—is applied to mixtures of metal salts and organic ligands without the use of solvents. The mechanical energy facilitates bond breaking and formation, leading to the creation of MOF structures. Unlike conventional solution-based methods, mechanochemical synthesis eliminates solvent use, reducing waste and making the process more sustainable. This feature makes it particularly attractive for green chemistry applications.^[60] The mechanochemical process can be performed using various devices, such as ball mills, pestles, or automated grinders. When subjected to mechanical stress, the reactants undergo localized heating and pressure, which initiate the reaction between the metal and ligand. This technique is especially beneficial for synthesizing MOFs that are sensitive to solvents or moisture, as the absence of a solvent minimizes potential degradation of the framework during synthesis.^[61] A notable example is the synthesis of Cu-MOFs, such as Cu-BTC (also known as HKUST-1). Using a mechanochemical approach, copper salts and trimesic acid (BTC) are mixed and ground together, resulting in the formation of the desired framework without the need for high temperatures or solvents. This method not only simplifies the synthesis process but also improves efficiency by eliminating solvent-related steps like drying and purification.^[62] Additionally, the energy consumption of mechanochemical synthesis is relatively low compared to solvothermal methods, further enhancing its appeal for large-scale MOF production. Beyond Cu-MOFs, the mechanochemical approach has been successfully applied to a wide range of MOFs, including those based on zinc, aluminum, and zirconium. It allows for the rapid and scalable production of MOFs while maintaining control over particle size and morphology^.[63] Recent advances in mechanochemical synthesis have even enabled the incorporation of functional additives or dopants during grinding, allowing for the customization of MOF properties for specific applications, such as catalysis, gas storage, or drug delivery^.[58] This versatility and sustainability position mechanochemical synthesis as a pivotal method in modern MOF research and production.

Electrochemical synthesis

Electrochemical synthesis is a method that uses an electric current to drive the formation of MOFs. In this approach, metal ions are generated via anodic dissolution from a metal electrode and subsequently coordinated with organic ligands in the reaction medium to form the MOF framework. This technique is particularly advantageous for producing MOFs with controlled structures, crystal sizes, and morphologies, as the application of the electric current can precisely regulate the reaction kinetics and crystal growth rates.^[47] During the process, the electrochemical reaction generates a continuous supply of metal ions, which react with the organic ligands dissolved in the electrolyte solution. The method allows for high yields and often eliminates the need for additional metal salts, making it more sustainable and cost-effective compared to traditional chemical routes. Electrochemical synthesis is particularly suitable for large-scale MOF production due to its straightforward setup and the ability to fine-tune synthesis parameters like current density, voltage, and reaction time. An example of this method is the synthesis of copper-based MOFs, such as HKUST-1 (Cu- BTC). In this case, copper is electrochemically dissolved from a copper anode in the presence of trimesic acid (BTC) ligands in a solvent system. The copper ions released from the electrode react with the ligands to form the MOF framework. The process is often conducted at room temperature, making it energy-efficient while allowing precise control over the crystal morphology and size. ^[58] This method has also been employed to synthesize other MOFs, including MIL-53, MIL-100, and ZIF-8, by using different metal electrodes (such as aluminum or zinc) and organic linkers. Electrochemical synthesis has shown promise for producing high-quality MOFs with desirable properties for applications in gas storage, catalysis, and drug delivery.^[63] Moreover, the ability to fabricate MOFs directly on conductive substrates through this method opens avenues for developing MOF-based devices, such as sensors and electrodes for energy storage.

