Application of Covalent Organic Framework-Based Nanosystems in Biomedicine

Zitao Hu; Yin Ding

doi:10.7536/PC201214

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (11) : 1935-1946 DOI: 10.7536/PC201214

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Application of Covalent Organic Framework-Based Nanosystems in Biomedicine

Zitao Hu
, Yin Ding ^*

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Abstract

Covalent organic frameworks(COFs)is a highly ordered crystalline porous polymer synthesized by dynamic covalent chemical method. Low density, large specific surface area, adjustable porosity, simple and diverse synthesis routes, designable functional units and structures, easy functionalization of surface and pore channels, and high physicochemical stability are the main characteristics of COFs. It has received extensive attention in molecular adsorption and separation, energy storage, photoelectricity, sensing, catalysis, chromatography materials, water treatment materials and biomedicine domains. This paper focuses on the recent research progress of COFs-based nanosystems in biomedical fields, such as biological detection and imaging, drug delivery, optical therapy and combination therapy, and finally summarize the current challenges and future development opportunities of COFs in biomedical field.

Contents

1 Introduction

2 COFs for biosensors and imaging

3 COFs for drug delivery

4 COFs for phototherapy

4.1 COFs for photothermal therapy

4.2 COFs for photodynamic therapy

4.3 COFs for synergistic therapy

5 Other application of COFs

6 Conclusion and outlook

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Keywords

covalent organic frameworks(COFs) / drug delivery / photodynamic therapy / photothermal therapy / bioimaging

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Zitao Hu, Yin Ding. Application of Covalent Organic Framework-Based Nanosystems in Biomedicine. Progress in Chemistry, 2021, 33(11): 1935-1946 DOI:10.7536/PC201214

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1 Introduction

Since Yaghi's group first reported two kinds of porous crystalline organic materials (COF-1 and COF-5) connected by covalent bonds in 2005, covalent organic frameworks (COFs) have been developed for more than a decade^[1]. COFs are a class of crystalline organic porous materials composed of light elements such as H, B, C, N, Si and O, which are connected together by covalent bonds (C — C, C = N, C = N — N, C — O, C — N and B — O)^{[2⇓⇓⇓~6]}. According to the principle of topology, different sizes and shapes of pores can be obtained by designing different building units of COFs materials. The pore structure of COFs is periodic, and the shape of pore channels can be divided into regular tetrahedron, regular hexagon, square, rhombus and triangle. Selecting the geometric configuration of the building blocks and adding rigid monomers to restrict the intramolecular rotation are helpful to improve the structural stability of COFs materials. COFs can be divided into two-dimensional (2D) and three-dimensional (3D) COFs in terms of structural dimensions^{[7⇓⇓⇓⇓⇓~13]}. 2D COFs materials are usually layered materials composed of one or more planar building units, so they have only one-dimensional pore structure. However, 3D COFs must have at least one 3D configuration in their building blocks, usually using tetrahedral monomers as scaffolds, and are obtained by polymerization with other monomers. There are five common synthesis methods of COFs: solvothermal synthesis, ionothermal synthesis, microwave synthesis, room temperature synthesis and physical grinding^{[14⇓⇓~17]}^[18⇓~20]^[21~22]^{[23⇓⇓~26]}^[27⇓~29]. Relatively speaking, the synthesis methods of COFs are relatively simple, and the active functional groups at the end of COFs provide conditions for the further functionalization of COFs materials^{[30⇓⇓~33]}.

As an emerging porous crystalline material, COFs have attracted much attention in adsorption and separation, energy storage, optoelectronic devices, chemical sensing and catalysis^[34⇓~36]^[37]^[38⇓~40]^[41⇓~43]^[44⇓~46]. In addition, COFs have also been used in biological imaging and cancer therapy^{[47⇓⇓⇓⇓⇓⇓~54]}. In terms of nanomedicine applications, compared with other nanosystems, COFs have the following characteristics. (1) Presetability: The symmetry and molecular size of the building monomers determine the shape and size of the COFs^{[55⇓⇓~58]}. The topological structure, pore size and functional properties of COFs can be pre-designed through reasonable monomer selection, which is helpful to build a COFs diagnosis and treatment system with ideal structure and properties. (2) Controllability: The active functional groups on the framework of COFs provide the possibility for the functionalization and pore modification of COFs materials, which is conducive to molecular recognition and drug loading^{[59⇓⇓~62]}. (3) High stability: COFs are linked by covalent bonds and have good thermal and chemical stability^[63⇓~65]. (4) Biocompatibility: The metal-free characteristics of COFs avoid the toxicity of heavy metal ions, so the nano-diagnosis and treatment system based on COFs has good biocompatibility.

