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Covalent organic frameworks (COFs) are emerging organic crystalline polymer materials, which are formed by reversible condensation reactions between lightweight molecular fragments. They have excellent properties such as low density, good porosity and crystallinity, and high thermal stability. These materials are biodegradable due to the reversible condensation process between the monomers. Compared with another widely studied material with metal-organic frameworks, COFs have no additional toxicity caused by introducing metal ions. Therefore, a high potential exists in biomedicine. The chapter aimed to introduce the application of biomaterial COFs in oncotherapy and identify the specific advantages of different types of COFs for specific biomedical applications.
Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
*Address all correspondence to: guiyangzhang@ahmu.edu.cn
1. Introduction
Porous materials have significantly affected biomedical applications and have been widely used in biomaterials, drug delivery, immune engineering, tissue engineering, and biomedical devices [1, 2, 3]. Note that these porous materials have the advantage of encapsulating drugs within their pores and can sustain drug release in drug delivery [2, 4]. Porous polymeric materials traditionally used in biomedicine are amorphous, so there is no porosity in the matrix to optimally encapsulate drugs. For example, poly (lactide-co-glycolide) acid (PLGA) has been widely used as a biomaterial for preclinical and clinical research [5, 6, 7]. However, polylactic acid-glycolic acid copolymers are usually amorphous and have no well-defined porous structure. Therefore, the synthesis of biomaterials should be optimized to maximize the drug encapsulation efficiency. On the other hand, high-purity crystalline materials have a well-defined porous structure, which significantly affects the biomedical field [8, 9]. Nanocarriers generally have multiply layers, mesoporous, and hollows, and their unique nanometer size, pore structure, and good biocompatibility make them good drug carriers [10]. The advantages of the current application of nanomaterials in tumors mainly include the following aspects: (1) large specific surface area and high drug encapsulation efficiency; (2) improving the permeability of cell membranes and drug utilization, with efficient drug delivery; (3) a long half-life in vivo; (4) controllable release in the slightly acidic environment of tumors; (5) the functionalized surface [11]. Ideal cancer therapy cannot be achieved due to the current single treatment method. The use of nanomaterials as carriers for drug co-delivery or the integration of multiple therapeutic modalities can overcome the inherent shortcomings of single therapeutic strategies. Organic frameworks are newly developed crystalline porous composites in recent years. Metal/covalent-organic frameworks have been widely studied and used for oncotherapy due to their advantages such as good biocompatibility, large specific surface area, and easy modification [12].
Since COFs were first reported by Yaghi and his colleagues in 2005, the development of COFs with unique structural features and properties has attracted great research interest in the scientific community [13]. It has great application potential in biomedical applications due to its unique properties, such as controllable pore size, easy modification, high stability, and good biocompatibility [14]. COFs are promising new porous materials synthesized by covalent bonding. Note that the 2D or 3D porous crystal structures with specific spatial subunit organization endow them with highly desirable features: low density, structural diversity, porous structure, high specific surface area, free of heavy metal ions, and tunable pore size [14, 15]. The covalent bonds (B-O and C-N bonds) in the common structures of COFs are chemically and thermally stable. Importantly, the internal ordered structure of COFs is different from other groups of covalent polymers. Organic molecules linked by covalent bonds produce short-range ordered structures within small regions, resulting in amorphous or semi-crystalline materials. Interestingly, slow and reversible reactions between organic ligands or building blocks enable these short-range ordered structures to grow, which generates long-range structures and forms COFs. Besides reversible reactions, other features (rigidity) also contribute to the formation of structurally regular COFs [14, 15]. For structurally regular COFs synthesis, these factors require some basic preconditions, such as the reaction and choice of rigid building blocks for COFs. The pore size and porous structure of COFs are affected by the molecular length and established element type. Based on the above characteristics, reversible reactions have been generally recognized as the preferred synthetic route to generate COFs [16].
Materials are generally subjected to post-modification in exploring material applications to make them have more excellent properties, or achieve the functional effect consistent with the expectation. Functional groups are modified on the material surface by chemical or physical methods, and the same is true for studying COFs. COFs expand their applications in catalysis, sensing, separation, and drug delivery after these functional modifications. The advantages of COFs are mainly reflected in the following aspects: (1) COFs are easy to modify due to their structural characteristics and can realize biomedical applications such as tumor targeting, fluorescence imaging, and cancer therapy. (2) The cavities of COFs can encapsulate guest molecules due to their inherent porosity; therefore, they can serve as carriers for drug delivery. (3) COF monomers have different energy level structures under the framework due to their conjugated structure. (4) COFs do not contain metal ions, which can avoid the biological toxicity caused by metal elements [17, 18]. In addition, the inherent limitations of COFs, such as poor physiological stability, poor dispersion, and non-specific targeting, limit their applications in cancer therapy [19, 20, 21, 22].
However, based on their superior properties, COFs are still considered a promising and efficient organic material platform for cancer therapy. The section summarizes the applications of COFs in oncotherapy. Although the preparations and applications of COFs are still in their infancy and face many challenges, the huge potential of COFs is bound to provide some new approaches for future oncotherapy and pharmaceutical fields.
2. Research progress in the application of COFs in the drug therapy of tumors
Recently, COFs as carriers have been widely used in cancer therapy research. COFs can deliver drugs to targets and use their photothermal and photodynamic effects to kill tumor cells. The applications of COFs in oncotherapy mainly include the following four types: chemotherapy, photodynamic therapy, photothermal therapy, and combination therapy.
