Metal organic frameworks (MOFs), as a porous coordination polymer, are two-dimensional or three-dimensional network structures composed of organic ligands and inorganic metal ions or metal clusters through coordination bonds. They are highly porous and crystalline materials. By selecting appropriate organic ligands and metal clusters, MOFs can have tunable physical and chemical properties such as surface area, pore diameter, morphology, hydrophilicity or hydrophobicity, and can be applied in many fields, such as gas storage and separation, imaging, sensing, catalysis, energy, analytical chemistry, biomedicine, etc. In particular, MOFs have adjustable porosity, adjustable size and structure, and functionalized surface, making it one of the most popular materials in the biomedical field. It has developed rapidly as a new drug delivery system and has broad prospects.
Figure 1. The graphical representation of MOFs in drug delivery. (He S, et al.; 2021)
Skin drug delivery preparations are preparations that use the skin as a drug delivery route, which are divided into traditional local action preparations and modern transdermal drug delivery systems. The principle is to deliver drugs to the skin surface or to the systemic blood circulation to exert local or systemic therapeutic effects. On the one hand, skin drug delivery can effectively avoid drug metabolic degradation caused by the first-pass effect of the liver and reduce drug side effects. On the other hand, it can concentrate active substances in the skin and has been widely used in clinical treatment. However, traditional biomaterials used in skin treatment are often simple in structure and single in function, and can only play a physical support or dispersion role, which seriously hinders the efficiency and application of skin drug delivery. In addition, in order to achieve the expected performance of the drug, chemical penetration enhancers, preservatives, adhesives and other additives are usually added to cosmetics or skin preparations, which not only increases the cost and complexity of the drug, but also gives rise to biosafety risks of the drug. In recent years, with the extensive research of biomedical nanomaterials in the field of biomedicine, researchers have also tried to apply them to skin drug delivery preparations. At present, common biomedical nanomaterials in skin treatment, such as liposomes, micelles, nanoemulsions, etc., although they have improved the drug loading and efficacy to a certain extent, they also have problems such as poor physical stability, low processability, and difficulty in modification or functionalization.
In recent years, the application potential of MOFs as drug carriers in skin drug delivery has attracted more and more attention. MOFs have been used as drug carriers by many research teams due to their good biocompatibility, controllable adsorption and controlled release properties, and certain antibacterial activity. Their ability to resist bacterial infection, treat chronic ulcers, and be used in skin care products has been studied by modification and loading of effective ingredients. This article mainly reviews the advantages and research progress of MOFs as drug carriers or active ingredients for skin preparations based on their applications in skin drug delivery in recent years.
Advantages of MOFs in Skin Drug Delivery Preparations
Biocompatibility is the primary factor in testing whether a material is suitable for use in the biomedical field, and is also an important indicator for evaluating materials in biomedical applications, especially for susceptible populations, where drugs must have good biocompatibility. Therefore, when using MOFs as drug carriers for skin drug delivery, its biocompatibility must also be considered first, mainly testing cytotoxicity, hemolytic behavior, and skin irritation. Then, MOFs whose data results meet clinical safety standards are selected for further drug loading, transdermal, and other follow-up experiments. For example, in the MOFs evaluation system as a drug carrier created by Duan et al., the above indicators of various MOFs in the MOFs library they established were first evaluated. 13 MOFs were selected for cytotoxicity experiments on human skin fibroblasts, 3T3 cells, and Hela cell lines. The experimental results show that the median toxic concentration (CC50) of zinc-based and copper-based MOFs is low, less than 1000 mg/mL, while the CC50 of other MOFs is greater than 5000 mg/mL, indicating that iron-based, zirconium-based and aluminum-based MOFs have lower cytotoxicity than zinc-based and copper-based MOFs, and have the potential to become good transdermal carriers. Combined with the molecular size of MOFs, it can be seen that the cytotoxicity of MOFs is related to its particle size. The larger the particle size, the less likely it is to be absorbed by cells and the lower the cytotoxicity. Iron-based, zinc-based and zirconium-based MOFs have low toxicity and have been widely selected by researchers in recent years. Some researchers injected three porous MOFs synthesized from trivalent iron ions and three different carboxylates intravenously into adult female mice. After 7 days, compared with the control mice, the experimental mice showed no signs of death or obvious poisoning, and their weight and behavior were normal, verifying the good biocompatibility of iron-based MOFs. In addition, Duan et al. also tested the hemolysis rate and skin irritation of MOFs. Except for HKUST-1(Cu) which had poor water stability and failed to obtain hemolysis data, the hemolysis rates of the remaining MOFs were far below 5% (the highest hemolysis rate of clinical safety standards), among which iron-based MOFs had the lowest hemolysis rate. In the skin irritation test, the skin of mice treated with all MOFs showed no erythema or edema, indicating that MOFs have low allergenicity. Based on the above, it can be concluded that most MOFs in this MOF library have good biocompatibility, especially iron-based MOFs have better performance than other MOFs.