In conclusion, COFs have great potential for biomedical applications. In this review, we will focus on the recent applications of COFs in biological detection and imaging, drug delivery, optical therapy, combination therapy and immunotherapy, so as to provide a comprehensive understanding of COFs in the field of biomedicine and promote the cross-research between COFs and nanomedicine.

2 Biological Detection and Imaging

Covalent organic frameworks have a wide range of applications in the field of biological detection and imaging, which are mainly based on fluorescence sensing and imaging. One is that COFs have their own fluorescence, which can be directly used as fluorescent sensors or fluorescent labels for fluorescence detection and imaging of cells or small biological molecules, nucleic acids and metabolites in vivo. The other is that COFs themselves do not emit light, but can be used as carriers of some metal nanoparticles or fluorescent dye molecules to improve their imaging effect.

The luminescent properties of fluorescent COFs are closely related to their structural units, connection modes and topological structures. Fluorescent COFs are mainly synthesized from aromatic building blocks containing large π-bond conjugated structures, such as triazine, tetrazine, pyrene, phthalocyanine and porphyrin, or from monomers with aggregation-induced luminescence properties, such as polyphenylsilole, triphenylethylene and tetraphenylethylene. The common covalent bonding modes of fluorescent COFs include B — O, C = N and C = N — N = C. Compared with the bulk COFs, the fluorescent properties of the flaky or point-like COFs are better. Therefore, it is a research direction in this field to improve the photoluminescence properties of COFs such as nanosheets by different exfoliation methods^[66].

Jiang et al. reported the first light-emitting semiconductor COF (TP-COF) in 2008^[67]. TP-COF is polymerized by 2,3,6,7,10,11-hexahydroxytriphenyl and dipyrene boronic acid, and has a 2D overlapping structure. High quantum yield (about 60%) can be obtained by suppressing the rotation of the macrocyclic structure, which can capture photons in a wide wavelength range and achieve energy transfer and migration. Trabolsi et al. Successfully synthesized triazine-based COF (TTA-DFP COF) using a simple microwave-assisted method^[21]. Through liquid exfoliation of TTA-DFP COF, the particle size was reduced to nanoscale to obtain TTA-DFP CONs, and the photoluminescence properties were improved by 6 times compared with those before exfoliation. Based on the strong luminescent properties, suitable nano-size and high dispersion in biological media, they used it as a fluorescent probe for cell labeling on HeLa cells. The stripped TTA-DFP CONs can be used as a nuclear probe for bioimaging without additional targeting, and can enter the nucleus through clathrin-mediated endocytosis within 30 min, showing a strong blue signal. With the increase of co-culture time, the fluorescence intensity increased, which proved the excellent internalization and imaging ability of the material. Given the paucity of nuclear-labeled common dyes for cellular imaging, TTA-DFP CONs would be a new option.

Two-photon imaging (TPI) can reduce phototoxicity and improve the resolution of three-dimensional focal spot. Zhang et al. constructed COF (TPI-COF) based on benzothiadiazole and p-phenylenediamine by using D-π-A-π-D chromophore configuration strategy, and greatly improved the long-range crystal domain and overlapping π-π superposition structure by increasing polarization charge distribution, constructing large π-conjugated domain, limiting intramolecular bond rotation, and weakening TPI chromophore superposition (Fig. 1)^[68]. Cell experiments showed that TPI-COF had efficient two-photon fluorescence performance and could be phagocytosed by 4T1 cells under 810 nm near-infrared light irradiation. In the animal model, the tumor tissue also showed obvious punctate fluorescence signals, and the maximum detection depth could reach about 150 mm, which had deeper tissue penetration ability than ordinary fluorescence.