2.1 Application of COFs in chemotherapy
Chemotherapy is one of the main methods for the clinical treatment of tumors. However, the efficacy of chemotherapeutic drugs is limited by many factors, such as poor stability and dispersibility in aqueous solutions, low permeability of cell membranes, non-specific targeting, and uncontrollable drug release. Therefore, the use of chemotherapy drugs directly in patients has certain limitations. COFs-based porous materials have become ideal materials for drug delivery due to their excellent properties such as large specific surface area, porosity, and tunable pore size [23]. COFs as nanocarriers for drug delivery have the following advantages: (1) The coordination bonds in COFs are reversible, which makes them biodegradable. (2) With high drug loading, drugs can be encapsulated through surface mesopores. However, their dispersibility in water is poor compared with other common porous materials, such as nano-silica and polymers.
Zhao’s research group synthesized two-dimensional COFs (PI-2-COF and PI-3-COF) in 2016. They have good biocompatibility-existing stably in water in the form of nanoparticles and maintaining a good pore structure. Three different drugs, 5-fluorouracil (5-FU), captopril, and ibuprofen (IBU), were loaded using these two 2D COFs, respectively. The drug-loaded COFs are characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT-IR), and the drug loading effect of COFs is determined by TGA. The results show that the drug loading is as high as 30%. The survival rate of MCF-7 cells treated by the drug-loading system is significantly reduced [24]; however, the unmodified COFs-based drug-loading system has no cancer-cell targeting.
Banerjee’s group selected TpASH to modify COFs and synthesized and prepared folic acid-conjugated covalent organic nanosheets (CONs) for targeting in 2017 (Figure 1a). Such targeted CONs deliver the drug 5-FU to breast cancer cells via endocytosis and kill them. Ultraviolet-visible (UV-Vis) absorption spectroscopy analysis showed that such CONs are loaded with 12% 5-FU. Cell migration and cellular uptake are investigated by MTT experiments and fluorescence microscopy, respectively, indicating that the system has good cancer-cell targeting. Although this system has great potential value in targeted drug delivery, its low drug load limits its development to some extent [25].
Figure 1.
(a) Structure of TpASH-FA-CONs and cancer therapy [25]. Reproduced with permission from ref. [25]. Copyright 2017, American Chemical Society; (b) Synthesis process and oncotherapy of DOX-loaded PEG-CCM@APTES-COF-1 nanomaterials [26]. Reproduced with permission from ref. [26]. Copyright 2018, Springer Nature; (c) Synthesis scheme of thin platelet-polymer COFs-based nanocomposite, establishment of the tumor model, and treatment scheme for BMRC [27]. Reproduced with permission from ref. [27]. Copyright 2020, Royal Society of Chemistry; and (d) PcS@COF-1-mediated photooxidation and photodynamic therapy [28]. Reproduced with permission from ref. [28]. Copyright 2020, Royal Society of Chemistry.
Lin’s group dissolved 1,3,5 Tris(4-aminophenylbenzene) and 2,5 dimethoxyterephthalaldehyde in a solvent to explore a simpler assembly process of COFs and drugs in 2019. The reaction is carried out under the catalysis of acetic acids to obtain TAPB DMTP COF. Then DOX and TAPB-DMTP-COF are assembled into a COFs-based drug-loading system. COFs have good binding to DOX by FT-IR results. According to the absorption intensity of DOX in the UV-Vis spectrum, the drug loading of the system is about 32.1 wt%, which is much higher than previously published results. Besides, in vivo experiments are performed in mice by intratumoral injection, showing that the system has a good killing effect on cancer cells [29].
In addition to the modification of targeting groups on the surface of COFs, polyethylene glycol (PEG) derivatives can also be modified to enhance their hydrophilicity, prolong their circulation time in vivo, and facilitate their accumulation at tumor sites. Jia et al. prepared a series of PEG-modified COF nanomedicines PEGX-CCM@APTES-COF-1@DOX (X = 350, 1000, and 2000) with better dispersibility (Figure 1b). The nano-drug is self-assembled from curcumin (CCM)-modified PEG and amino-functionalized APTES-COF-1@DOX [26]. PEGX-CCM coatings endow the nanomaterials with fluorescence imaging capability and significantly enhance the cellular uptake of materials, the in vivo blood circulation time, and the accumulation capability at tumor sites. APTES-COF-1 can be dissociated under acidic conditions to release the internally loaded DOX. In vitro fluorescence imaging shows that the PEG2000-CCM@APTES-COF-1@DOX group accumulates more drugs in tumor tissues than in the other groups. In vivo anti-tumor experiments prove that PEG2000-CCM@APTES-COF-1@DOX has an excellent tumor-inhibiting effect compared with other groups.
Subsequently, Zhang et al. developed an amphiphilic platelet-like polymer, COFs-based nanocomposite (PEG350-CCM@APTES-COF-1@PA). Efficient delivery of the tyrosine kinase inhibitor drug PA can be achieved for treating brain metastases from renal cancer (BMRC) (Figure 1c) [27]. As a drug delivery vector, the nanomaterials can enhance drug retention in brain tumors. In vivo imaging experiments demonstrates that these COFs-based nanocomposites can cross the blood-brain barriers in mice and accumulate at orthotopic intracranial tumor sites of BMRC. The acidic environment of intracranial tumors degrades COF-based polymer nanocomposites due to boronate ester bonding and releases the drugs, which finally inhibits BMRC.