- Better Penetration-Promoting Performance
The transdermal absorption of drugs is divided into transepidermal absorption and trans-adnexal absorption. The adsorption capacity of oleic acid by MOFs is significantly lower than the adsorption capacity of triacetin. Each 1.0 mg of PCN-333 (Fe) can adsorb 6.1 mg of triacetin and 3.5 mg of oleic acid respectively, which is significantly higher than traditional porous materials such as activated carbon and diatomaceous earth, reflecting the excellent adsorption performance of MOFs. In the MIL-101 series tested, MOFs with substituents have better sebum adsorption than the original MIL-101. This is because the hydrophobic groups (bromo, nitro, methyl) can enhance the hydrophobicity of MOFs. There are two types of adsorption affinity of sebum and absorption. Transepidermal absorption is the main way of drug absorption. It refers to the process in which drugs enter the active epidermis through the epidermal stratum corneum, then diffuse to the dermis and are absorbed by capillaries into the systemic circulation. Therefore, high-quality drug carriers for skin delivery must have good penetration-promoting properties, which can promote the skin penetration and absorption of drugs, thereby improving the bioavailability of drugs. According to the process of drug transdermal absorption, skin drug delivery can be divided into two steps: drug release and drug transdermal. Drugs with large release amounts and high permeability of active ingredients through the skin should have higher bioavailability. Therefore, the skin cleaning ability and controlled release ability of MOFs as drug carriers for skin delivery can be investigated based on this. The skin cleansing ability of MOFs mainly refers to its absorption performance of skin secretions (sebum). Skin secretions can cause a variety of pathological reactions, induce seborrheic dermatitis and hirsutism, etc. Excess sebum can also hinder the penetration and delivery of drugs and reduce drug efficacy. In addition, the stronger the MOFs' ability to release drugs, the more active molecules are in contact with the skin, which can promote the skin penetration of drugs.
- Strong Antibacterial Activity
In skin treatment, the growth of microorganisms can easily lead to infection or decay of the surface skin, thus causing various skin diseases such as dermatitis or skin ulcers. MOFs, as a new type of three-dimensional porous structure, has excellent antibacterial properties similar to the principle of metal nanoparticles. However, while metal ions kill microorganisms, they are also toxic to normal tissues and cells. Many metal nanoparticles reported to be toxic due to excessive release of metal ions. MOFs can gradually release metal ions through the biodegradation of their own framework structure, maintain a low metal ion concentration, and provide a sustained antibacterial effect. As an antibacterial agent, MOFs have the advantages of a broad antibacterial spectrum, good antibacterial effect, long durability, and inhibition of metal release. As a drug carrier for skin preparations, it can avoid the addition of antibiotics or related additives and reduce the risk of irritation or side effects.
Application of MOFs in Skin Drug Delivery Preparations
- MOFs for Wound Healing of Bacterial Infections
MOFs can load antibacterial drugs on their surface or in the voids through forces such as van der Waals forces, hydrogen bonds, π-π interactions, coordination bonds and electrostatic forces, and adsorb or bind antibacterial active ingredients as drug delivery systems to make antibacterial preparations for wound healing of bacterial infections. In addition, most MOFs can release bioactive metal ions or ligands into the medium through the decomposition of the coordination bonds between metals and ligands, showing good antibacterial activity. However, similar to metal nanoparticles, excessive release of metal ions may also be harmful to normal tissue cells while killing bacteria. In order to solve this problem, many researchers are working hard to increase the stability of metal ions by optimizing the structure and modifying the surface coating to achieve the effect of controlled and sustained release. Hydrogel matrices are mostly natural or synthetic polymers, which have certain physical and biological similarities with the extracellular matrix of tissue cells. They are also highly concerned as drug delivery carriers because of their high-water content, high biocompatibility, adjustable structure, and ability to block biological invasion. Therefore, in recent years, researchers have prepared a variety of hydrogel preparations containing antibacterial substances (such as nanosilver, antibiotics, MOFs, etc.) for use in antibacterial infections.