In addition to biological imaging, COFs materials can also be used as carriers of detection or imaging reagents to improve the effect of detection or imaging. Wang et al. prepared CMC-COF-LZU1 hydrogel by using benzenetricarbaldehyde and p-phenylenediamine as the main raw materials, modifying with carboxymethyl cellulose, and reacting at 25 ℃ for 72 H. Pb (II) was further coordinated with CMC-COF-LZU1 hydrogel in situ, and Pb nanoparticles were generated by solvothermal method and loaded on CMC-COF LZU1 to generate Pd NPs/CMC-COF LZU1 composite nanoparticles^[69]. Due to the in-situ formation and loading of Pd nanoparticles, the size of the colloidal particles changed little, which was about 500 nm before and after loading. By loading the Pd nanoparticles, the activity and the stability of the Pd nanoparticles are improved, and the activity reduction of the Pd nanoparticles due to agglomeration is avoided. The color and fluorescence conversion of N-butyl-4-amino-1,8-naphthalimide (NPH) can be realized by catalyzing N-butyl-4-allyloxycarbonyl to protect amino-1,8-naphthalimide (NNPH). They used folic acid as a recognition element and NPH and NNPH as signaling molecules to perform colorimetric analysis and multicolor imaging of cancer cells through the COFs composite. The entire strategy enables the COF-based nanoplatform to accurately and sensitively detect and image folate-positive cancer cells. Zhang et al. used trihydroxybenzenetricarbaldehyde and 4-aminosalicylhydrazide as monomers to generate imine-linked COF-TpASH by Schiff base condensation method. The reaction conditions were mild, and the reaction time was 12 H at 90 ℃ in aqueous solution. The enol-ketone tautomeric structure in the molecule was irreversible, which made TpASH more stable and suitable for biological applications^[70]. However, because the size of the initial TpASH is micron-sized and is difficult to be taken up by cells, the ultrathin TpASH nanosheet with nanoscale thickness is obtained after liquid-assisted ultrasonic stripping, and the two-photon fluorescent probe NPHS is further modified and grafted.The obtained TpASH-NPHS two-photon fluorescence probe is easy to be taken up by cells, and can be used for detecting hydrogen sulfide in organisms under the excitation of near-infrared light; and cell and animal models confirm that the material has low cytotoxicity, excellent light stability and long-term biological imaging capability. In addition, the detection process is not interfered by endogenous enzymes, and has a certain clinical application prospect.

The size of the colloidal particles that can be used in biological systems should be less than 200 nm, but the current preparation methods of COF materials can not obtain colloidal particles with regular morphology below 200 nm. Tan et al. Developed a core-mediated method, in which nanoparticles are used as the core and COF is wrapped outside the nanoparticles to form core-shell composite nanoparticles^[71]. The up-conversion nanoparticles were used as cores, which were wrapped by imine-linked polymeric COFs to obtain UCCOFs-1 for efficient near-infrared activated PDT and in situ ROS generation detection. The particle size of UCCOFs-1 is controlled in the range of 30 ~ 60 nm, which is very suitable for biological applications. Loading indocyanine green (ICG) on UCCOFs-1 as a ROS probe, the up-conversion luminescence (UCL) of UCCOFs-1 at 654 and 800 nm was quenched due to the spectral overlap between ICG and UCCOFs. Under NIR irradiation, ICG degrades while UCCOFs-1 continues to produce singlet oxygen, resulting in enhanced UCL signals of UCCOFs-1 at 654 and 800 nm to show singlet oxygen production. With the increase of irradiation time, the UCL of UCCOFs-1 at 800 nm is gradually enhanced, so that the generation of singlet oxygen in vivo can be monitored in real time.

3 Drug delivery

Effective drug delivery systems need to be characterized by high drug loading capacity, sustained drug release, local control of in vivo release, and water solubility. In addition, biocompatibility and degradability are also important. Common drug delivery systems include microtubules, polymer nanoparticles and inorganic nanoparticles, but they often have the problems of easy drug leakage and low loading rate^[72].

Based on the unique advantages of COFs, such as high porosity, adjustable structure and good stability, the early research on COFs mainly focused on gas storage and separation. In recent years, the study of COFs as a nanoplatform for drug delivery has become an emerging field due to their tunable pore structure, easy functionalization and low toxicity. The channels of COFs will provide a suitable space for the loading of therapeutic drugs to avoid premature leakage of drugs, thus achieving the enrichment of drugs in the tumor site^[73,74]. The first work on a drug delivery system based on COFs appeared in 2015, when Yan et al. prepared two morphologically consistent three-dimensional porous crystalline polyimide COFs (PI-COFs) (Fig. 2a)^[75]. PI-COFs have high thermal stability and specific surface area. PI-COF-4 has a specific surface area of 2403 m²·g^-1,PI-COF-5 and a specific surface area of 1876 m²·g^-1. PI-COF-4 and PI-COF-5 had 24 wt% and 20 wt% ibuprofen (IBU) loading capacity, respectively, and IBU release experiments showed that most of the drugs were released in about 6 days, and the total release amount could reach 95% of the initial IBU (Figure 2B), with good release control effect.