To sum up, chemotherapy drugs still occupy a vital position in cancer treatment. However, traditional drug delivery systems lack targeting, and drugs are distributed everywhere in the body, resulting in various serious toxic and side effects. To solve this problem, COFs have been developed as carriers for traditional chemotherapeutic drugs recently. The drug-loading system enhances the effect of permeability and retention (EPR) at tumor sites through nanocrystallization, which improved the accumulation of the nano-drug system at tumor sites. Meanwhile, COFs are easy to modify, and specific modifications can improve hydrophilicity and targeting as well as reduce the toxic and side effects. Based on their inherent tunable porous structures, the drug loading and drug release rate can be adjusted by adjusting pore sizes and polarity of COFs to meet different drug uses. Most of the reports show that the use of COFs to deliver chemotherapeutic drugs is targeted and controllable, and the efficacy of the compound system is often better than that of single chemotherapeutic drugs. Therefore, other therapies should be combined to exert the synergistic effect between different therapies, which achieves high anti-tumor efficacy and reduce adverse reactions after medication.
2.2 Application of COFs in photodynamic therapy
Similar to chemotherapeutic drug delivery, the improved effect of nanocarriers on photodynamic therapy (PDT) is mainly reflected in the enhanced accumulation of photosensitizer molecules at tumor sites. Traditional photosensitizers are usually organic molecules with a wide range of conjugation systems. They have poor water solubility and tend to aggregate. Small molecules of photosensitizers accumulate less in tumor tissue after systemic administration, which is difficult to satisfy in vivo applications. Combining small photosensitizer molecules with nanocarriers can make up for the above deficiencies through passive and active targeting.
On the other hand, nanomaterials can improve the photochemical properties of photosensitizers. The loading of photosensitizers inside nanoparticles can prevent their aggregation at the molecular level, which avoids fluorescence quenching and improves the quantum yield of 1O2. The photosensitizers can be adsorbed on the COF surface to prepare COF-photosensitizer materials using the interaction between COFs and photosensitizers. Yuan et al. used APTES-COF-1 nanosheets to adsorb phthalocyanine photosensitizers to prepare PcS@COF-1 (Figure 1d) [28]. Phthalocyanine dyes are highly dispersed on the APTES-COF-1 surface, so PcS@COF-1 exhibits good photodynamic performance under 660-nm laser irradiation, which has obvious killing effects on CT26 cells.
Lin et al. used the COF as a nano template to grow gold nanoparticles (Au NPs) on the COF surface in 2020. Hyaluronic acid (HA) is introduced to improve biocompatibility after covering the material surface with a thin layer of manganese dioxide (MnO2) (Figure 2a) [30]. Synthetic product COF-Au-MnO2 participates in multiple processes in the tumor microenvironment, which forms a cascade reaction. COF-Au-MnO2 first reacts with intratumoral H2O2 to generate O2 in the tumor hypoxic environment, which enhances type-II PDT. Next, Au NPs can decompose glucose to generate H2O2, which promotes starvation treatment and increases O2 concentration in tumor tissues. Besides, MnO2 depletes glutathione (GSH) to enhance the antitumor effect. The released Mn2+ is used for T1-weighted magnetic resonance imaging (MRI). Both in vitro and in vivo experiments prove that COF-Au-MnO2 nanoparticles have good tumor-killing effects.
Figure 2.
(a) Synthesis process and therapeutic mechanism of COF-Au-MnO2-HA [30]. Reproduced with permission from ref. [30]. Copyright 2020, Springer Nature; (b) Preparation process of CONDs-PEG nanodots and the use of COF nanoparticles as photodynamic agents for cancer treatment [31]. Reproduced with permission from ref. [31]. Copyright 2019, Elsevier Ltd; (c) Fabrication of therapeutic COF nanoplatforms for tumor imaging, PDT, and prognostic assessment applications [32]. Reproduced with permission from ref. [32]. Copyright 2020, Royal Society of Chemistry; and (d) Synthesis and working of the COFs-based nanoplatform [33]. Reproduced with permission from ref. [33]. Copyright 2019, Royal Society of Chemistry.
Given the unique structural advantages of COFs, photosensitizers can directly participate in constructing COFs as monomers. The photosensitivity of some porphyrin-based COFs has been reported; however, their applications in PDT are still scarce. Qu et al. synthesized the ultra-small nanodots of porphyrin-based TphDha COFs (Figure 2b) with PDT properties [31]. First, TphDha COFs are synthesized in a Pyrex test tube using tetraaldehyde phenyl porphyrin and 2,5-dihydroxyterephthalaldehyde as starting materials. Subsequently, ultrasonic stripping and surface modification with DSPE-PEG are performed. Finally, the CONDs-PEG nanodots are obtained by filtration and separation. The PEG-coated COF nanodots have good physiological stability and biocompatibility. The uniformly dispersed porphyrin molecules on the COF surface endow the CONDs-PEG nanodots with superior light-triggered-induced reactive oxygen species (ROS) generation ability, which shows the excellent PDT effect and good tumor accumulation ability.
COFs have emerged as a promising material for analysis and biomedicine. However, simultaneous use of COFs for cancer diagnosis and treatment remains a challenge. Tang’s group reported a COF-based therapeutic nano-platform. Dye-labeled oligonucleotides (TSAS) are modified on porphyrin-based COF nanoparticles (COF NPs) for efficient cancer diagnosis and treatment (Figure 2c) [32]. The fluorescence of dyes on TSAS is quenched by COFs via fluorescence resonance energy transfer (FRET). When tumor marker mRNA exists, TSAS form more stable double strands and dissociate from COF NPs. Fluorescence signal recovery can be used for selective cancer imaging. Moreover, porphyrin-based COF NPs generate a large amount of ROS through PDT under near-infrared laser irradiation to induce cancer-cell apoptosis. In vitro and in vivo experiments demonstrate that the COF nano-platform can specifically recognize cancer cells and be used for oncotherapy.