Direct synthesis (one-pot synthesis)

Direct synthesis, also known as one-pot synthesis, is a straightforward approach for preparing MOFs by mixing metal salts and organic ligands in a single step. This process typically involves dissolving the reactants in an appropriate solvent under ambient or slightly elevated conditions to enable the formation of the MOF framework47. The simplicity of this method makes it highly attractive, as it does not require multiple stages or the isolation of intermediates, thereby reducing the overall time and complexity involved in the synthesis.^[64] One of the key benefits of direct synthesis is its efficiency in yielding MOFs with minimal preparation steps. However, achieving high crystallinity and purity can be a challenge, as the conditions may not always favor the controlled growth of the MOF crystals. Compared to more controlled methods such as solvothermal or hydrothermal synthesis, the crystals produced via direct synthesis might exhibit lower uniformity in terms of size and structure. Optimizing reaction parameters like temperature, concentration, solvent type, and pH can improve these outcomes.^[58] A notable example of MOF synthesis using this method is ZIF-8, a zinc-based imidazolate framework. In this approach, zinc nitrate or zinc acetate (as the metal source) is mixed with 2- methylimidazole in a solvent such as methanol or water. The reaction leads to the rapid precipitation of ZIF-8 crystals, which can then be collected, washed, and dried. The method has been widely adopted due to its ease of use and scalability, making it suitable for industrial and research applications.^[65] Direct synthesis is not limited to ZIF-8 and has been employed for a variety of MOFs, including MIL-53 and HKUST-1, under appropriately chosen reaction conditions. It is particularly suitable for applications requiring high-throughput production or when the focus is on feasibility rather than achieving the highest-quality crystalline frameworks.^[58]

Microwave-assisted synthesis

Microwave-assisted synthesis leverages microwave radiation to rapidly heat the reactants in a controlled manner, significantly accelerating the synthesis process of MOFs compared to conventional solvothermal methods^.[66] In this technique, the reaction mixture—typically comprising metal precursors and organic linkers dissolved in a solvent—is subjected to microwave irradiation, which provides uniform and efficient heating. This localized heating effect enhances reaction kinetics, leading to faster crystallization, reduced reaction times (sometimes within minutes), and improved energy efficiency. One of the significant advantages of microwave-assisted synthesis is the potential to achieve high yields of MOFs with desirable properties, such as better crystallinity, uniform particle size, and tunable morphology. The ability to precisely control reaction conditions (e.g., temperature and time) makes this method particularly useful for synthesizing temperature- sensitive MOFs or frameworks that require specific heat profiles to form. It also opens pathways to "green" chemistry, as this technique often eliminates the need for prolonged heating and large solvent volumes, reducing environmental impact.^[58]  An example of a MOF synthesized via this method is MIL-53(Fe), where microwave irradiation at optimized temperatures and durations results in well-crystallized particles with narrow size distributions. Similarly, ZIF-8 has been efficiently synthesized using this approach, demonstrating high yields and exceptional structural properties within short reaction times. These examples highlight the utility of microwave-assisted synthesis for biomedical and industrial applications, where time efficiency and scalability are critical.^[58] This approach is increasingly being adopted to prepare MOFs for applications ranging from drug delivery to catalysis, as the rapid and uniform heating ensures the reproducibility and scalability of the synthesis process.

Liquid-liquid diffusion method

The liquid-liquid diffusion method is a straightforward and efficient technique for synthesizing metal-organic frameworks (MOFs) in a two-phase liquid system. In this method, two immiscible liquids—one containing a metal precursor and the other containing an organic ligand—are brought into contact. The components diffuse across the liquid-liquid interface, initiating the crystallization of the MOF at this boundary. This process is driven by the gradual interaction and reaction of the metal ions with the organic linkers as diffusion progresses^.[47] One of the key advantages of this method is the precise control over the diffusion rates of the reactants, which allows for the fine-tuning of crystal size, morphology, and uniformity. This is particularly useful for synthesizing MOFs with well-defined properties for specific applications. Additionally, because the reaction occurs at the interface, it minimizes the use of excess reactants and solvents, making the method relatively eco-friendly. The liquid-liquid diffusion method has been successfully used to synthesize MOFs such as Cu- BTC (copper-based MOF, also known as HKUST-1) and Co-MOFs (cobalt-based MOFs). For instance, in the synthesis of Cu-BTC, copper salts are dissolved in an aqueous phase while benzene-1,3,5-tricarboxylic acid (BTC) is dissolved in an organic solvent such as ethanol or acetone. When the two solutions are layered or placed in contact, the slow diffusion of BTC into the aqueous layer containing copper ions facilitates the nucleation and growth of MOF crystals at the interface. ^[58] This method is particularly valued for applications where control over particle size and morphology is critical, such as in drug delivery systems, catalysis, or gas adsorption. By optimizing parameters like diffusion rates, solvent selection, and reaction time, researchers can tailor the properties of the resulting MOFs to meet specific functional requirements.