COFs materials can be used for drug delivery, and simple preparation methods, regular nanostructures and segmental structures that can respond to the microenvironment of targeted cells to achieve controlled drug release are the focus of current research. Zhang et al. Constructed an imine-linked COFs material (F68 @ SS-COFs) with disulfide bond structure responding to redox environment in vivo by using Schiff base method^[76]. The size of F68 @ SS-COFs is 150 nm, and the specific surface area reaches 1125 m²·g^-1, which can effectively load doxorubicin (DOX) with a loading rate of 21%. After uptake by tumor cells, COFs with disulfide bond structure disintegrate in the environment of high concentration of GSH and release DOX rapidly.

In order to simplify the preparation process of drug-loaded COFs nanoparticles, Lin et al changed the previous strategy of loading drugs on the synthesized COFs, and successfully synthesized DOX-loaded COFs materials (TAPB-DMTP-COF) by one-pot method at room temperature from monomers 1,3,5-tris (4-aminophenyl) benzene, 2,5-dimethoxybenzene-1,4-dialdehyde and DOX^[77]. The drug loading rate of this one-pot synthesis was as high as 32.1 wt%, and the controlled release of DOX could be achieved by adjusting the pH. In vitro and in vivo experiments showed that TAPB-DMTP-COF had good biocompatibility and tumor inhibition effect.

How to improve the stability and dispersibility of drug-loaded COFs and achieve the versatility of the carrier has also been explored after the drug loading has been improved to a certain extent. Among them, the modification of COFs with polymers is an effective method. Jia et al. synthesized the nanocomposite PEG-CCM @ APTES-COF-1 through the self-assembly of PEG-CCM and Amine functionalized COF-1 (APTES-COF-1) (Figure 3A)^[78]. The pharmacokinetic modifier PEG-CCM can effectively improve the biocompatibility of the nanocomposites and prolong the blood circulation time. The TEM image of PEG-CCM @ APTES-COF-1 shows its flaky structure with good water dispersibility (Figure 3 B). PEG-CCM @ APTES-COF-1 can be degraded in the acidic tumor environment to achieve effective drug release. The in vivo anti-tumor experiment shows that the PEG₂₀₀₀-CCM@APTES-COF-1 added with DOX has obvious tumor growth inhibition compared with the PEG₂₀₀₀-CCM@APTES-COF-1 added with DOX alone.

In addition to the surface modification of COFs, the subsequent reaction of active functional groups on the COFs skeleton can be used to modify the pore channels of COFs, which provides more selectivity for drug encapsulation and controlled release of COFs. For example, the boron atom in the borate bond is an electron-deficient group, which can coordinate with the amine and imidazole groups in proteins or insulin through nitrogen-boron complexation. Based on this, Jia et al. developed an insulin nano-COF carrier based on glucose and pH dual-response^[79]. They encapsulated insulin and glucose oxidase into COFs by the Brnsted and Lewis action (N: → B). In the hyperglycemic state, glucose is converted into gluconic acid under the catalysis of oxidase, and then insulin is released after degradation due to the instability of boroxyl COFs under acidic conditions. Through the dual response of hyperglycemia and pH, polymer COFs composites can effectively cope with the increase of blood glucose, thus maintaining the normal level of blood glucose. Li et al. Synthesized 8-hydroxyquinoline functionalized COFs (COF-HQ)^[80]. The introduction of the quinoline group enables the material to have better water dispersibility and higher 5-fluorouracil drug loading. Meanwhile, the existence of a large number of conjugated nitrogen atoms of the quinoline heterocycle and the COF main chain enables COF-HQ to controllably release 5-fluorouracil in a weak acidic environment.

4 Phototherapy

4.1 Photothermal therapy

Photothermal therapy (PTT) is an important cancer therapy. Photothermal agents (PTAs) first absorb light energy, and then the energy is dissipated in the form of heat through non-radiative relaxation. When it reaches a certain temperature, it can kill tumor cells. At present, the nanomaterials with high photothermal conversion efficiency mainly include conjugated polymers, plasmonic metal nanostructures, semiconductors and ferromagnetic nanoparticles^[81,82]^[83,84]^[85,86]. Compared with closed porous systems that limit heat flow, the open pores of COFs can quickly transport the generated heat to the environment, so COFs materials have great potential for photothermal therapy. At present, the research of PTT based on COFs is mainly divided into two types: (1) COF composites loaded with PTAs; (2) COFs materials with inherent photothermal properties.

