Nanoparticles for Therapeutic Vehicles-HOFs

Crystalline porous materials can be divided into pure inorganic crystalline porous materials and crystalline porous materials containing organic components. The former mainly includes zeolites and molecular sieves, while the latter mainly includes metal-organic frameworks (MOFs) or porous coordination polymers (PCPs), covalent organic frameworks (COFs) and hydrogen-bonded organic framework materials (HOFs). Compared with pure inorganic crystalline porous materials, crystalline porous materials containing organic components have richer structures, easier pore shapes and sizes Features such as adjustment and easier modification of the surface of the pores.

Figure 1. Schematic diagram of the formation of 8PN HOFs.

HOFs are a kind of crystalline porous framework materials formed by organic or metal-organic building units connected by hydrogen bonds. In addition to hydrogen bonds, other intermolecular forces such as π-π interaction, electrostatic interaction and van der Waals force affect HOFs’ construction and stability of HOFs also play a very important role. The research on HOFs can be traced back to 1969. Marsh and Duchamp used trimellitic acid as the building unit to report an example of a crystalline compound with a hexagonal honeycomb structure. However, in the following decades, the development of HOFs basically stagnated. It was not until the early 1990s, after Wuest et al. reported a series of HOFs constructed by hydrogen bonds, that HOFs materials began to slowly develop. Although the concepts of using hydrogen bonds to construct HOFs materials and using coordination bonds to construct MOFs materials were put forward in parallel at almost the same era, the development of HOFs is much slower than that of MOFs. This is mainly because the hydrogen bond has weak force, strong flexibility and poor directionality, so the target HOFs structure is not only difficult to accurately synthesize, but the stability of the framework is generally much worse than the corresponding MOFs. In fact, the framework of the early synthesized HOFs often collapsed after removing the solvent filled in the pores, and the early scientists did not pay much attention to the porosity of HOFs, so the development of HOFs was extremely slow. Until about 2010, The porosity of HOFs began to be gradually established. In 2011, scientists proposed the definition of HOFs and applied HOFs as a class of porous materials (HOF-1) to the separation of ethylene/ethane for the first time. The establishment and development of the porosity of HOFs has opened a new era in the development of HOFs materials, and since then HOFs have officially appeared in front of scientists as a new and unique porous framework material.

In recent years, some HOFs with ultra-high stability have also been developed. Since MOFs/COFs/HOFs are crystalline porous materials containing organic components, they have some common characteristics, for example: They all have theoretically Common features such as large specific surface area, diverse structures, adjustable pore shape and size, and pore surface modification. However, because HOFs are constructed by hydrogen bonds, the hydrogen bond force is generally weaker than the strength of coordination bonds or covalent bonds Due to its strong reversibility, HOFs materials have some unique advantages: (1) The preparation conditions of HOFs are more gentle; the preparation of HOFs usually only needs to be synthesized through the natural volatilization of the solvent, the diffusion of the poor solvent to the good solvent, or the recrystallization process. (2) HOFs have better solution processing properties, so they are easier to make devices than COFs/MOFs; HOFs materials are constructed by intermolecular forces such as hydrogen bonds, so HOFs materials are Specific solvents can have good solubility, and when the solvent evaporates, HOFs may be crystallized out, giving HOFs the solvent processing performance of materials. (3) HOFs materials have better self-healing and regeneration capabilities; HOFs materials are constructed based on hydrogen bonds. The flexibility and reversibility of the hydrogen bond give HOFs good self-healing and regeneration capabilities. MOFs, COFs and HOFs have been used many times in practice after recycling, the frame may be damaged to varying degrees, resulting in a decrease in performance, and the self-repair and regeneration of the structure is very important for the large-scale practical use of materials. HOFs can be regenerated through a simple recrystallization process, and even such the material has good solvent repair/self-healing ability, which is very meaningful for reducing the actual use cost of HOFs. (4) Since most HOFs materials do not contain metal ions, this non-metallic property gives HOFs materials better Biocompatibility and lower cytotoxicity make HOFs show great potential in biological applications.

Although HOFs have the above-mentioned advantages, the weak hydrogen bond force and poor directivity also restrict the development of HOFs. First, it is much more difficult to synthesize the target structure of HOFs than MOFs and COFs. This is because hydrogen bonding force is weak and the flexibility is strong. The structure of HOFs is very susceptible to external factors such as other intermolecular forces. Its final structure is highly dependent on the solvent and synthesis conditions used for preparation. Secondly, the stability of most HOFs materials is relatively Poor, the framework is easy to collapse after removing the solvent in the channel. How to remove the solvent in the channel while maintaining the stability of the HOFs framework is still a huge challenge. Fortunately, some supramolecular synthons composed of multiple hydrogen bonds have been It has been proven to have strong acting force and directionality, and has been effectively used in the construction of HOFs with target structures. Even theoretical calculations have been successfully used to predict and design the structure and performance of HOFs. By enhancing intermolecular Forces such as the introduction of multiple hydrogen bonds, π-π stacking, electrostatic interaction, van der Waals forces and the introduction of interlocking, some HOFs materials with ultra-high stability and ultra-large specific surface area have also been prepared. With the development of functional porous HOFs materials, the uniqueness of HOFs is gradually reflected in different application fields.