Real-time and in situ monitoring of ROS generation is critical to minimize non-specific damage caused by the high doses of ROS required during PDT. However, phototherapeutic agents generating ROS-related imaging signals during PDT are rare, which prevents easy prediction of future treatment outcomes. Tan et al. developed an upconverting COFs-based nano-platform with upconverting nanoparticles (UCNPs) as the core. A layer of TphDha COF was grown in situ on its surface to realize near-infrared (NIR) light-excited PDT (Figure 2d) [33]. When the UCNP core is excited with a 980-nm laser, the emissions at 541 and 654 nm are absorbed by the TphDha COF shell to produce 1O2. When the shell thickness was 15 nm, the cell hoes of TphDha COFs have the optimal ability to generate 1O2 as well as the optimal inhibitory effect on HeLa cells. 1O2-labile indocyanine green (ICG) fluorescent dyes are loaded into the pores of TphDha COFs, which enables in situ monitoring of 1O2 and oncotherapy in vivo.
Ca2+ is a ubiquitous but subtle regulator of cellular physiology tightly controlled within cells. However, intracellular Ca2+ regulation, such as mitochondrial Ca2+ buffering capacity, may be disrupted by 1O2. Therefore, intracellular Ca2+ is overloaded by the synergistic effect of 1O2 and exogenous Ca2+ delivery, which is recognized as one of the important pro-death factors. Dong et al. constructed NCOF-based nanoformulation CaCO3@COF-BODIPY-2I@GAG [34]. The small molecules of BODIPY-2I photosensitizer are modified with amino residues on its surface, and CaCO3 NPs are loaded in the COFs-based channel. Finally, glycosaminoglycan (GAG) molecules are surface-modified for targeting CD44 receptors in gastrointestinal tumor cells. After intravenous injection of CaCO3@COF-BODIPY-2I@GAG NPs, the premature leakage of CaCO3 NPs during in vivo circulation was avoided under the protection of COFs. CaCO3 NPs are decomposed in the acidic environment of lysosomes to release Ca2+ after entry into tumor cells via CD44 receptor-mediated endocytosis. Besides, BODIPY-2I covalently attached to the surface can generate 1O2 for PDT under laser irradiation. In vitro and in vivo experiments demonstrate that the PDT synergistic treatment mode of Ca2+ overloads can significantly increase the anti-tumor efficiency.
Photodynamic therapy does not induce tolerance to treatments due to its low toxicity. The therapy is considered to be a promising mode of oncotherapy due to its unique advantages such as low invasiveness for patients. However, the current application of photodynamic therapy is mainly in superficial and flat lesions. The lesions are observed through endoscopy, and it is taken as adjuvant therapy for surgery [35]. However, photodynamic therapy is not effective for solid tumors, large tumors, and deep tumors. According to the principle of photodynamics, the curative effect of photodynamic therapy consists of light, photosensitizer, and oxygen. Defects from these three elements greatly limit the efficacy of photodynamic therapy in actual treatment.
Overall, photodynamic therapy, as a unique non-invasive and selective method, has been applied in the clinical treatment of diseases such as cancers. The development of nanotechnology can increase the photodynamic effectiveness and biocompatibility of photosensitizers. Besides, nanotechnology has been used to address issues such as hydrophobicity and the retention and aggregation of photosensitizers as well as improve pharmacokinetic properties and photosensitizer concentration within tumor cells. Although research using COFs for PDT is still in its early stages, these materials offer compelling advantages. For example, the absence of metal elements in their structures may improve their safety and biocompatibility; more importantly, they have excellent photosensitivity and photodynamic properties. Moreover, the PDT performance of COFs can be improved by changing the dimension, composition, and structure of COFs.
2.3 COFs used for photothermal therapy (PTT)
PTT, as an effective cancer treatment strategy, has attracted the attention of researchers. PTT absorbs NIR excitation energy through photothermal agents (PTAs). It is subsequently dissipated in the form of heat, which increases the temperature around the cancer cells and kills cancer cells [36, 37]. PTT has also become one of the most effective ways to treat tumors. Heteropoly blue (HPB) is an ideal PTA with good photothermal conversion efficiency. Wang et al. loaded HPB into COFs in situ by a one-pot method (Figure 3a). The resulting HPB@COF platform exhibits ideal biocompatibility, pH-responsive release properties, and high tumor-suppressive efficiency for PTT, which inhibit tumor growth. A safer and more effective COF-based nano-delivery platform is fabricated for future pH-responsive photothermal therapy [38].
Figure 3.
(a) Synthesis process of HPB@COF; Mechanism by which HPB@COF protects normal cells and kills cancer cells [38]. Reproduced with permission from ref. [38]. Copyright 2022, Royal Society of Chemistry; (b) Preparation of COF-GA and enhanced mild-temperature photothermal therapy [39]. Reproduced with permission from ref. [39]. Copyright 2021, Royal Society of Chemistry; and (c) Synthesis process of GA@PCOF@PDA nanocomposite; Therapeutic principle of multifunctional COFs-based nanocomposites for low-temperature synergistic oncotherapy [40]. Reproduced with permission from ref. [40]. Copyright 2021, Springer Nature.