In 2016, Wang et al. Proposed a method to convert amorphous organic networks into crystalline covalent organic frameworks under the condition of maintaining colloidal nano-size and uniform morphology^[87]. The Fe₃O₄ nanoclusters are encapsulated by the disordered polyimide network, and the formed imine bonds can be reconstructed under thermodynamic control, transforming the polyimide network into imine-linked COFs in situ. The core-shell microspheres have uniform size and shape, controllable shell thickness, good modifiability and dispersibility, high specific surface area, periodic micropores and good magnetic properties. The photothermal curing effect was demonstrated on the nanolayer under near-infrared light irradiation. Based on the previous research, Pang et al. Successfully prepared monodisperse micron-sized flower-like COF (HCOF) with trihydroxybenzenetricarboxaldehyde and p-phenylenediamine as monomers by solvent aging method at room temperature without using any soft or hard templates.The Fe-HCOF obtained by post-metallization with trivalent iron has good photothermal effect and anti-tumor effect in vivo, which further proves the feasibility of post-functionalization of COFs in PTT^[88].

A large number of photothermal reagents with near-infrared absorption are mainly located in the first near-infrared region. However, the PTAs in NIR-Ⅱ (1000 ~ 1350 nm) have deeper penetration into biological tissues, lower light scattering and higher maximum allowable exposure. Therefore, NIR-Ⅱ PTAs have also attracted extensive research. Dong et al. reported a nanoscale microporous carbon nanomaterial, which was generated from COF precursors with 1,3,5-tris (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde as monomers by simple pyrolysis at high temperature^[89]. The obtained carbon nanoparticles (CNPs) have a broad absorption peak in the NIR-II region (1 064 nm) and a high photothermal conversion efficiency (η = 50.6%). In addition, in vivo and in vitro experiments have fully demonstrated that the material can be used as a highly efficient NIR-II PTA to achieve tumor ablation through PTT.

The binding energy of organic radicals to COFs endows COF materials with significant optical, electronic, and magnetic functions with unique redox activity. Guo et al. proposed a new strategy to transform the COF prepared by the 2,2 '-bipyridine and 1,3,6,8-tetrakis- (p-aminophenyl) -pyrene Schiff base condensation method from neutral to positively charged COF and finally to the cation radical framework, which enables the redox centers within the framework to be superimposed on each other (Fig. 4)^[90]. The non-radiative relaxation process of near-infrared absorption and photothermal conversion can be enhanced by the charge transfer between the π-coupled multilayers, and the photothermal conversion efficiencies of the two cationic COF materials are as high as 63. 8% and 55. 2% under 808 and 1064 nm laser irradiation, respectively. The COFs were further modified by PEG.The particle size of the modified COFs was about 178 nm, which was suitable for biological application.Photoacoustic imaging and photothermal therapy of tumor-bearing mice under near-infrared light irradiation were successfully realized.

4.2 Photodynamic therapy

Photodynamic therapy (PDT) requires the participation of photosensitizers (PSs), light and oxygen. Under the irradiation of specific wavelength light, non-toxic PSs can absorb light energy and react with oxygen to produce ROS and achieve cell apoptosis and necrosis^[91,92]. PDT has the advantages of non-invasive and spatial accuracy, which can reduce side effects and reduce the recurrence rate of tumors^[93⇓~95]. Porphyrin-based photosensitizers are generally considered to be PDT agents for clinical transformation due to their reasonable photodynamic therapeutic window and relatively high singlet oxygen quantum yield. However, these photosensitizers with planar aromatic macrocyclic structure still have some defects, such as poor water solubility and easy aggregation, which greatly limit their application in PDT. COFs have unique advantages, such as high specific surface area and adjustable pore structure, and have excellent PSs loading capacity. Meanwhile, the active functional groups on the skeleton can further graft PSs to achieve efficient PDT. In addition, the development of COFs with intrinsic photosensitive properties for direct use in PDT is also a hot spot in PDT research.

Yuan et al. prepared PcS @ COF-1 nanosheets with a size of about 131. 4 nm and a thickness of 12. 9 nm by loading phthalocyanine (PcS) and amine-functionalized COF-1 nanosheets and then ultrasonically exfoliating them. The high specific surface area of COF-1 greatly improved the loading capacity of PcS^[96]. PcS @ COF-1 nanosheets have little absorption in the visible and near-infrared regions, which can effectively reduce the quenching of singlet oxygen. PcS @ COF-1 can produce more singlet oxygen than PcS alone under light irradiation, which is an effective anti-tumor photodynamic therapy material.

