Metal organic framework (MOF) is an organic-inorganic hybrid porous crystalline material assembled by metal ions or ion clusters and organic ligands through coordination bonds. MOF has the characteristics of large specific surface area, adjustable pore structure, clear structure, regular shape, high porosity and strong guest molecule encapsulation ability. Through different synthesis methods or replacement of organic ligands and metal ions, the structure and function of MOF can also be effectively regulated. The above characteristics make MOF have excellent application prospects in many fields such as molecular recognition, gas storage, separation, catalysis, etc. In recent years, MOF has also been widely studied for drug delivery in the field of pharmacy. However, most of the MOFs reported so far are composed of non-renewable petrochemical materials and transition metals, with relatively high preparation costs and certain pollution to the environment. Most importantly, the biocompatibility of the material is a prerequisite for its application in the field of biomedicine. The organic ligands and metal ions required to constitute MOF have the potential biological toxicity seriously limiting the application of MOF in the field of biomedicine. Therefore, the preparation of biocompatible MOF materials has attracted more and more attention from researchers in the medical field. Although MOFs composed of natural materials such as amino acids, nucleobases, peptides, and proteins have appeared as organic ligands, most biological molecules from natural sources have the disadvantages of asymmetry and weak coordination with metal ions, making it difficult to obtain a stable porous structure. In 2010, Smaldone et al. successfully obtained an edible MOF-cyclodextrin metal organic framework (CD-MOF) through a simple slow volatilization method, which opened up the application of MOF in the field of biomedicine.
Figure 1. γ-Cyclodextrin Metal-Organic Framework as a Cyclosporine A Pulmonary Delivery Vehicle. (Huang Y, et al.; 2024)
Preparation of nano-scale CD-MOF
The constituent materials of CD-MOF have excellent biocompatibility. CD-MOF is composed of γ-cyclodextrin (γ-CD) and potassium ions. The essence of γ-CD is a symmetrical cyclic oligosaccharide formed by D-pyranose glucose connected by α-1,4 glycosidic bonds. It can be obtained by enzymatic hydrolysis of natural starch or starch derivatives and has good biocompatibility (LD50＞5000mg·kg－1). γ-CD can form complexes with hydrophobic molecules of appropriate size to improve the solubility of guest molecules. It has been widely used in food, cosmetics and biomedical fields. Potassium is a constant element in organisms and is well tolerated by the body. The preparation method of CD-MOF is simple and mild. In short, potassium hydroxide and γ-CD are dissolved in pure water at a molar ratio of 8:1 and then filtered. The filtrate is placed in a closed environment containing methanol for 2 to 7 days. As methanol gradually evaporates and diffuses into the aqueous solution of γ-CD and KOH, colorless cubic CD-MOF crystals will gradually appear. CD-MOF is a cubic particle with a body-centered structure and a porosity of up to 54%. The (CD)6 structural unit that constitutes CD-MOF has a 1.7nm hydrophilic spherical pore structure in the center, and the inner surface of two adjacent γ-CD molecules forms a 1.0nm hydrophobic pore structure. There are also 0.4nm triangular pores along the axial plane of the crystal. These pores of different sizes are arranged regularly, and together they constitute the rich pore structure of CD-MOF, providing ample space for drug encapsulation. In addition, CD-MOF has both hydrophilic and hydrophobic pores, and can encapsulate both hydrophobic and hydrophilic drugs. Therefore, CD-MOF has broad application prospects in drug delivery.
