Application of Covalent Organic Frameworks (COFs) in Stimulus-Responsive Drug Delivery

Background of COFs

COFs are a class of emerging crystalline porous organic materials constructed by covalent bonds. Compared with other organic polymer materials, COFs have the characteristics of clear structure, controllable porosity, good chemical stability, and designable functions. Studies have shown that COFs are highly crystalline polymers similar to metal organic frameworks. Unlike metal organic frameworks, COFs are prepared by covalent bonding reactions based on network chemistry. COFs are composed of light elements (C, H, O and N). Due to their unique intrinsic properties, such as good stability, high specific surface area, convenient electron/ion transport, highly adjustable functions, designable redox centers and adjustable pore size, COFs have become one of the fastest growing fields. Modular design using rich molecular building blocks, simple nanosynthesis methods to balance stability and biodegradability, and easier post-synthesis modification make it easier to rationally design according to specific applications to achieve the desired purpose. The above unique advantages of COFs have enabled COFs to have advanced applications in many fields. Especially in the fields of gas separation, photoelectrocatalysis, dye degradation and biomedicine.

Advantages of COFs as Drug Carriers

COFs, as a new type of crystalline porous framework material, has attracted increasing attention in biomedicine due to its huge potential for post-modification, good adsorption performance, no metal toxicity, excellent stability and negligible dark cytotoxicity. The development of nano-COFs with suitable nano-size (10-200 nanometers) has prolonged the blood circulation time of COFs materials, avoided rapid clearance by the kidneys, and made nano-COFs materials more suitable for use in tumor therapy.

Figure 1. Characteristics and applications of covalent organic frameworks. (Singh N, et al.; 2022)

The systemic distribution of small molecule drugs can lead to unnecessary toxic side effects in tissues and organs without lesions. The development of smart nano-carriers has solved this problem well. The most obvious advantage of nano-COFs materials being used as drug delivery carriers is that the shape and size of the nano-COFs pores can be designed according to the size of the drug molecules by selecting suitable molecular structural units, thereby improving the selectivity of COFs carriers in the loading and release process of guest drug molecules. Among them, nano-COFs as drug delivery carriers for tumor chemotherapy are currently in a relatively mature stage.

The interaction between nano-COFs and drug molecules (π-π stacking, hydrogen bonding, hydrophobic interaction, electrostatic force) as well as the high specific surface area and porosity give nano-COFs an ultra-high drug loading capacity. Studies have found that the drug loading rate of ibuprofen (IBU) can be as high as 24wt% when PI-COFs are used as carriers. In contrast, the loading efficiency of most polymers for IBU is only around 10wt%, or even less than 5wt%.

The Significance of Stimulus-Responsive COFs

The interaction between nano-COFs and small molecule drugs creates the characteristic of high drug loading of nano-COFs, but also leads to slow drug release (especially poorly water-soluble drug molecules), insufficient accumulation of drugs at the target site, and often leads to treatment failure. Moreover, conventional nano-drugs are usually indiscriminate chemotherapy, and the indiscriminate killing of cancer cells and normal cells will cause serious damage to the animal body. The targeted delivery of drugs to the tumor site through external or internal stimulation can greatly reduce the toxic side effects during chemotherapy. Therefore, it is particularly important to construct stimulus-responsive covalent organic frameworks.

The diversity and flexible adjustability of molecular structural units provide unlimited possibilities for the development and design of different types of new functional nano-COFs materials. Based on this, active sites can be introduced into the framework to construct flexible nano-COFs. Nano-COFs with active sites can respond to certain external stimuli after formation, so that the in situ release of active sites can be easily achieved through specific post-treatment methods.

In the field of drug delivery, the earliest strategy for designing and synthesizing nano-COFs with active sites is to use surfactants/drugs as active sites to achieve controlled release of drugs. Some researchers have constructed PEG-CCM@APTES-COF-1 modified with a monofunctional curcumin derivative modified with polyethylene glycol (PEG-CCM). PEG-CCM is unlocked inside the cell, resulting in the release of loaded DOX. Compared with free DOX, PEG-CCM@APTES-COF-1 exhibits superior anticancer efficacy, which fully demonstrates the necessity of developing an intelligent delivery system. Other researchers have synthesized folic acid-functionalized nano-COF for targeted delivery of 5-Fu to tumor sites. Under the targeted action of folic acid, nanomedicines can induce programmed cell death of MDA-MB-231 cells. The small molecule drug DOX can bind to protons in an acidic environment, increase its solubility, and achieve pH-responsive release.

However, the stimulus-responsive nano-COFs of the above mechanism will not weaken the interaction between drug molecules and the COFs skeleton, and the drug release rate will still be limited. In order to solve this problem, some researchers introduced disulfide bonds as active sites into the COFs framework for the delivery of the chemotherapy drug DOX. After the nanodrug enters the tumor cells, it can quickly respond to the high concentration of GSH in the tumor cells, achieve controllable and efficient drug delivery in cancer cells, and effectively inhibit the growth of tumor cells. Later, some people introduced azo bonds as active sites into the building blocks of COF, designed and synthesized hypoxia-responsive COFs for tumor treatment combined with photodynamic therapy and chemotherapy. Photodynamic therapy exacerbates the degree of hypoxia in tumor cells. Under hypoxic conditions, the azo bonds in the COF framework are opened and the framework collapses, further promoting drug release and realizing the efficient combination of photodynamic therapy and chemotherapy. Under the action of endogenous stimuli, the skeleton of COFs is destroyed, weakening the interaction between COFs and drug molecules, thereby achieving efficient drug release. And under the action of endogenous stimuli, it can effectively distinguish the lethality of drugs on normal cells and cancer cells, thereby achieving the purpose of targeted treatment.

References

1. Singh N, et al.; Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications. Bioact Mater. 2022, 21:358-380.
2. Zhou S, et al.; Covalent organic framework-based assembly systems for the intracellular delivery of proteins: opportunities and challenges. Nanomedicine (Lond). 2021, 16(15):1259-1262.