In addition to improving the loading capacity of porphyrins and other photosensitizers, it is also one of the current research hotspots that porphyrins are directly used as the framework of COFs. Qu et al. Synthesized highly dispersed ultrafine (2.9 nm) porphyrin-based COF nanodots (CONDs) based on 5,10,15,20-tetrakis (4-aminophenyl) -21H, 23H-porphyrin and 2,5-dihydroxyterephthalaldehyde through a liquid exfoliation strategy, and modified them with polyethylene glycol (PEG) to improve their physiological stability and biocompatibility^[97]. CONDs-PEG has good phototriggered ROS generation ability and shows good PDT efficiency both in vivo and in vitro. Due to its ultra-small size, CONDs-PEG can be removed from the body by the kidneys without causing long-term toxicity.

Tang et al. loaded dye-labeled oligonucleotides onto porphyrin-based COFs. In the presence of the biomarker survivin mRNA, the fluorescence previously quenched by fluorescence resonance energy transfer can be restored for cancer cell imaging. Under near-infrared light irradiation, a large amount of ROS can be produced, which induces oxidative stress, reduces mitochondrial membrane potential and leads to cell apoptosis^[98].

Because of the loss of blood vessels in the tumor site and the proliferation of tumor cells, especially the extrusion of extracellular matrix (ECM) and cancer cells on the tumor blood vessels, the oxygen supply in the tumor site is insufficient, and the efficacy of PDT is greatly limited. Considering these factors, Zhang et al. Built a COF-based nanosystem to enhance tumor PDT by destroying ECM^[33]. 2,4,6-tris (4-aminophenyl) -1,3,5-triazine and 2,5-dihydroxyterephthalaldehyde were used as monomers to prepare COF_TTA-DHTA, which was loaded with pirfenidone (PFD) to obtain spherical PCPP with a diameter of about 60 nm. After intravenous injection, it accumulates in the tumor site through EPR effect, releases PFD in situ, and down-regulates the level of tumor ECM components, resulting in the reduction of tumor solid phase stress and the alleviation of tumor hypoxia. The depletion of ECM in PCPP treatment clearly enhanced the enrichment of the administered protoporphyrin PPIX in the tumor area. The alleviation of hypoxic state at the tumor site and the improvement of PPIX uptake greatly promote the generation of ROS, thus achieving excellent PDT effect.

In addition to using traditional photosensitizers to achieve photodynamic therapy, reasonable design of PDT inactive molecules can also lead to COFs with good ROS generation efficiency. Deng et al. coupled two molecules that could not produce ROS to obtain two COFs (COF-808 and COF-909) with ordered shape and uniform crystallization, and used them as photosensitizers (Figure 5A)^[99]. Compared with the band gap energy of the linker (2.79 eV), the band gap energy of COF-909 is 1.96 eV at the optical absorption wavelength of 630 nm. The bandgap of COFs shrinks, providing the appropriate energy spectrum overlap, greatly facilitating the PDT performance. The results of in vitro and in vivo experiments showed that COF-909 had good biocompatibility and high PDT efficiency, and had obvious inhibitory effect on tumor growth (Fig. 5B).

4.3 Combined phototherapy

Multifunctional functional groups, bonding defects on the framework, and large internal channels allow COFs to achieve PDT/PTT synergistic therapy through further modification or host-guest encapsulation strategies.

CuSe is a biodegradable PSs, and the selenium released at the same time reduces the occurrence of liver, lung, and prostate cancers. Pang et al. Prepared highly monodisperse COF-LZU-1 using benzenetricarbaldehyde and p-phenylenediamine as monomers by liquid-phase synthesis at room temperature^[100]. The as-synthesized nanosized COFs showed good photodynamic effect under laser irradiation at 650 or 808 nm. Then COF-CuSe with high photothermal conversion efficiency and photodynamic effect was prepared by coupling CuSe nanoparticles with COF and successfully used for synergistic therapy. In view of the excellent NIR-II imaging properties of Ag₂Se QDs, Pang et al. prepared COF-Ag₂Se nanocomposites on the basis of COF-CuSe through a cation exchange process between Ag⁺ and Cu²⁺^[101]. In vitro and in vivo studies have shown that COF-Ag₂Se nanocomposites have a significant inhibitory effect on tumor growth through the combination of photodynamic and photothermal therapy.