Seed-assisted synthesis

Seed-assisted synthesis is a powerful method used in the preparation of metal-organic frameworks (MOFs), where pre-synthesized MOF crystals, known as "seeds," are introduced into a reaction mixture containing the necessary precursors—metal salts and organic linkers. These seeds serve as nucleation centers, facilitating the orderly growth of new MOF structures on their surfaces. This technique is particularly advantageous for achieving precise control over the morphology, size, and crystallinity of the resulting MOFs.^[47]

One of the primary benefits of seed-assisted synthesis is its ability to produce MOF crystals with a uniform size and shape, which can be challenging with other methods. By adjusting factors such as the quantity of seeds, the composition of the reaction mixture, and the reaction time, researchers can fine-tune the crystal growth process to obtain large and well-defined MOF structures ^[47]. This method is especially useful for growing large single crystals, which are often required for detailed structural analysis or specific applications like catalysis, separation, and sensing. For example, in the synthesis of ZIF-8, a zinc-based zeolitic imidazolate framework, small seed crystals are prepared initially and added to a fresh reaction solution containing zinc nitrate and 2-methylimidazole. The seeds act as templates, promoting the uniform deposition of additional layers of the MOF structure^.[67] This approach enhances the scalability and reproducibility of ZIF-8 production, making it suitable for industrial applications. Seed-assisted synthesis is also utilized for creating hierarchical MOFs, where a secondary MOF grows around or on top of the seed crystals, leading to composite structures with enhanced functionality. This is particularly valuable in applications like drug delivery, where the outer MOF layer can provide controlled release properties, while the inner seed core offers structural stability or additional active sites for interaction with therapeutic molecules^.[68] These methods offer a variety of options for synthesizing MOFs with different properties, including size, porosity, and functionality. The choice of synthesis method depends on factors such as the desired application, the metal and ligand used, and the required properties of the final product. Each method has its own advantages and challenges, and in some cases, combinations of these techniques may be used to optimize the MOF structure for specific uses.

Drug Loading

Drug loading in metal-organic frameworks (MOFs) involves incorporating therapeutic agents into the porous structure of MOFs for drug delivery applications. The process leverages the high surface area, tunable pore sizes, and chemical functionality of MOFs. Drug loading methods can be categorized into two primary approaches: incorporation during synthesis and post-synthetic drug loading^.[5]

Drug Loading During MOF Synthesis

Drug loading during MOF synthesis involves incorporating drug molecules into the reaction mixture containing metal precursors and organic ligands. As the MOF crystallizes, the drug molecules become encapsulated within the framework. This method is advantageous because it typically results in high drug-loading capacity and allows for a uniform distribution of the drug throughout the MOF structure. The inclusion of drugs in the synthesis stage also helps to stabilize the drug molecules, as they become trapped within the stable, porous structure of the MOF.^[63] However, this method does have some limitations. The harsh conditions required for MOF synthesis, such as high temperatures and the use of organic solvents, can potentially degrade sensitive drugs, limiting the types of drugs that can be incorporated during the synthesis process. Despite this, it remains a highly effective approach for creating drug-loaded MOFs for various therapeutic applications. For example, anticancer drugs like doxorubicin (DOX) have been successfully co-crystallized with MOFs during synthesis, resulting in drug-loaded nanoparticles with controlled release profiles suitable for targeted cancer therapy^.[69]