CD-MOF has good safety, but as a qualified drug carrier, it should also have a suitable particle size. Usually, the particle size of CD-MOF prepared by slow volatilization method is about 40 to 500 μm. CD-MOF crystals of this size cannot enter the capillaries and lymphatic circulation, and thus cannot be effectively taken up by cells, making it difficult to be applied in the field of biomedicine. The key to the application of CD-MOF in drug carriers lies in the research and preparation of monodispersed nanoscale CD-MOF. Therefore, how to solve the particle size problem of CD-MOF in drug delivery applications has become a research hotspot for CD-MOF in recent years. Studies have shown that adding an appropriate amount of surfactant hexadecyltrimethylammonium bromide (CTAB) in the process of preparing CD-MOF by solvent diffusion method can slow down the crystal growth rate, increase the number of nucleations, and obtain CD-MOF with a size of 200 to 300 nm. The researchers further improved the solvent diffusion method. In their study, they found that by adding 10% (v/v) methanol to the KOH solution of γ-CD in advance, and then placing it in a 50°C environment to cultivate crystals, and adding CTAB to adjust the MOF morphology after 6 hours, micrometer- and nanometer-scale CDMOF with uniform particle size can be obtained. This optimized solvent diffusion method shortens the preparation time of CD-MOF from 1 week to 6 hours, while the crystallinity and porosity of the crystals will not change. They found that the crystal size of CD-MOF can also be adjusted by changing the concentration of reactants, temperature, time, the ratio of γ-CD to KOH, and the concentration of surfactant. They also found that CD-MOF of 100 to 300 nm can be quickly obtained through microwave-assisted synthesis. In addition, a method for preparing nanoscale CD-MOF using short-chain starch nanoparticles as seeds combined with an anti-solvent method has been reported. Among these methods, the improved solvent diffusion method is simple to operate, has mild conditions, low instrumentation requirements, controllable particle size, and high yield. It is the preferred method for laboratory preparation and research of CD-MOF.
Application of CD-MOF in drug delivery
Based on existing research results, CD-MOF has the characteristics of uniform and clear structural rules, large specific surface area, high porosity, etc. of traditional MOF, and also has the advantages of good biocompatibility, simple preparation method, economic and environmental protection, and large-scale preparation. It has great potential in the field of biomedicine. At present, there are reports of CD-MOF successfully encapsulating drug molecules. CD-MOF carries drugs through weak drug-carrier interactions, which are specifically manifested as physical adsorption or co-crystallization. Studies have shown that the use of CD-MOF to encapsulate guest molecules not only has a high encapsulation rate, but also can effectively improve the physicochemical stability of guest molecules, and can effectively improve the solubility and bioavailability of guest molecules. Some researchers have found that compared with free curcumin, the phenolic hydroxyl groups of curcumin in CD-MOF will interact with the hydroxyl groups on cyclodextrin by hydrogen bonds, which increases its storage stability by at least 3 orders of magnitude. When CD-MOF loaded with curcumin is dispersed in water, CD-MOF gradually disintegrates. However, curcumin does not directly detach from the CD-MOF skeleton. Instead, it forms a special adduct with free γ-CD and K+ through complexation, further avoiding the chemical degradation of curcumin. Other researchers have found that after coenzyme Q10 (CoQ10) forms a crystalline solid dispersion (CoQ10/CD-MOF-1) with CD-MOF, the CH group on the isoprene side chain of CoQ10 and the OH group of CD-MOF interact by hydrogen bonds, which can effectively improve its solubility, which is nearly 100 times higher than that of CoQ10, and the bioavailability is also greatly improved. The co-crystal formed by the non-steroidal anti-inflammatory drug ibuprofen and CD-MOF can have a drug loading of up to 26% (wt). Although the blood uptake rate and bioavailability of the co-crystal are similar to those of pure potassium salt of ibuprofen, the half-life of ibuprofen is doubled, which not only quickly relieves pain but also prolongs the analgesic time.
Limitations and Solutions of CD-MOF as a Drug Carrier
In addition to the appropriate size and low toxicity, drug carriers must also have good stability. However, due to the high brittleness and high solubility in aqueous media of CD-MOF, it is difficult to maintain structural integrity before reaching the target tissues and organs, which seriously limits its application in the biomedical field. In recent years, in order to realize CD-MOF as a drug delivery carrier, a lot of research has been carried out on how to effectively solve the stability of CD-MOF, such as cross-linking CD-MOF free hydroxyl groups, encapsulating hydrophobic contents, and preparing CD-MOF into composite microspheres.
References
- Huang Y, et al.; γ-Cyclodextrin metal-organic frameworks as the promising carrier for pulmonary delivery of cyclosporine A. Biomed Pharmacother. 2024, 171:116174.
- Gassensmith J.J., et al.; Strong and reversible binding of carbon dioxide in a green metal-organic framework. J. Am. Chem. Soc. 2011, 133:15312–15315.