Inspired by the biomimetic mineralization strategy of nanoparticles, Xie et al. developed a homogeneous and stable COF material (COF-B) with 5,10,15,20-tetrakis (4-aminophenyl) -21H, 23H-porphyrin and trihydroxybenzenetrialdehyde as monomers under the modification of bovine serum albumin, which not only has good water dispersibility, but also has good photostability and biocompatibility^[102]. It has good photothermal and photodynamic activity under single wavelength 685 nm laser irradiation, and can effectively inhibit or even completely eliminate tumors.

Chen et al. Synthesized a COF material based on 5,10,15,20-tetrakis (4-aminophenyl) -21H, 23H-porphyrin and terephthalaldehyde, which was dispersed into covalent organic framework nanoparticles (COF-366 NPs) with a size of about 100 nm by ultrasound^[103]. The COF structure can reduce the quenching of porphyrins and broaden the absorption spectrum of COF-366 NPs, so that the material can simultaneously act as a photosensitizer and a photothermal agent to generate ROS and heat under the irradiation of a single wavelength of 635 nm light. The large specific surface area of COF-366 NPs also increases the light-harvesting ability, and the porous structure is beneficial to oxygen storage and active oxygen diffusion. Dong et al. Prepared nanoscale COF (NCOF) from 1,3,5-tris (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dialdehyde at room temperature^[104]. They adopted the strategy of end-group functionalization, loading and encapsulation to achieve PDT/PTT synergistic therapy by covalently grafting porphyrin PSs and loading naphthalocyanine PTA. Under red and near-infrared light irradiation, VONc @ COF-Por showed high ¹O₂ generation and photothermal conversion ability.In vitro and in vivo experiments showed that VONc @ COF-Por could significantly inhibit the proliferation and metastasis of tumor cells through the combined PDT/PTT effect.

5 Other

Photodynamic therapy and photothermal therapy can effectively inhibit tumor growth and produce tumor-associated antigens (TAAs) to promote anti-tumor immune response after the elimination of the primary tumor. The COF @ ICG @ OVA synthesized by Pang et al. Can ablate primary tumors under 650 and 808 nm laser irradiation, and has high photothermal conversion efficiency and ROS generation ability^[105]. After the production of tumor-associated antigens, further combined with anti-PD-1 checkpoint blockade therapy, it can effectively eliminate the primary tumor, produce a strong immune response and inhibit the metastasis of cancer cells.

Hypoxic tumor microenvironment and self-quenching of photosensitizers can prevent PDT from inducing immune passive cell death (ICD) and weaken the effect of systemic anti-tumor immune response. Yuan et al. spontaneously adsorbed indocyanine green onto COFs synthesized from benzenetricarbaldehyde and 1,3,5-tris (4-aminophenyl) benzene through small molecule conjugation, and then ultrasonically stripped and coated with dopamine (PDA) to construct a new phototherapeutic agent ICG @ COF-1 @ PDA with enhanced efficacy (Fig. 6)^[106]. After a single round of near-infrared laser irradiation, significant ICD was induced, triggering antitumor immunity in colorectal cancer, with an inhibition rate of 62.9% for untreated distant tumors. ICG @ COF-1 @ PDA also showed a significant phototherapeutic effect on breast lung metastases in 4 T1 mice.

Disruption of cellular or subcellular Ca²⁺ homeostasis can cause cytotoxicity and trigger cell death. Therefore, the disruption of Ca²⁺ homeostasis through calcium overload is expected to become one of the potential means of anti-tumor therapy. However, intracellular Ca²⁺ maintenance mechanisms, such as mitochondrial and endoplasmic reticulum buffering function, make it difficult to change intracellular Ca²⁺ concentration by delivering drugs. Dong et al. reported a CaCO₃@COF-BODIPY-2I@GAG based on NCOFs, which were modified by stepwise modification of COFs with 1,3,5-tris (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dialdehyde as monomers, coated with BODIPY-2I photosensitizer, CaCO₃ nanoparticles and modified with GAG targeting coating (Fig. 7)^[107]. Under light irradiation, BODIPY-2I can produce ¹O₂ to cause mitochondrial dysfunction and loss of Ca²⁺ regulation function, so that the CaCO₃NPs protected by COF matrix can enter tumor cells smoothly through endocytosis and release Ca²⁺ under the action of lysosomes, resulting in Ca²⁺ homeostasis disorder. The anti-tumor efficiency in vivo and in vitro experiments was significantly improved by synergizing PDT and Ca²⁺ overload triggered by ¹O₂.

COFs have also been used for synergistic chemotherapy, hyperthermia, and magnetic resonance MRI imaging. Traboulsi et al. prepared imine-linked TAB-DFP-nCOFs with a particle size of 237 ± 31 nm^[108]. DOX was further loaded on the surface of COFs, and magnetic iron oxide nanoparticles (γ-Fe₂O₃NPs) were coated on the surface of COFs. Finally, poly (L-lysine) cationic polymer was used to modify the COFs to obtain pH-responsive and superparamagnetic γ-SD/PLL. The nanoparticle allow that drug to be selectively released in the acidic microenvironment of canc cells, and meanwhile, because the gamma-SD/PLL has a heat-conducting porous structure, the gamma-SD/PLL can effectively generate heat under an alternating magnetic field to realize thermotherapy.

6 Conclusion and prospect

In this paper, the applications of COFs-based diagnostic and therapeutic systems in bioimaging, drug delivery and cancer therapy in recent years are introduced. The COFs system has the advantages of large specific surface area, adjustable pore size and pore structure, and presettable functional units, and can also improve the dimensional stability, water dispersibility, biocompatibility and cellular uptake ability of the nanosystem through surface modification. To sum up, in recent years, COFs have made great progress in drug delivery and chemotherapy, PDT, PTT, and synergistic therapy. However, compared with other nanomaterials such as ordinary polymers, mesoporous silica and MOFs, COFs are still in the initial stage of development, and there are still many problems to be solved.

In order to meet the requirements of biomedical applications, it is necessary to carry out in-depth studies on the synthesis methods, size control, surface and pore regulation and modification, improvement of solubility or dispersion stability, increase of targeting specificity and biocompatibility, cytotoxicity and animal experiment evaluation of COFs materials. At present, the common synthesis methods of COFs materials used in the field of biomedicine include Schiff base reaction, ester condensation reaction of boric acid, trimerization reaction of aromatic nitriles, etc., and Schiff base reaction is the most commonly used method. Among them, boron is extremely sensitive to the attack of nucleophiles due to its electron-deficient nature, so the chemical stability of COFs condensed with borate ester is poor, and it is easy to decompose in moisture, so its skeleton needs to be strengthened in biological applications. Triazine-based COFs materials usually need to be reacted at extremely high temperatures, which requires high thermal stability of the precursors and is difficult to synthesize, and the crystalline state and regularity of the products are poor. The Schiff-base reaction has mild reaction conditions, does not need expensive transition metals, and avoids the problem of residual metal catalysts in the preparation process of COFs. In addition, Schiff-base reaction is a thermodynamically controlled reversible reaction, and the formation of imine bond (C = N) can obtain thermodynamically more stable products, which can exist stably in common organic solvents, water, and even acid/base solutions. In the aspect of size control of COFs materials in the field of biomedicine, the more important challenge is the preparation of nano-scale monodisperse and high crystallinity nano-COFs. Most nanoscale COFs are achieved by mechanical separation, but it is difficult to achieve highly uniform nanoscale COFs with this method. Most of the currently reported COFs are hydrophobic, and the solvents for preparation are limited, so the generated COFs materials have poor dispersibility in solvents, and it is urgent to develop directly prepared hydrophilic COFs which are water-stable and can be taken up by cells. Theoretically, introducing hydrophilic groups into monomers can directly improve the hydrophilicity of COFs, but there are few related studies. At present, COFs must be constructed based on reversible dynamic covalent bonds, which limits the development of aqueous synthesis methods. Therefore, the development of new methods to construct new COF structures based on irreversible chemical processes will greatly expand the diversity and structural stability of COFs materials. In the detection and imaging of fluorescent COFs, the fluorescence of fluorescent materials mainly comes from conjugated organic ligands, especially aryl aldehydes, boronic acid compounds and halogenated aryl compounds with large conjugated structures. Compared with ordinary fluorescent molecules, fluorescent COFs materials have less number and lower fluorescence quantum yield, and have lower fluorescence resolution and weaker targeting ability of subcellular organelles in cell imaging. Before entering the clinical application, not only the functional units, molecular topology, host-guest interaction and colloidal properties of COFs should be studied, but also the long-term biological toxicity of COFs should be further evaluated. Long-term studies are needed to investigate the degradability, interactions with cells and tissues, pharmacokinetics, biodistribution, toxicity, and therapeutic efficacy of COFs. Finally, it is also suitable for the application of COFs materials in other fields, the research and development of COFs materials with high stability, low cost and excellent performance, and the in-depth study of the structure-activity relationship of COFs.Combining theory with practice, improving the processability of COFs materials and exploring the process route suitable for industrial production are the only way for COFs materials to enter the clinical application of biomedicine.

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