HKUST-1 (Hong Kong University of Science and Technology-1, MOF -199): A copper-based MOF that has become very interesting in drug delivery for its unique structural and chemical composition. HKUST-1 is a molecule of copper ions bound to benzene-1,3,5-tricarboxylate (BTC) linkers with high-pore porosity, large surface area and adjustable pores that could be used in many biomedical applications such as drug delivery. MOFs such as HKUST-1 are very attractive because they can be filled with many therapeutic agents such as small molecules, proteins, nucleic acids, even imaging agents and provide controlled release profiles for therapeutic application. Because HKUST-1's porosity is very high, and surface modification could lead to improved stability and biocompatibility, it presents a promising model for the fabrication of sophisticated drug delivery systems capable of solving the problems that existing carriers are unable to. What is most prominent in HKUST-1, which makes it a great candidate for drug delivery, is its large surface area and porosity. HKUST-1 has copper(II) centers aligned to BTC linkers, which are arranged in a network with big pores of about 1-2 nm in size. These pores are wide enough to accommodate therapeutic molecules and deliver optimal drug encapsulation. The fact that the porosity and surface properties of HKUST-1 can be customized through the synthesis conditions or the BTC linkers further extends its utility as a carrier drug. The copper centers of HKUST-1 also have the ability to cross-react with some biomolecules (peptides, nucleic acids, proteins, etc.) This could improve therapies in disorders where selective drug delivery is critical. Thus, HKUST-1 can be seen as more than just a passive transporter – and even a possible active facilitator of drug-target interactions. The stability of HKUST-1 in the body is also another factor that favors HKUST-1 for drug delivery. Copper-based MOFs are also stable in water and biological fluids, which is a prerequisite for any substance to be used in the body. Because HKUST-1 is essentially stable, it can both protect encapsulated drugs from degradation and help ensure the therapeutic molecules are released in a controlled rate. Further, the degradation products of HKUST-1, which include copper ions and carboxylate derivatives, are usually biocompatible and can be metabolised by the body without much toxicity. This biocompatibility and the fact that release kinetics of the encapsulated drug can be optimized for improved stability render HKUST-1 an ideal candidate for extended drug delivery, particularly for long-term or chronic disease.
Figure 1. Crystal structure of HKUST-1 with three types of pores designated by differently colored spheres.( Zeleňák V, et al.; 2021)
Targeted drug delivery with HKUST-1 is an interesting research potential. Using functional groups or ligands on the surface of the MOF, it is possible to create drug delivery systems targeting a particular cell or tissue for maximum therapeutic effects and minimum side effects. Targeting moieties like antibodies, peptides, or aptamers, for instance, can be attached to the surface of HKUST-1 to enable selective detection of some receptors on cancer cells or in other tissues with diseases. This flexibility to alter the surface chemistry of HKUST-1 gives flexibility to design highly specific and effective drug delivery systems. HKUST-1 can contribute to enhanced clinical outcomes in disease states including cancer, inflammatory conditions, and infection by more precisely releasing drugs to the site of action. Alongside targeted administration, HKUST-1's controlled release is also useful when administered for long-term, sustained release drugs. Because HKUST-1 is porosity, any number of physicochemically diverse drugs including hydrophilic and hydrophobic molecules can be encapsulated. This is adjustable via changing the shape of the MOF or the external environments in which it is applied. For instance, encapsulated drugs can be released when pH, temperature, or even certain enzymes or ions in the tissue of the organ being absorbed cause it to react. This responsiveness is one more element of control that makes HKUST-1 the perfect platform for the design of smart drug delivery systems to provide spatiotemporally modulated release of therapeutics. Such systems could cut the amount of time needed for medication to be given and increase compliance, especially in chronic therapies such as cancer care or chronic inflammation. One promising research direction is combining HKUST-1 with other therapies (phototherapy or gene therapy) to create multiple drug delivery systems. When coupled to light-sensitive molecules or genetically engineered platforms, HKUST-1 can be used as a transporter for small molecules, but also more sophisticated therapeutics such as siRNA, mRNA or gene editing tool. Particularly, copper-derived MOFs such as HKUST-1 have been tested for delivery of RNA-based therapies, which must be protected and released in precisely defined controlled dosages to be stable and effective. By using HKUST-1 as a vehicle for such complex agents, scientists are opening the way to future powerful combination therapies that work on multiple pathways at once, and new hope for diseases that traditional drug delivery systems simply can't solve.
Though there are many benefits, the use of HKUST-1 in drug delivery has several limitations that must be overcome to make it clinically more widespread. The major problem here is the release of copper ions from the MOF structure as the process degrades. Although copper ions are native to the body and are important for many biochemical reactions, if released too much copper can be toxic, especially in tender organs or tissues. This is why designing HKUST-1 to reduce copper leaching or to regulate the rate of copper ion release is so critical to make sure it is safe to use in vivo. This could be overcome by encapsulating copper in the MOF framework in a form that makes it less bioavailable or by using surface treatments that stabilize the copper centres. That would retain HKUST-1's therapeutic properties and avoid the risk of copper-induced toxicity. The other obstacle is large-scale, reproducible synthesis of HKUST-1. While the HKUST-1 synthesis has been very well-proven in the lab, scaling up the manufacturing for clinical applications is a problem in terms of consistency of particle size, morphology, and drug encapsulation efficiency. A reproducible, controlled manufacturing procedure for HKUST-1 compatible with drug delivery applications will be key to commercializing it. Perhaps more advanced synthetic techniques, like continuous flow reactors or more effective sol-gel reactions can solve some of these problems and make MOF more efficient. And they are exploring the possibility of hybrid systems, combining HKUST-1 with another material, like liposomes, hydrogels or nanoparticles, to increase stability, drug-loading and accessibility. In the long term, the combination of HKUST-1 with other innovative technology such as nanomedicine, personalized medicine, and combination therapy promises to enable novel ways to deliver drugs. As we understand how diseases work, designing MOF-based drug delivery systems that change in accordance with disease or patient-related variables will be a prime target. Researchers are also looking at HKUST-1 combined with diagnostics, which can enable theranostic use cases where drug delivery and disease detection are combined in one device. HKUST-1 and other MOFs may have an even larger part to play in the next generation of targeted, controlled and personalized drug delivery systems, re-writing the history of medicine and bringing novel therapies for previously untreatable diseases.
Alternate Names:
Cu-BTC
Copper(II) Trimesate
Copper-Trimesic Acid MOF
Cu3(BTC)2
Copper-Organic Framework
HKUST-1 MOF
HKUST-1 Crystals
Cu3(TMA)2
References:
1. Zeleňák V, Saldan I. Factors Affecting Hydrogen Adsorption in Metal-Organic Frameworks: A Short Review. Nanomaterials (Basel). 2021, 11(7):1638.
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