Biological Applications of HOFs

Most HOFs do not contain metal ions, so HOFs generally have lower cytotoxicity and better biocompatibility than MOFs. Combined with structural diversity and porosity, HOFs have broad application prospects in biological applications.

Biological macromolecules or biological assembly systems such as enzymes, peptides, proteins, DNA and RNA generally have advanced spatial structures. These spatial structures are very sensitive to the environment, so their functions are easily affected by the external environment, such as enzyme catalytic activity very susceptible to temperature, pH, metal ions, ionic strength and other enzymatic degradation factors. Therefore, use HOFs to protect biological assembly systems or biological macromolecules, thereby improving their ability to resist external environmental interference and increase operability, Is conducive to their large-scale practical application. Encapsulating biological assembly systems or biological macromolecules in porous materials such as HOFs framework is a way to reduce their exposure to external conditions. Based on the above considerations, White, Falcaro and Doonan report a case of biocompatible HOF material (BioHOF-1) capable of encapsulating and protecting biological macromolecules is reported. BioHOF-1 is self-assembled by polyamidine cation (M) and polycarboxylate anion (C6) in aqueous solution. It has an open channel with a one-dimensional square.

When biological macromolecules such as fluorescent yellow-labeled catalase (FTCA) self-assemble with M and C6, FTCA can be loaded in-situ and uniformly in the BioHOF-1 framework to obtain FTAC@BioHOF-1 composite material. BioHOF -1 Not only can encapsulate FTAC, but also can effectively reduce the influence of external conditions on the catalytic activation of encapsulated FTAC. For example, the optimal pH for FTAC to catalyze the decomposition of hydrogen peroxide is 7-8. At other pH values, its catalytic activity will be greatly reduced. However, FTAC@BioHOF-1 not only maintains the very good catalytic activity of FTAC, but also at a pH of 5-10, its catalytic activity can still reach 90% of the optimal catalytic activity; FTAC at 60℃ or heat trypsin (proteolytic enzyme) or urea (chaotropic agent), its catalytic activity basically disappears. and FTAC@BioHOF-1 can still maintain good catalytic activity under the same experimental conditions (the best catalytic activity is achieved) 75%～79%; In addition, it is difficult to recycle FTAC after use, and the catalytic activity of FTAC@BioHOF-1 is basically not reduced after being recycled 10 times. Using the same packaging strategy, fluorescent yellow labeled alcohol oxidase (FTOx) Is also very easy to load in BioHOF-1 materials. Similarly, BioHOF-1 can not only effectively improve the ability of FTOx to resist harsh external conditions, but also maintain the structure and activity of FTOx better than analog materials MOFs, for example: FTOx@ The activity of BioHOF-1 to catalyze alcohol oxidation reached 60% of the activity of FTOx, and when FTOx was encapsulated in a metal-organic framework material such as ZIF-8, ZIF-60 or MAF-7, its catalytic activity completely disappeared. These results fully indicate HOFs are very promising for the protection of biological macromolecules or biological self-assembly systems to improve their stability and operability.

References:
1. He Y, et al.; A microporous hydrogen-bonded organic framework for highly selective C2H2/C2H4 separation at ambient temperature. J Am Chem Soc. 2011,133(37):14570-3.
2. Luo J., et al.; Hydrogen-bonded organic frameworks: design, structures and potential applications. CrystEngComm. 2018, 20, 5884.
3. Lü J, Cao R. Porous Organic Molecular Frameworks with Extrinsic Porosity: A Platform for Carbon Storage and Separation. Angew Chem Int Ed Engl. 2016, 55(33):9474-80.
4. Simard, M., et al.; Use of hydrogen bonds to control molecular aggregation. Self-assembly of three-dimensional networks with large chambers. J. Am. Chem. Soc. 1991, 113, 4696.
5. Duchamp, D. J., Marsh, R. E. The crystal structure of trimesic acid (benzene-1,3,5-tricarboxylic acid). Acta Crystallogr. B. 1969, 25, 5.
6. Wenbin Yang, et al.; Exceptional Thermal Stability in a Supramolecular Organic Framework: Porosity and Gas Storage. J. Am. Chem. Soc. 2010, 132, 41, 14457–14469.
7. Pulido, A.; et al.; Geometric landscapes for material discovery within energy–structure–function maps. Nature. 2017, 11(21): 5423–5433.
8. Yin, Q.; et al.; An Ultra-Robust and Crystalline Redeemable Hydrogen-Bonded Organic Framework for Synergistic Chemo-Photodynamic Therapy. Angew. Chem. Int. Ed. 2018, 57, 7691-7696.
9. Ting Liu, et al.; A novel hydrogen-bonded organic framework for the sensing of two representative organic arsenics. Canadian Journal of Chemistry. 2020, 98(3): 352-357.