Post-Synthetic Drug Loading

This approach involves first synthesizing the MOF, followed by introducing the drug into its pores via diffusion or adsorption. Refer figure 5. There are several variations:

Incubation/Immersion

In the incubation or immersion method of post-synthetic drug loading, the MOF is immersed in a solution of the drug, allowing the drug molecules to diffuse into the framework’s pores. This technique is relatively simple and does not require altering the MOF’s synthesis process, making it versatile for various drugs. The drug loading occurs as the drug molecules enter the pores by diffusion, where they become adsorbed or trapped within the structure. For instance, MOF-74 has been used for loading ibuprofen (IBU) by immersing it in an ethanol solution of the drug.^[70]

However, one limitation of this method is the potentially long diffusion times required to achieve high loading efficiency, particularly for larger or more complex drug molecules. The time needed can depend on the porosity and surface area of the MOF, as well as the solubility of the drug in the solvent. As a result, it may be challenging to achieve high drug loading in a short period. Despite this limitation, incubation and immersion remain valuable methods for loading drugs into pre-synthesized MOFs, particularly when post-synthesis modification is desired.^[5]

In vacuum loading, the MOF is first subjected to a vacuum to remove air from its pores, creating a higher affinity for drug molecules. Once the pores are evacuated, the MOF is exposed to a drug solution, and the vacuum aids in the penetration of the drug molecules into the framework. The reduced pressure enhances the diffusion of drug molecules into the MOF's pores, ensuring that the drug is effectively adsorbed.^[63] This technique is particularly useful for loading hydrophobic drugs that may not easily diffuse into the pores under normal conditions. For example, ZIF-8, a well-known MOF, has been successfully loaded with hydrophobic drugs like paclitaxel under vacuum conditions. The vacuum loading method provides a way to load a high quantity of drug molecules, enhancing the drug's therapeutic efficacy by improving its bioavailability.^[31]

However, a potential challenge of this method is the difficulty in achieving uniform drug distribution within the MOF if the drug does not diffuse evenly throughout the material. Additionally, the method can be time-consuming, as the duration of vacuum application and drug loading can affect the overall efficiency of the process. Nonetheless, vacuum loading remains a valuable technique for enhancing drug encapsulation in MOFs, especially for poorly soluble or hydrophobic compounds^.[71]

Supercritical CO? Loading

Supercritical CO? loading utilizes supercritical carbon dioxide as a solvent to dissolve the drug, which is then transferred into the MOF pores under controlled conditions of pressure and temperature. In its supercritical state, CO? behaves as both a gas and a liquid, allowing it to penetrate the MOF structure and effectively deliver the drug into its porous framework. After the drug is loaded, the pressure is reduced, causing CO? to evaporate, leaving the drug trapped within the MOF. ^[72] This technique offers several advantages. First, it is solvent-free, which reduces the environmental impact associated with traditional solvent-based methods. Additionally, supercritical CO? is particularly effective for loading hydrophobic drugs that are poorly soluble in conventional solvents. The process also provides a high degree of control over the loading conditions, allowing for precise tuning of the drug loading amount. ^[73] For example, ibuprofen has been successfully loaded into MIL-101(Cr) using supercritical CO?, demonstrating the effectiveness of this method for enhancing the loading of hydrophobic drugs. The use of supercritical CO? for drug loading is beneficial for improving the bioavailability of poorly soluble drugs, making it a promising technique for pharmaceutical applications. However, the method does require specialized equipment to achieve the supercritical state of CO?, which can make the process more costly compared to other loading methods. Additionally, the process conditions, such as temperature and pressure, must be carefully optimized to prevent damage to the drug or the MOF structure. Despite these challenges, supercritical CO? loading remains a promising technique, particularly for applications where traditional solvent-based methods are less effective. ^[74] This technique is particularly useful for loading hydrophobic drugs that may not easily diffuse into the pores under normal conditions. For example, ZIF-8, a well-known MOF, has been successfully loaded with hydrophobic drugs like paclitaxel under vacuum conditions. The vacuum loading method provides a way to load a high quantity of drug molecules, enhancing the drug's therapeutic efficacy by improving its bioavailability. ^[31]