- MOFs for the Treatment of Diabetes
Diabetes is one of the most common chronic diseases in the world and is the third leading cause of death after cardiovascular and cerebrovascular diseases and malignant tumors. The ideal treatment for diabetes is to secrete different doses of insulin according to the level of blood sugar to control the blood sugar level. This method requires the design of a complete glucose-responsive insulin delivery system. Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, with high mortality, morbidity and recurrence rates, and can eventually lead to non-traumatic amputation due to infection. A large amount of evidence shows that the angiogenesis disorder caused by chronic hyperglycemia cannot provide sufficient oxygen and nutrients to the wound surface, which seriously delays the healing of diabetic foot ulcers. Scientists have developed a new hydrogel that can promote diabetic wound healing. They selected the lipophilic antioxidant α-lipoic acid (α-LA), which can scavenge reactive oxygen, enhance glucose uptake and reduce cell apoptosis. Then, chitosan (CS), hyaluronic acid (HA) and potassium-based γ-cyclodextrin metal organic framework (K-γ-CD-MOFs) were used to load α-LA to make a hydrogel with antibacterial activity and antioxidant properties. In vitro analysis experiments showed that the hydrogel can effectively promote cell proliferation and migration. In vivo analysis using a full-thickness wound model in diabetic rats showed that the hydrogel also significantly promoted the wound healing process, with more granulation tissue formation and collagen deposition, indicating that it has the potential to become a treatment for chronic full-thickness skin wound healing. Copper-based MOFs can promote angiogenesis, growth factor expression, collagen deposition and other antibacterial and wound healing-related processes by slowly releasing Cu2+ while acting as drug carriers, and avoid the toxicity of excessive Cu2+.
- MOFs for Cancer Treatment
Melanoma, an aggressive skin cancer, is caused by the carcinogenesis of melanocytes in the skin. Dacarbazine (DTIC), an alkylating agent used in traditional chemotherapy, has a short half-life, poor solubility in water, slow absorption in the body, and non-specific toxicity to normal cells. Therefore, the design of MIL-100 (Fe) with good biocompatibility for loading and controlled release of DTIC for in vitro treatment of melanoma was carried out. MIL-DTIC and MIL-DTIC-PEG encapsulated with PEG were synthesized without using any harmful solvents, and their drug release and cytotoxicity to melanoma A375 cell line were studied. Release kinetic modeling studies demonstrated that the main mechanism of DTIC release from MIL-DTIC and MIL-DTIC-PEG structures is diffusion. Cytotoxicity evaluation results demonstrated that MIL-DTIC and MIL-DTIC-PEG were more toxic to cancer cells and less toxic to normal cells than DTIC alone. Therefore, MIL-DTIC-PEG is expected to be an effective method for DTIC treatment of melanoma.
Application of MOFs in Cosmetics
Caffeine (CAF) has been used in the cosmetics field. It can directly act on adipocytes, inhibit phosphodiesterase, enhance the activity of triglyceride lipase and cyclic adenosine monophosphate, promote fat degradation, and thus stimulate the microcirculation of the skin to achieve the purpose of fat reduction. However, the special crystal configuration of CAF often leads to its poor loading effect (<5 (wt)%) and uncontrollable release, which limits its widespread use in the cosmetics industry. An attempt was made to load CAF into MIL-100 (Fe) to make a skin patch for local administration. Various polymers with good biocompatibility (low molecular weight polyvinyl alcohol and pig skin gel (GEL)) were combined with MIL-100 (Fe)-CAF nanoparticles and compared with commercially available preparations. The results show that compared with polyvinyl alcohol, pig skin gel has low water solubility, low polarity, and high gel strength. The amino acids contained in it can interact strongly with the Lewis site of MIL-100 (Fe), making the structure connection in GEL-MIL-100 (Fe)-CAF more tightly, with a lower hydrophobic/hydrophilic balance, and showing better CAF controlled release performance, which is expected to be applied to cosmetic preparations. This also shows that MOF is expected to be used as an excellent carrier of CAF and combined with other materials to make new skin preparations for use in cosmetics and beauty fields.
References
- Duan F, et al.; Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA. Biomaterials. 2017, 144:155-165.
- Liu C, et al.; Research Progress of Metal-Organic Frameworks as Drug Delivery Systems. ACS Appl Mater Interfaces. 2024, 16(33):43156-43170.
- He S, et al.; Metal-organic frameworks for advanced drug delivery. Acta Pharm Sin B. 2021, 11(8):2362-2395.