Photothermal therapy ablates tumors by hyperthermia (>50°C) under laser irradiation. However, hyperthermia inevitably damages surrounding healthy tissues, which causes additional damage. Therefore, effective cancer treatment by mild photothermal therapy at low temperatures is vital. Sun et al. designed nano-agents (COF-GA) to inhibit heat shock protein (HSP90), which enhances photothermal hypothermia for cancer therapy (Figure 3b). Nanoscale COFs can raise the temperature of tumor tissues under laser irradiation, which converts the laser light into heat to kill cancer cells. Gambogic acid (GA), as an inhibitor of HSP90, is used to overcome the thermotolerance of tumors and achieve efficient mild-temperature photothermal therapy. With the increased laser-irradiation time, COF-GA increases the temperatures at tumor sites. In vivo experiments demonstrate that tumor growth is significantly inhibited after COF-GA treatment. Mild photothermal therapy exhibits excellent antitumor efficacy at relatively low temperatures and minimizes nonspecific thermal damage to normal tissues [39].
Feng et al. synthesized GA@PCOF@PDA nanocomposites using stepwise bonding defect functionalization (BDF) and guests (Figure 3c) for encapsulation and surface modification processes of cryogenic cancer therapy. The resulting GA@P COF@PDA reverses the thermal resistance of tumor cells by inhibiting the expression of HSP90. It is the first example of using enhanced light therapy to suppress primary and metastatic tumors at low temperatures. The approach can be further applied to other therapies involving hypothermia and broaden the development of NCOF-based multifunctional nanomedicines for safe and effective clinical applications [40].
COFs have shown great potential in catalysis and biomedicine, but it is difficult to obtain monodisperse COFs with adjustable sizes. Jing et al. developed a series of COFs based on electron donor-acceptor (DA) under mild conditions. Synthesized COFs exhibit excellent colloidal stability and uniform spherical morphology. Sizes can be flexibly adjusted by catalyst content, and absorption spectra also vary with sizes. By changing the electron-donating ability of the monomers can corresponding COFs possess a broad absorption spectral range, which can even be extended to the second near-infrared biological window. Obtained COFs have strong photothermal activity under laser irradiation, which inhibits tumor growth [41].
Zhao et al. prepared two types of 2D COFs containing naphthalene diimide (NDI) as electron acceptor (A) and triphenylamine (PT-N-COF) or triphenylbenzene (PT-B-COF) as electron donor (D). In-plane donor and acceptor units are linked by imine bonds with precise spatial distribution. The charge transfer (CT) process induced by the D-A interaction in the 2D plane results in a pronounced near-infrared absorption property. Unique structural modifications in the COF framework lead to huge differences in photophysical properties and photothermal conversion properties. Compared with PT-B-COF, PT-N-COF containing triphenylamine as donor has stronger D-A interaction and CT effect, which exhibits distinct red-shifted absorption in the NIR region. The photothermal conversion efficiency reaches 66.4%, which is in sharp contrast to 31.2% of PT-B-COF. EPR spectra confirm unpaired electrons, consistent with CT interactions in the ground state. DFT molecular-orbital simulations reveal photophysical properties and the CT process [42].
Liu et al. developed an efficient strategy to synthesize nanoscale DA-structured COFs with tunable sizes, long-term water dispersibility, and special selectivity recently. The designed DA structure provides channels for efficient charge-carrier transport, which endows COFs with excellent photothermal properties and greatly enhances starvation treatment efficiency. The large surface area and porosity in the cross-linked crystals allow for a high loading capacity of glucose oxidases (GOx). Surface modification with biomolecules endows it with colloidal water stability and targeting selectivity. All these good properties guarantee better tumor ablation in vitro and in vivo than monotherapy, with excellent anti-migratory effects. Detailed apoptosis studies show that combination therapy is effective in generating reactive oxygen species. The endogenous mitochondrial apoptotic pathway and Caspase-3 activation process induce apoptosis, which ultimately makes cancer cells more sensitive to insufficient energy supply and high temperatures [43].
COFs are considered to be good carriers with good biocompatibility for photothermal therapy. They are widely used due to their excellent properties such as tunability, high thermal stability, and porous structure. The effects of COFs on the photothermal system can be divided into two types. (1) COFs are taken as the carriers of photothermal material, and the effect of photothermal therapy is achieved through complexes. (2) COFs, as multifunctional carriers, can simultaneously load antitumor drugs, photosensitizers, and photothermal agents to achieve the synergistic effect of photothermal therapy and other therapies. Another type of COFs has a π-conjugated structure through structural design, which can significantly improve photothermal absorption and photostability. They are carriers and photothermal materials and have efficient reactive oxygen species (ROS) generation and photothermal-conversion ability under near-infrared light irradiation.
2.4 COFs used for immunotherapy
COFs have a larger surface area and volume, and COFs can take up a large number of molecules and deliver them to the body. Unlike amorphous polymer particles, COFs have a crystalline structure, resulting in a larger surface area to deliver molecules. Besides, the reversible covalent bonds found in COFs can be degraded in the human body to release the encapsulated molecules.
COFs can be used for protein delivery in addition to small molecules. One challenge of protein delivery is how to maintain protein activity and prevent protein denaturation during loading large amounts of protein. Importantly, the loading of COFs can be controlled by controlling pore sizes. Also, the chemical properties of COFs can be modified. Specific proteins are selectively absorbed based on protein sizes, which allows greater loading and prevents protein denaturation. The possibility of local release of proteins from COFs is important for treating autoimmune diseases and cancers.
As a form of non-inflammatory programmed cell death (PCD), the efficacy of apoptosis is often limited by apoptosis resistance in cancer cells, resulting in suboptimal therapeutic effects. Pyroptosis and ferroptosis are immunogenic PCD in contrast to apoptosis. It is a powerful anti-cancer strategy due to its favorable ability to elicit antitumor immune responses by releasing sufficient risk-associated molecular patterns (DAMPs). Zhang et al. reported a series of multi-enzyme-mimicking COFs, COF-909-Cu, COF-909-Fe, and COF-909-Ni (Figure 4a) as pyroptotic inducers for remodeling the tumor microenvironment, which facilitates cancer immunotherapy. Mechanistic studies suggest that these COFs can act as the steady-state destroyers of hydrogen peroxide (H2O2) to increase intracellular H2O2 levels. They exhibit excellent superoxide dismutase (SOD) mimetic activity and convert superoxide radical (O2•⁃) into H2O2 to alleviate H2O2 scavenging. They also mimic the depleted glutathione (GSH) of glutathione peroxidase (GPx). The excellent photothermal therapy properties of these COFs can accelerate the Fenton-like ionization process, which enhances their chemokinetic therapy. COF-909-Cu, one of these members, strongly induces gasdermin E (GSDME)-dependent pyroptosis and remodels the tumor microenvironment. Durable anti-tumor immunity is triggered, which increases the response rate of αPD-1 checkpoint blockade and inhibits tumor metastasis and recurrence [44].
Figure 4.
(a) Engineering multienzyme-mimicking COFs as apoptosis inducers to enhance antitumor immunity [44]. Reproduced with permission from ref. [44]. Copyright 2022, Wiley-VCH; (b) Representation of COF-606-mediated 2PA-induced PDT to enhance immune checkpoint blockade therapy. COF 606-induced PDT with strong two-photon absorption, the biological process triggering immunogenic cell death (ICD), and the underlying mechanism for the synergy of PDT with PD-1 blockade therapy. TAA, the tumor-associated antigen; DAMP, the molecular pattern associated with risk [45]. Reproduced with permission from ref. [45]. Copyright 2021, Wiley-VCH; and (c) COF-618-Cu for enhancing antitumor immunity: Different structures between overlapped-stacked COFs and staggered-stacking COFs; Biological processes and underlying mechanisms of COF-618-Cu-mediated PDT and PTT for triggering cancer immunotherapy [46]. Reproduced with permission from ref. [46]. Copyright 2022, Wiley-VCH.
Immune checkpoint blockade therapy is revolutionizing the traditional treatment paradigm for tumors but remains ineffective for most patients. PDT has been shown to induce cancer cell death and trigger an immune response and may represent a potential strategy for synergy with immune checkpoint blockade therapy. Yang et al. reported COF-606, a zigzag-filled COF (Figure 4b). Its excellent two-photon absorption (2PA) properties and photostability largely avoid aggregation-induced quenching. Therefore, it provides high ROS generation efficiency and can be used as a 2PA photosensitizer for PDT in deep tumor tissues. COF-606-induced PDT is demonstrated for the first time to be effective in inducing immunogenic cell death, eliciting an immune response, and normalizing an immunosuppressive state. 2PA-induced PDT using COF can combine with the immune checkpoint blockade therapy of programmed cell death protein 1. This combined therapeutic strategy leads to strong ectopic tumor suppression and durable immune memory effects, which is promising for cancer therapy [45].
Phototherapy-induced cancer immune responses are severely limited by the inherent photobleaching and aggregation-caused quenching (ACQ) of photosensitizers as well as intrinsic-antioxidant tumor microenvironments (TMEs), e.g., hypoxia and overexpressed glutathione (GSH). Zhang et al. designed COF-618-Cu, a novel porphyrin-based staggered-stacked COF, as an amplifier of ROS to address these issues. COF-618-Cu can consume endogenous hydrogen peroxide to generate enough oxygen because of its excellent catalase-like activity, which alleviates tumor hypoxia (Figure 4c). Besides, overexpressed intracellular GSH is also depleted to reduce ROS scavenging due to the glutathione peroxidase-mimicking activity of COF-618-Cu. Mechanistic studies show that the unique staggered-stacked pattern between the COF-618-Cu interlayers can alleviate the photobleaching and ACQ effects that cannot be obtained with ordinary COFs. Furthermore, COF-618-Cu, coupled with its excellent photothermal properties, is beneficial to inducing robust immunogenic cell death and remodeling TME to enhance antitumor immune effects [46].
Immunotherapy has become one of the hot topics in cancer treatment with the growing understanding of how cancer interacts with the immune system. Immunotherapy mainly attacks tumor cells by stimulating the body’s innate immune system [47]. Current immunotherapies mainly include cancer vaccination [48], immune checkpoint blockade therapy [49], and chimeric antigen receptor T-cell immunotherapy (CAR-T) [50, 51]. However, solid tumors are difficult to eliminate by immunotherapy alone, so it is necessary to combine with other treatments to inhibit tumor growth and metastasis.
COFs as new photosensitizers are widely used in photothermal and photodynamic therapy of tumors. However, photothermal and photodynamic therapy using COF materials can only kill superficial tumors in irradiated areas. Triggering an immune response is difficult due to the limited ability to generate ROS, and it is still a great challenge to use COF materials to inhibit tumor metastasis and recurrence. Compared with 2D COF materials, 3D COF materials can avoid the fluorescence quenching caused by the aggregation of photosensitizers and have a penetrating pore structure conducive to ROS transport. However, the use of 3D COF materials in tumor immunotherapy has not been reported due to the difficulty of 3D COF synthesis.
2.5 Application of COFs in combination therapy for tumors
COFs have been widely used in the nano-drug delivery system of chemotherapy, photothermal therapy, and photodynamic therapy due to their dense pore structure and lipophilicity. Monotherapy is not effective in treating cancers. For example, the self-quenching of photosensitizers in the hypoxic tumor microenvironment can hinder the release of ROS [52, 53, 54, 55], resulting in low therapeutic efficiency. However, COFs can be combined with a variety of components and modified to form a nano-drug delivery system for various combination therapies, which can obtain better therapeutic effects.
Anthocyanin (IR783), typical in the combination therapy of hyperthermia and chemotherapy, has received extensive attention recently due to its good absorption of light in the near-infrared region and good biocompatibility. Chen’s research group synthesized a new type of COFs (TP-Por COFs) and exfoliated the COFs into IR783-loaded COFs nanosheets (COF@IR783) by ultrasonic exfoliation in 2019. After that, cis-aconitic anhydride-modified doxorubicin (CAD) is loaded to form a photothermal drug-chemotherapy combination therapy system (Figure 5a). In vitro cell experiments show that COFs do not affect cell viability, but the system has an obvious combined killing effect on tumor cells. Later, the tumor tissues of mice treated with this system are significantly necrotic [56].
Figure 5.
(a) Applications of COFs in the combination therapy of photothermal therapy and chemotherapy and that of photodynamic therapy and chemotherapy: (A) COF@IR783@CAD in oncotherapy [56]; Reproduced with permission from ref. [56]. Copyright 2019, American Chemical Society; and (b) PFD@COFTTA-DHTA@PLGA-PEG in oncotherapy [57]; Reproduced with permission from ref. [57]. Copyright 2020, Elsevier Ltd. (c) CaCO3@COF-BODIPY-2I@GAG in oncotherapy [34]. Reproduced with permission from ref. [34]. Copyright 2020, Wiley-VCH.
Zhang’s group combined the anti-fibrotic drug pirfenidone (PFD) with COFTTA-DHTA in the combination therapy of photodynamic and chemotherapy. Amphiphilic polymer poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) is used to synthesize PFD@COFTTA-DHTA@PLGA-PEG(PCPP) (Figure 5b). PFD released by PCPP in the tumor area can destroy the extracellular matrix (ECM) of tumors in this structure, which promotes the uptake of the subsequently injected photosensitizer protoporphyrin peptide coupling nano-micelles (NM-PPIX) by tumor cells and enhances the efficacy of PDT on tumors [57]. Excessive intracellular Ca2+ content can lead to cell death, and its concentration is tightly controlled within cells. The control is easily destroyed by ROS, so theoretically, the combined action of PDT and the addition of exogenous Ca2+ can promote cell death.
Inspired by this mechanism, Dong’s group reported a nano-covalent organic framework (NCOF)-based nanostructure (CaCO3@COF-BODIPY-2I@GAG) (Figure 5c). This structure uses Boron-dipyrrolemethene (BODIPY2I) as the photosensitizer and CaCO3 as the material providing exogenous Ca2+. ROS generated by the system under illumination can directly kill tumor cells and increase Ca2+ content in tumor cells to kill cells, showing a significant anti-tumor effect [34]. Trabolsi’s group loaded DOX through nanoscale TAB-DFP-nCOF in the combination therapy of magnetic hyperthermia and chemotherapy. Afterward, magnetic iron oxide nanoparticles (γ-Fe2O3 NPs) and polylysine cationic polymer (PLL) are modified separately to obtain system γ-SD/PLL with an average particle size of 300 nm. γ-SD/PLL generates a lot of heat and releases drugs to kill cancer cells in an alternating magnetic field (AMF). The survival rate of cancer cells can be as low as 10% after 1 h of γ-SD/PLL and AMF treatment [58]. Although the development of COFs is still in its infancy, remarkable achievements have been made in chemotherapy, photothermal therapy, photodynamic therapy, and combination therapy.
Completely inhibiting tumor growth is impossible due to the complexity of the tumor microenvironment and the inherent shortcomings of monotherapy. However, combination therapy can overcome the shortcomings of monotherapy and further improve the therapeutic effect. Chen et al. synthesized COF TP-Por condensed with 5,15-bis(4-boronphenyl) porphyrin and 2,3,6,7,10,11-hexahydroxytriphenyl by a stripping method and further loaded DOX in 2019. The resulting 2D covalent organic nanosheets (CONs) can produce both PDT and PTT effects under 635-nm laser irradiation after ultrasonic stripping of TP-Por, which inhibits tumor growth [56]. Pang’s group synthesized COFs based on 1,3,5-tris(4-aminophenyl) benzene (TAPB) and 1,3,5-benzenetricarbaldehyde (BTCA) by Schiff base condensation reaction for OVA and ICG loads in 2020. PDT and PTT effects occur under 650- and 808-nm laser irradiation. Combined with checkpoint blockade therapy, it shows a stronger immune effect, which can inhibit tumor metastasis and recurrence [59].
Phototherapy has recently received a lot of attention due to its simplicity, non-invasive features, and excellent therapeutic effects. The combination of PTT and PDT holds great promise in oncotherapy. A suitable photosensitizer is a prerequisite to obtaining satisfactory antitumor efficacy. Pang’s group prepared highly monodisperse COF nanoparticles at room temperatures by a mild solution-phase synthesis method in 2019. The synthesized nonporphyrin-containing COF-based nanoparticles are used as novel photosensitizers for PDT and exhibit excellent photodynamic effects under 650- or 808-nm laser irradiation. Then ideal photothermal agent CuSe nanoparticles are coupled with COFs to form the bifunctional photosensitizer for phototherapy. The resulting COF-CuSe platform exhibits excellent synergistic photothermal and photodynamic effects. In vitro and in vivo experiments demonstrate enhanced therapeutic effects in killing cancer cells and inhibiting tumor growth. The study demonstrates the great potential of nonporphyrin-containing COFs as photosensitizer for photodynamic cancer therapy and provides a simple and effective approach. COFs are combined with other functional materials to construct COFs-based multifunctional therapeutics for cancer diagnosis and treatment (Figure 6) [60].
Figure 6.
(a) Synthesis of COFs-based composites and their applications in PTT and PDT [60]. Reproduced with permission from ref. [60]. Copyright 2019, American Chemical Society.
Based on the versatility of COFs, they can integrate monotherapies such as drug delivery, photodynamic therapy, and photothermal therapy to build an intelligent, multifunctional platform for targeted therapy. Combined therapy on a platform can precisely kill cancer cells based on COFs. Moreover, COFs can be metalized before or after synthesis for imaging technology, which lays the foundation for integrating diagnosis and therapy. Therefore, designing functionalized COFs-based nanomedicines for drug co-delivery and multimodal cancer therapy is a promising strategy. In addition, we also summarize the COF combination therapy published in the past 2 years, as shown in Table 1.
Therapeutic methods are used in cancer treatment, such as PDT, PTT, chemotherapy, immunotherapy, and targeted therapy with the understanding of cancers. PDT is a minimally invasive treatment method utilizing PSS to absorb light energy, which stimulates oxygen to generate reactive oxygen species (such as 1O2, .OH, and .O2−). It has good controllability, low toxicity, and low invasiveness. However, its insufficient light penetration depth and dependence on oxygen limit its development.
PTT adsorbs near-infrared-light excitation energy by PTAs. The temperature around the cancer cells rises by heat losses, which kills cancer cells. However, PTT lacks selectivity for cancer cells, so it is impossible for specific treatments. Immunotherapy works by stimulating the body’s innate immune system to attack tumor cells. All of the above cancer treatments have inherent problems. That is to say, a single treatment method cannot treat tumors at all. COFs have unique advantages as emerging antitumor materials with the development of nanotechnology. Given this, the work exploited the crystalline porosity, stability, versatility, and good biocompatibility of COFs with emerging therapeutic approaches. Meanwhile, the problems existing in the preparation and treatment of COFs were improved to construct a feasible multifunctional nanosystem for cancer treatment. Despite the above examples, further research is needed on biosafety, biocompatibility, sterilization, drug loading, and controlled drug release in vivo. The integration of COFs with other biomaterials is expected to greatly expand the biological applications of COFs. However, the idea of applying COFs to tumor therapy is still far from clinical translation. The main challenges and opportunities are as follows:
There is no universal method for mass production of COFs, because low yields and poor-quality consistency may arise in mass production. The currently available methods, including assisted solvothermal methods, steric-induced chemical exfoliation methods, and intercalation-induced delamination methods, may only be matched to specific species of COFs and high-power mechanical layering has low output and is not suitable for industrial production.
The safety of COFs in tumor therapy still needs to be confirmed. Current researches mostly focus on materials uptake rather than metabolic pathways due to the short development history. COFs are usually composed of non-metallic light elements and irreversible chemical bonds. These chemical bonds ensure the stability of COFs; however, they may cause the accumulation of COFs in the body, and the toxicity of long-term use is still unpredictable. Some easily degradable COFs have potential to generate aromatic compounds in the body and cause in-vivo toxicity. The current safety evaluation of COFs-based oncotherapy is mostly based on cytotoxicity, a comprehensive assessment is required for their hemocompatibility, histocompatibility, cytotoxicity, neurotoxicity, and genotoxicity at cellular and tissue levels.
Cancer is a complex, tricky disease. There is an urgent need to develop an intelligent and multifunctional therapeutic platform for diagnosis and targeted therapy to realize COFs-based precision cancer therapy. Besides drug delivery, photodynamic therapy, and photothermal therapy, COFs can be used for combined therapy, which kills most tumor cells in multiple directions and layers. Besides, COFs possess the properties of ordered porous nanomaterials and can be easily modified. For example, metallization can be used in imaging techniques such as two-photon fluorescence imaging either before or after synthesis, with the opportunity to integrate diagnoses and treatment. The pre- and post-synthesis of COFs can be modified to increase their targeting, water solubility, etc., for better oncotherapy. It is beneficial for building a smart therapy platform based on COFs.
In summary, COFs have unique applications in nanomedicine due to their easy synthesis, large pore size, tunable structure, versatility, chemical stability, and good biocompatibility. The work briefly discussed recent advances in COFs-based drug delivery and synergistic therapy. The application of COFs in biomedicine has yielded some exciting results. Their application as nano-drugs in biomedicine is greatly limited due to the difficulty of precise control of the size and structure of COFs-based nano-platforms as well as their poor dispersibility in water. Besides, the targeting of COFs-based nano-loading systems needs to be further studied. COFs require further synthesis to achieve the pore geometries and precise crystal structures required for specific biomedical applications (e.g., protein delivery) after considering emerging approaches such as bottom-up and top-down approaches.
This chapter was financially supported by the Basic and Clinical Collaborative Research Promotion Program of Anhui Medical University (No. 2021xkjT024) and the Ph.D. Start-up Fund of Anhui Medical University.
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Written By
Guiyang Zhang
Submitted: 14 July 2022Reviewed: 08 August 2022Published: 15 September 2022
Open access peer-reviewed chapter