Covalent Attachment

Covalent attachment involves the formation of a strong chemical bond between the drug and the MOF framework, usually through functional groups that are incorporated into the organic linkers of the MOF. This method can enhance the stability of the drug within the MOF structure, preventing premature release and enabling controlled, sustained release over time. The covalent bonding ensures that the drug is tightly held in place, which is particularly beneficial for drugs that are prone to rapid leaching or degradation in aqueous environments.^[75] For instance, MOFs with functionalized linkers, such as those incorporating carboxyl or amino groups, can be used to covalently attach small molecules like anti-inflammatory drugs. By chemically attaching the drug, the system improves stability and reduces the likelihood of burst release, making it more suitable for applications requiring prolonged drug release or targeted therapy. Covalent attachment is also advantageous because it can help control the drug release profile, as the drug is slowly released when the bond is broken under specific conditions, such as changes in pH or the presence of specific enzymes. This method is particularly useful for drugs that require a longer duration of action or those that may otherwise be unstable or susceptible to premature release^.[7] The covalent attachment approach is highly customizable depending on the nature of both the drug and the MOF. However, it can be more complex and require more sophisticated synthetic strategies compared to other methods like simple adsorption or encapsulation.

Factors Influencing Drug Loading

The efficiency of drug loading into Metal-Organic Frameworks (MOFs) is influenced by several key factors:

Pore Size and Surface Area:

MOFs with larger pores and higher surface areas can accommodate more drug molecules, leading to higher drug-loading capacities. The larger the available space, the greater the potential to encapsulate or adsorb a larger quantity of the drug. This is one reason why MOFs with high porosity, such as MIL- 101 or ZIF-8, are particularly attractive for drug delivery applications^.[7]

Functional Groups:

The chemical compatibility between the drug and the MOF structure plays a crucial role in the drug loading process. MOFs with functional groups (e.g., hydroxyl, carboxyl, amine) can interact with drug molecules via hydrogen bonding, ?-? stacking, or electrostatic interactions. These interactions can enhance the drug’s binding efficiency and stability within the MOF pores, making the loading process more efficient and controlled.

Solvent Choice:

The solvent used in the drug-loading process can significantly impact the solubility and stability of the drug during loading. The solvent must dissolve the drug efficiently and also interact favorably with the MOF. A poorly chosen solvent may lead to precipitation or poor distribution of the drug, thus affecting the loading efficiency. Solvents that can create a mild and controlled environment for drug loading are preferred for preserving the stability of both the MOF and the drug.

Drug Concentration and Loading Time:

Higher drug concentrations and longer loading times generally result in better drug-loading efficiency. Higher concentrations of the drug can increase the likelihood of more molecules entering the MOF pores. Extended loading times also allow the drug to diffuse more thoroughly into the MOF structure, improving the overall encapsulation or adsorption efficiency. However, the balance must be maintained as excessive drug concentration or time may lead to saturation or premature release^.[5]

Each of these factors contributes to the overall efficiency and effectiveness of the drug loading process and optimizing them can enhance the therapeutic potential of MOF-based drug delivery systems.

Characterization Of Metal-Organic Frameworks (MOFS)

Characterization of Metal-Organic Frameworks (MOFs) involves a variety of techniques to determine their structural, chemical, and physical properties. These methods are crucial for understanding the material's porosity, surface area, crystallinity, morphology, and drug loading capabilities. Included in figure 6. Commonly used characterization techniques for MOFs include: