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The Application of Nanoscale Metal-Organic Frameworks for Tumor Targeted Therapy

Haidi Feng , Lu Zhao , Yunfeng Bai , Feng Feng

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (8) : 1863 -1878.

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Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (8) : 1863-1878 DOI: 10.7536/PC21
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The Application of Nanoscale Metal-Organic Frameworks for Tumor Targeted Therapy
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Abstract

Metal-organic frameworks (MOFs) are a kind of porous coordination polymers formed by the assembly of metal ions and organic ligands, exhibit excellent advantages as a nanocarrier, such as easy modification, high drug loading as well as controllable drug release. The diversities of metal ions and organic ligands lead to the diversities of MOFs, which make them wide application in many fields such as storage and separation, catalysis, sensing, biomedical application and others. With high porosity, versatile MOFs allow for the facile encapsulation of various therapeutic agents with exceptionally high payloads. Especially when the particle size of MOFs is controlled down to the nanometer level, named nanoscale metal-organic frameworks (NMOFs), they exhibit a series of structural advantages. Based on the above advantages, NMOFs exhibit excellent application prospects for drug delivery and cancer therapy. NMOFs can be used as therapeutic agents, as well as nanocarriers of drug, photothermal agents, photosensitizers and Fenton reaction catalysis to using passive targeting, active targeting, physicochemical targeting, or combination of the three. The review focuses on the application of chemotherapy (CT), photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT) and various combination therapies. Finally, we will elaborate the current challenges and future development prospects of NMOFs in cancer application.

Contents:

1 Introduction

2 NMOFs-based monotherapy

2.1 Chemotherapy(CT)of cancer

2.2 Photothermal therapy(PTT)of cancer

2.3 Photodynamic therapy(PDT)of cancer

2.4 Chemodynamic therapy(CDT)of cancer

3 NMOFs-based combined therapy

3.1 Dual-modal combined therapy

3.2 Three-modal combined therapy

4 Conclusion and outlook

Graphical abstract

Keywords

nanoscale metal-organic frameworks / tumor / target / monotherapy / combined therapy

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Haidi Feng, Lu Zhao, Yunfeng Bai, Feng Feng. The Application of Nanoscale Metal-Organic Frameworks for Tumor Targeted Therapy. Progress in Chemistry, 2022, 34(8): 1863-1878 DOI:10.7536/PC21

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1 Introduction

Cancer is one of the most serious malignant diseases affecting human health, and its incidence and mortality are increasing year by year. According to statistics, there will be about 1.9 million new cancer cases and 610,000 cancer deaths in the United States in 2021[1]. The treatment of cancer generally includes early diagnosis and late treatment, usually using magnetic resonance imaging, optical imaging, X-ray computed tomography imaging and other biological imaging methods for early diagnosis, and late treatment through radiotherapy, chemotherapy, surgery, gene therapy, immunotherapy and combination therapy[2,3]. Among the above methods, Chemotherapy (CT) is the main means to treat cancer, but CT has the disadvantages of large toxic side effects, lack of specificity and poor patient tolerance. Compared with the traditional direct administration, nanocarrier administration has the advantages of good targeting, high uptake rate and small toxic side effects[4]. In the past few decades, scientists have developed many materials (such as mesoporous silica, organic micelles, liposomes, dendrimers, Metal-organic frameworks (MOFs), and covalent organic frameworks) as nanocarriers of drugs for cancer therapy[5,6]. Compared with mesoporous silica, organic micelles, liposomes, dendrimers and covalent organic frameworks, MOFs have many excellent characteristics: (1) MOFs have large specific surface area and high pore volume, and have high loading capacity for drugs[7,8]; (2) MOFs are biodegradable and easy to be eliminated from the body to prevent their endogenous accumulation[9]; (3) MOFs are more likely to break the coordination bond in the acidic Tumor microenvironment (TME) to achieve controlled drug release; (4) The surface of MOFs is modified by polymer, which has no effect on its structure[4]. Although MOFs also have some disadvantages, such as the toxicity of metal ions and organic ligands produced by decomposition in vivo, the toxicity can be reduced to the allowable range by selecting biocompatible metal ions and organic ligands, so MOFs have good application prospects in drug delivery and cancer therapy[10].
MOFs are a new class of organic-inorganic hybrid materials composed of different metal ions or ion clusters connected with organic ligands through coordination bonds[11⇓~13]. In 1995, Yaghi et al. Successfully prepared a crystal composed of metal and organic matter, and named it "metal-organic framework"[14,15]. MOFs have been widely used in catalysis, gas adsorption, separation, storage, nonlinear optics, sensing, detection, and biomedicine due to their outstanding physicochemical properties such as easy synthesis and functionalization, tunable pore size, variable structure, large specific surface area, high loading capacity, good biocompatibility, and good biodegradability[16⇓⇓~19]. Appropriate size and uniform morphology are very important for cellular uptake and targeting, so the MOFs used in biomedical applications such as cancer therapy are usually Nanoscale metal-organic frameworks (NMOFs), and the size is generally within 200 nm. Compared with MOFs, NMOFs have the advantages of Enhanced permeation and retention (Enhanced permeation and retention, EPR) effect, long blood retention time, and strong internalization to cells, and are often used as drug delivery systems for tumor therapy[2,20].
NMOFs drug delivery systems include CT, Photothermal therapy (PTT), Photodynamic therapy (PDT), Chemodynamic therapy (CDT), etc. In terms of mode of action, it includes treatment with a single mode of action and combination therapy with multiple modes of action. In terms of targeting mode, it includes passive targeting, physicochemical targeting and active targeting. Ordinary NMOFs rely on the EPR effect of nanoparticles to aggregate to the tumor site, and stimulus-responsive NMOFs can achieve physicochemical targeting through the special properties of TME, but the bioavailability of drugs is low only by passive targeting and physicochemical targeting[21]. Ligands with high affinity to tumor cells are modified on the surface of NMOFs to achieve active targeting, which is conducive to improving the utilization rate of drugs, reducing the dosage and side effects of drugs, and achieving precise treatment of tumors[22]. At present, folic acid, hyaluronic acid, cRGD peptide, aptamer and so on have been reported[23][24][25][26⇓⇓~29]. This review will introduce the latest research progress of monotherapy of NMOFs in tumor CT, PTT, PDT, CDT, and combination therapy of multiple modes of action.

2 Monotherapy based on NMOFs

NMOFs have the advantages of large specific surface area, high porosity and controllable size. They can be used as photothermal agents, photosensitizers and Fenton reaction catalysts for PTT, PDT and CDT of tumors. In addition, they can also be loaded with therapeutic agents (drugs, photothermal agents, photosensitizers, etc.) For CT, PTT, PDT, CDT and other single treatments of tumors.

2.1 CT

Currently, NMOFs have been used as nanocarriers for a variety of chemotherapeutic agents. In 2006, the F FÉrey group used Cr-MOFs as a drug delivery system to study the drug loading and delivery ability of Cr-MOFs, and the loading rate was as high as 60%[30]. Nanomedicine only relies on EPR effect to passively target tumor cells, which has the problem of poor specificity and selectivity. The modification of targeting agents on the surface of NMOFs not only reduces the toxic and side effects of nanomedicine, but also realizes the active delivery of nanomedicine to tumor cells. Active targeting methods currently used in chemotherapy include: (1) modifying folic acid to actively target folate receptor-overexpressing tumor cells; (2) the modified polypeptide actively targets integrin αvβ3 receptors of tumor cells; (3) Molecularly imprinted polymer (MIP) actively targeting the overexpressed protein on the surface of tumor cell membrane; (4) The modified aptamer actively targets the aptamer protein-overexpressing tumor cells.
In 2013, Huang's research group first prepared Fe (bbi) constructed by Fe2+ and 1,1 '- (1,4-butanediyl) bis (imidazole) (bbi) by deposition method to load Doxorubicin (DOX), and applied it to the active targeted therapy of tumors. The loading rate of DOX was as high as 98%. Folic acid was coupled to the surface of Fe (BB) coated with SiO2 to achieve the specific targeting of HeLa cells. Experiments proved that the nano-drug had little toxic and side effects[23]. In order to improve the biocompatibility of NMOFs, Fang's team modified folic acid with Polyethylene glycol (PEG), and then coated PEG-FA on the surface of ZIF-8 loaded with PEGCG. PEG not only facilitated the coupling of folic acid, but also improved the dispersion and biocompatibility of ZIF-8 to prevent drug leakage. Experiments showed that nanomedicine had a significant inhibitory effect on the growth of HeLa cells[31]. Long-term use of drugs can lead to Multidrug resistance (MDR) in tumor cells. In order to solve the MDR effect, Luan's team used PEG-FA functionalized ZIF-8 as a Multidrug nanocarrier to encapsulate VER (VER is an inhibitor of drug efflux P-glycoprotein) and DOX in situ for the treatment of MCF-7 A. The release of drugs was pH-dependent, and the tumor inhibition rate in mice was 95.4%[7].
In addition to functionalizing the surface of NMOFs, targeting agents can also be attached by modifying the drug. Zhang's team modified DOX with a pH-sensitive linker containing two carboxylic acids to form prodrug CAD, and then implanted CAD into ZIF-8 through the mineralization process, which not only realized the loading of DOX, but also provided carboxylic acids for the surface of ZIF-8.Then folic acid is coupled to the surface of ZIF-8 through an amide bond to realize the triple response release of DOX, thereby achieving the precise release of the drug, having strong killing ability on triple negative breast cancer cells MDA-MB-231, and greatly reducing the cardiotoxicity of DOX[32].
NMOFs can also use polypeptides as targeting agents. In 2020, Liao's group wrapped the cRGD-modified erythrocyte membrane on ZIF-8 containing DOX to construct a delivery system precisely targeting the integrin αvβ3 receptor (Figure 1A). When the nanomedicine was intravenously injected into tumor-bearing mice of HeLa tumor model, the tumor inhibition rate was as high as 81.34%, and the blood circulation half-life was more than doubled compared with the delivery system without modified cRGD[33]. In addition, MIP prepared by using overexpressed tumor cell membrane glycoprotein as a template can also be used as a targeting agent. In 2020, Li's research group proposed to prepare MIP on the surface of FZIF-8/DOX by using CD59 cell membrane glycoprotein as a template. The skeleton of MIP can be degraded under the dual stimulation of GSH and pH to achieve the controlled release of DOX (Figure 1B). The uptake rate of FZIF-8/DOX-MIP by MCF-7 is very high, and the active targeting promotes the phagocytosis of nanoparticles. In vivo experiments show that the system has a good effect on tumor growth inhibition in MCF-7 tumor-bearing mice[34].
Aptamers are short DNA or RNA sequences that can specifically bind to target molecules. Aptamers have many kinds of targets, stable properties, and can be synthesized artificially[27]. In 2020, the Nie research team designed a novel anti-B-cell lymphoma nano-drug CD20 aptamer-RBCm @ Ag-MOFs/PFK15 (A-RAMP) (Figure 1C). Under the guidance of CD20, the nano-drug can precisely target lymphoma cells, and the loading rate of PFK15 (aerobic glycolysis inhibitor) is as high as 68.6%. The release of the drug is pH-dependent, and the Ag+ and PFK15 produced by the decomposition of the nano-drug can play a combined anti-tumor role[35]. Mousavi team modified Fe3O4@MOF-DOX-CDs with AS1411 aptamer, which not only targeted nucleolin overexpressing tumor cells, but also had the function of fluorescence imaging, thus realizing the integration of treatment and diagnosis[36]. Cell experiments showed that the nanomedicine had a greater ability to kill MDA-MB-231.

2.2 PTT

PTT is a method that relies on photothermal agents to convert light energy into heat energy under near-infrared laser irradiation, and the heat generated ablates the tumor and then kills the tumor[37]. Compared with traditional treatment methods, PTT is a local tumor treatment method with less invasiveness, high tissue resolution and easy implementation, which has attracted wide attention of researchers[38].
There are two main ways to use NMOFs to perform PTT on tumors. One is that NMOFs themselves are used as photothermal agents for PTT. There are two ways to synthesize such NMOFs: (1) using photothermal agents as organic ligands, such as IR825, perylene imide (PDI), etc.[39][40]; (2) charge transfer occurs between the metal ion and the organic ligand, for example, the Fe3+ is a metal node and is combined with organic ligands such as gallic acid, hydrocaffeic acid, ellagic acid and the like[41][42][43]. Another mode of action is that NMOFs are used as nanocarriers to load other photothermal agents, such as indocyanine green (ICG), gold nanospheres, etc[44][45].
In 2016, Liu's team used photothermal agent IR825 as an organic ligand and Mn2+ to prepare Mn-IR825 with photothermal properties through self-assembly (Fig. 2A), with an extinction coefficient of 78.2 L·g-1·cm-1. Mice injected with Mn-IR825 @ PDA-PEG showed complete elimination of tumors under laser irradiation and no signs of recurrence within 60 days[39]. After that, Yin's group prepared Zr-PDI NMOFs with a photothermal conversion efficiency of 52.3% by using Zr metal clusters and PDI organic ligands[40].
NMOFs with photothermal properties can also use charge transfer between metal and ligand for PTT therapy of tumors, in addition to using photothermal agents as organic ligands. In 2015, Wang's group used polyvinyl pyrrolidone (PVP) modified Fe-CPND(Fe3+ and gallic acid (prepared) as a photothermal agent for tumor therapy. The photothermal properties of this NMOFs are derived from the charge transfer effect between phenol and Fe3+ of organic ligands, which has a significant inhibitory effect on SW620 cells under laser irradiation[41]. After that, researchers synthesized NMOFs with photothermal properties by using hydrocaffeic acid and ellagic acid as organic ligands and Fe3+, respectively, and their photothermal properties were also dependent on the charge transfer generated by Fe-phenol structure[42][43].
In addition, NMOFs can also be used as a carrier to deliver the photothermal agent ICG, which is the only organic dye in the near-infrared region approved by the Food and Drug Administration (FDA) for clinical use, but its water solubility, poor specificity, and low sensitivity limit its clinical application[46]. In order to solve these problems, in 2017, Liu's team used hyaluronic acid-coated MIL-100 (Fe) loaded ICG to target CD44-overexpressing MCF-7 cells (Fig. 2B), and in vivo experiments proved that under near-infrared laser irradiation, tumors could be well eliminated without affecting the health of mice[44].
The aggregated gold nanospheres exhibit strong coupled plasmon resonance absorption in the near infrared region and have good photothermal properties[47,48]. Yang's team designed a nano-drug Au @ ZIF-8 that only responds to TME, effectively avoiding damage to normal tissues (Fig. 2C)[45]. Under 808 nm laser irradiation, the photothermal conversion efficiency was 22. 29%, the apoptosis rate of 4 T1 mice was 77. 48%, and the tumor disappeared completely on the 16th day of treatment.

2.3 PDT

PDT means that the photosensitizer transfers energy to the surrounding oxygen molecules under laser irradiation to produce cytotoxic reactive oxygen species (ROS) to kill tumor cells[49]. Similar to PTT, PDT is also a local treatment method for tumors, with the greatest advantages of less invasiveness, high selectivity and less damage to normal tissues. However, the mode of action is different from that of PTT, which kills tumor cells by increasing temperature, while PDT produces ROS to kill tumor cells[50]. There are two ways to use NMOFs for PDT of tumors: NMOFs itself as a photosensitizer and as a carrier to encapsulate the photosensitizer.
Porphyrins and their derivatives are common organic ligands for the preparation of NMOFs with photodynamic properties. In 2014, Lin's team used porphyrin ligands to prepare DBP-UiO with photodynamic properties, and used it in the treatment of drug-resistant head and neck cancer in vivo[51]. In 2016, Zhou's group prepared size-controllable porphyrin NMOFs through a bottom-up approach and functionalized them with folic acid to improve the therapeutic effect of PDT (Fig. 3A)[52].
NMOFs can also be used as carriers to load photosensitizers. In 2015, Ju's group encapsulated the photosensitizer TMPyP in Zn-based NMOFs modified with folic acid, and the apoptosis rate of HeLa cells was 53.91% under laser irradiation[53]. In addition, NMOFs can also be used to support Ce6 and ZnP to avoid their aggregation quenching. Liu's group embedded Ce6 in NMOFs with Cu2+ as metal nodes and H3BTC as organic ligands. After entering tumor cells, Cu2+ of NMOFs reacted with GSH to decompose and release Ce6. Ce6 contacted with oxygen to produce ROS to kill tumor cells under laser irradiation[54]. In 2021, Lin's research group loaded ZnP in HF-QC, and the results showed that the growth inhibition rate of ZnP @ HF-QC-mediated PDT on colorectal tumors was as high as 99%[57].
PDT is a kind of oxygen-consuming phototherapy. Oxygen consumption during treatment will further aggravate the hypoxic state of TME, and even lead to the failure of PDT treatment. Therefore, tumor hypoxia is the biggest limiting factor affecting the efficacy of PDT. Zeng's group encapsulated Ce6 and cytochrome (Cyt C) in ZIF-8 modified by hyaluronic acid, and Cyt C catalyzed H2O2 to produce O2, which solved the problem of hypoxia in PDT. In vitro and in vivo experiments showed that Ce6/Cytc @ ZIF-8/HA had good anti-tumor performance and low systemic toxicity[58]. In order to solve the problem of insufficient content of H2O2 in TME, Zhang's group used 4T1 cell membrane coated PCN-224 to load Glucose oxidase (GOx) and Catalase (CAT) (Fig. 3B), which converted Glucose in TME into H2O2, followed by the conversion of H2O2 into O2, with a tumor inhibition rate of 97.1% in 4T1 tumor-bearing mice[55]. In recent years, researchers have found that nanozymes have CAT-like properties. Nanoenzyme is a kind of nanomaterial with enzymatic catalytic properties. Compared with natural enzymes, nanoenzyme has the advantages of high stability, low cost and good durability[59]. The Pt nanoenzyme modified on PCN-224 by Qu's group could induce H2O2 to produce O2 (Figure 3C), significantly improving the PDT efficiency[56]. Jiang's team used MIL-88a containing manganese and iron as a template to obtain nanoenzyme MnFe2-MIL-88A, which can be used as a carrier to load Ce6 to significantly enhance the therapeutic effect of PDT[60].

2.4 CDT

Compared with PTT and PDT, CDT is an emerging treatment that does not require laser irradiation and can be triggered only by H2O2. CDT is a therapeutic method that uses the Fenton reaction of Fe2+ with H2O2 and the Fenton-like reaction of other metal ions or CAT-like nanoenzymes with H2O2 to convert H2O2 in TME into · OH[61⇓⇓~64]. There are two ways to use NMOFs for CDT of tumors: as Fenton reaction catalyst itself and as supported Fenton reaction catalyst. In 2017, Zhang's team used tannic acid and Fe3+ to prepare NMOFs as Fenton reaction catalyst, which induced H2O2 to produce · OH by Fenton reaction Fe2+ to cause cell apoptosis[65]. Zhan's team used folic acid as an etchant to synthesize hollow ZIF-8 as a CuS-loaded nanoplatform (Figure 4A), which was incubated with MCF-7 and HepG-2 cells to release Cu+ to produce · OH through Fenton-like reaction to promote apoptosis[66].
It was found that although the concentration of H2O2 in tumor cells (~ 100 μM) was much higher than that in normal cells (~ 20 nM), endogenous H2O2 did not achieve satisfactory CDT effect. Therefore, increasing the endogenous H2O2 concentration is the key factor to improve the efficacy of CDT[67]. There are two ways to increase the concentration of H2O2: (1) adding GOx to catalyze glucose to produce H2O2;(2) to disrupt the dynamic balance of H2O2 in tumor cells.
In 2020, Jiang's group adsorbed GOx and cubic nanoenzyme in ZIF-8 through electrostatic interaction to prepare a cascade reactor GOx @ Pd @ ZIF-8 to produce · OH. This composite catalyst can catalyze both glucose to produce H2O2 and H2O2 to produce · OH[68]. In vivo and in vitro experiments have shown that GOx @ Pd @ ZIF-8 exerts its anti-tumor activity by promoting apoptosis and inhibiting proliferation, and has a good therapeutic effect on lung cancer. Tong's group also constructed a cascade reactor Fe @ ZIF-8 @ GOx to prepare NMOFs with ferrimagnetic structure by using the mineralization of FeSO4·7H2O during the growth of ZIF-8, which replaced Pd nanoenzyme to produce stable · OH through Fenton-like reaction[69].
In 2020, Qu's group designed a nanoenzyme PZIF67-AT (Fig. 4 B) that interferes with H2O2 homeostasis by converting O · - 2 into H2O2 in cells.It promotes the production of H2O2, reduces the conversion of H2O2 to H2O by inhibiting the activity of CAT and consuming GSH, and inhibits the clearance of H2O2[70]. Thus breaking the dynamic balance of H2O2 and increasing the concentration of H2O2 in cells, and then converting it into more toxic OH through Fenton-like reaction. In vitro experiments showed that PZIF67-AT not only effectively killed HeLa cells, but also significantly killed A549 and 4T1 cells.

3 NMOFs-based combination therapy

In recent years, monotherapy based on NMOFs has been widely developed, but its therapeutic effect is still affected by some factors, such as the MDR effect produced by CT, the low efficiency of photothermal conversion in PTT, the obstruction of laser penetration depth and hypoxia encountered by PDT, and the ROS tolerance of CDT. In order to solve these problems, researchers have begun to construct multifunctional NMOFs drug delivery systems to combine two or more therapeutic methods in order to achieve better efficacy.

3.1 Bimodal combination therapy

3.1.1 CT and PTT combined therapy

On the one hand, the heat generated by PTT can kill tumors, on the other hand, it can accelerate the uptake of nanocarriers and the release of drugs in cells, thus increasing the concentration of drugs in cells[71]. The application of NMOFs in CT-PTT combination therapy mainly includes two aspects: photothermal agent and NMOFs form a core-shell structure to load drugs, and NMOFs are used as a carrier to load photothermal agent and drugs for CT-PTT combination therapy.
Polypyrrole (PPy) is a living polymer with good biodegradability and biocompatibility. In 2016, Zhang's research group coated MIL-100 (Fe) on the surface of PPy nanoparticles to adsorb DOX, synthesized a multifunctional composite material PPy @ MIL-100 (Fe)/DOX for CT-PTT combined therapy (Fig. 5A), and incubated with HeLa cells, the cell mortality rate was 50%, and the mortality rate increased to 75% after laser irradiation, indicating that CT-PTT combined therapy enhanced the killing effect on HeLa[72]. AuNPs can be combined with organic dyes to enhance Raman scattering signals and achieve the integration of therapy and diagnosis. Hu's group used 4-mercaptobenzoic acid (4-MBA) as a bridging molecule to coat the surface of AuNPs with Cu3(BTC)2 modified by A549 aptamer to adsorb DOX, and the photothermal conversion efficiency of the composite was 31. 2%, which had a high affinity for A549 cells and a good killing effect[73].
In addition, NMOFs can also be used as a photothermal agent to form a double NMOFs core-shell structure to improve the loading rate of drugs. In 2017, Zhou's team coated a layer of dense ZIF-8 on the surface of PB MOFs to prepare CSD-MOFs for loading DOX. The loading rate of DOX was as high as 85.23%, and the photothermal conversion efficiency was 23%[74]. In vivo experiments showed that its anti-tumor effect was 7. 16 times and 5. 07 times higher than that of chemotherapy and single hyperthermia.
NMOFs can also be loaded with photothermal agents and drugs for CT-PTT combination therapy. In 2018, Luan's team modified ZIF-8 with FA-BSA to load quercetin and CuS to achieve CT-PTT combination therapy (Fig. 5B)[75]. In vitro and in vivo experiments showed that the drug release was dependent on pH and light, and the anti-tumor effect under laser irradiation was significantly higher than that of CT or PTT monotherapy.

3.1.2 CT and PDT combined therapy

Compared with PTT, PDT can promote the accumulation of drugs in the tumor site by promoting vascular permeability[76]. More importantly, PDT highly consumes oxygen, increases the degree of hypoxia in TME, and enhances the cytotoxicity of DOX. g-C3N4 generates ROS under visible light. In 2015, Lee's research group wrapped ZIF-8 on the surface of g-C3N4 to load DOX to achieve CT-PDT combined therapy. Under light conditions, the cell mortality rate of g-C3N4@ZIF-8-DOX was 83.4%, which was greater than that of single chemotherapy (40.3%) and single phototherapy (44.9%), and the anti-tumor effect was significantly improved[77]. Visible light has a low degree of penetration and is only suitable for the treatment of epidermal tumors. Near-infrared light (700 ~ 1300 nm) can increase the depth of tissue penetration and effectively penetrate the skin to reach the deep tumor site. Rose Bengal (RB), similar to g-C3N4, is suitable for visible light excitation. Therefore, in order to improve tissue penetration and permeation, Lin's research group combined upconversion nanoparticles with NMOFs for deep tumor PDT. A layer of SiO2 was wrapped on the surface of upconversion material NaYF4:Yb/Er@NaYbF4:Nd@NaGdF4 as the carrier of RB, and DOX-loaded PEG-FA-ZIF-90 was wrapped on the surface of SiO2 for oxygen storage. RB was activated to produce ROS under 808 nm laser irradiation. In vitro and in vivo experiments showed that this nano-drug had good therapeutic effect[78].
PCN-224 has good biodegradability and large specific surface area, is stable in a wide pH range, and can produce ROS under laser irradiation. In 2019, Ryu's research group used coordination bonds to modify hyaluronic acid on the surface of PCN-224 for loading DOX. The modification of hyaluronic acid not only improved the biocompatibility and stability of nano-drugs in water, but also achieved specific targeting of CD44 and controlled release of drugs[79]. In vitro experiments showed that the nanomedicine had a high affinity for CD44-positive MDA-MB-231 and SCC-7 cells. In order to solve the problems of tumor hypoxia and GSH overexpression, Cheng's team wrapped a layer of MnO2 on the surface of PCN-224 to produce O2 and consume GSH (Fig. 6), which improved the therapeutic efficiency of CT-PDT[80].
In order to solve the problems of PDT laser power attenuation and inaccurate positioning causing damage to normal cells. In 2020, Yin's research team proposed a minimally invasive strategy of Interventional PDT (Interventional photo dynamic therapy, IPDT). HOOC-PEG-COOH was coated on the surface of DOX @ PCN-224 through electrostatic adsorption, and then linked to galactose (Gal), a targeting agent. The synthesized DOX @ Gal-PCN-224 could target liver cancer cells with high expression of glycoprotein receptors to achieve CT-IPDT combined therapy. In vivo experiments proved that after one laser interventional irradiation, the CT-IPDT combined therapy could be used in orthotopic liver[81].

3.1.3 PTT and PDT combined therapy

The heat generated by PTT can improve the blood flow of the tumor site, increase the oxygen supply, and then alleviate the hypoxia of TME, which enhances the efficacy of oxygen-dependent PDT. PDT can enhance the thermosensitivity of cancer cells, making PTT treatment more effective, so PTT-PDT combination therapy has great potential for selective phototherapy of tumors[37,50,82].
Two-dimensional nanosheets can respond quickly to laser, and their photothermal properties are better than those of three-dimensional bulk materials[83,84]. Wu's group synthesized Cu-TCPP nanosheets by solvothermal method. Under 808 nm laser irradiation, the Cu2+ undergoes d-d band transition to produce strong near-infrared absorption, which has photothermal properties. TCPP has ROS generation characteristics under 660 nm laser irradiation. Therefore, under 660 and 808 nm laser irradiation, the death rate of Saos-2 cells increased to 90%, and the median inhibitory concentration (IC50) decreased to 0.43 mg/mL. PTT-PDT combined treatment[85]. In 2020, Wu's group introduced Cu2+ into the ligand TCPP of PCN-224 at different doping levels, and the experiment proved that when 10% of Cu2+ was doped, the PTT-PDT combination therapy had the best effect under laser irradiation[86]. Lu's group used Zn2+ and TCPP to prepare Zn-TCPP nanosheets by hydrothermal method, which had a photothermal conversion efficiency of 14.4% and good photothermal stability. When the concentration of Zn-TCPP was 15 μM, the death rate of HeLa cells was still as high as 85%[87].
NMOFs can also form composite structures with other materials, thus having both PTT and PDT properties. In 2021, Li's research group prepared AuNR @ MOFs by growing Zr-TCPP on the surface of gold nanorods (AuNR) for PTT-PDT combined treatment of tumors. The photothermal conversion rate of AuNR @ MOFs was 22.5%. Under the combined irradiation of 808 and 640 nm lasers, the survival rate of 4T1 cells was only 17.7%. Tumors in tumor-bearing mice were completely eradicated[88].

3.1.4 CT and CDT combined therapy

Excess GSH in cancer cells depletes the · OH produced by CDT during treatment. In 2020, Liu's research group prepared biodegradable Fe-DSCP with cisplatin prodrug DSCP and Fe3+, which could effectively target C6 cells with αvβ3 integrin overexpression after surface modification by PEG and targeted modification by cRGD. The reaction of Fe-DSCP-PEG-cRGD with excessive GSH in cancer cells would release cisplatin and Fe2+ to achieve targeted CT-CDT combination therapy, and the survival rate of C6 cells was only 1.7%[25]. In addition to consuming GSH to improve CDT efficacy, Zhang's group and Zhan's group added DOX to folate-modified iron-based NMOFs to achieve targeted CT-CDT combination therapy[89][90].

3.1.5 PDT combined with CDT

CDT uses H2O2 in TME to continuously produce · OH and O2, which changes the level of ROS in TME and the state of hypoxia, and aggravates the oxidative damage of PDT under laser irradiation. In 2019, Lin's team designed a biodegradable system O2-Cu/ZIF-8@Ce6/ZIF-8@F127(OCZCF). Under laser irradiation, Ce6 can produce ROS, while ZIF-8 can release oxygen to alleviate tumor hypoxia[91]. The addition of Cu2+ not only increased the storage of oxygen, but also reacted with GSH to produce Cu+, resulting in Fenton-like reaction for CDT (Figure 7). In vitro experiments showed that OCZCF could effectively alleviate tumor hypoxia, and the tumor volume of mice in the OCZCF light group was 1/3 of that in the OCZCF-non-light group, indicating that PDT-CDT combination therapy significantly enhanced the anti-cancer effect.

3.1.6 PTT and CDT combination therapy

Recently, it has been reported that an increase in the temperature of the tumor site can improve the efficiency of CDT[62⇓~64,67]. Therefore, PTT-CDT combination therapy can enhance the therapeutic effect of CDT. In 2020, Peng's project assembled Zr-FC MOFs nanosheets with a thickness of only 16.4 nm, which are both excellent photothermal agents and efficient Fenton reaction catalysts (Figure 8), with a photothermal conversion efficiency of up to 53%.Zr-FC MOFs alone had a moderate killing effect on 4T1 cells, but almost all 4T1 cells were killed under laser irradiation, which proved that PTT played a dominant role in the treatment process and that the efficacy of CDT could be enhanced by local temperature rise[92].

3.2 Three-mode combination therapy

Although the dual-mode combination therapy of NMOFs has better efficacy than the single-mode therapy, the integration of three therapeutic agents into NMOFs to achieve three-mode combination therapy can improve the therapeutic efficiency, reduce the dose concentration, and further reduce the toxic and side effects[71].

3.2.1 PTT-PDT-CT

The ROS produced by PDT can promote the aggregation of drugs in cells, and the heat produced by PTT can promote the release of drugs and photosensitizers, so the therapeutic effect of CT-PTT-PDT is stronger than that of the dual-mode combination therapy. Zhang's team used functionalized AuNR as seed crystals to grow PCN-224 on its surface to load camptothecin to achieve PTT-PDT-CT combined therapy[93]. Under 808 nm laser irradiation, the photothermal conversion efficiency was 20. 6%, and under dual laser irradiation, the survival rate of 4T1 cells was only 12%, which showed significant killing effect on tumors and inhibited tumor metastasis.
In 2021, Tian's research group prepared hollow porphyrin NMOFs (H-PMOF) by ZIF-8 self-sacrificial template method to load DOX and ICG, and then wrapped it with cancer cell membrane to achieve active targeting, with the loading capacity up to 635 wt%. The photodynamic performance of H-PMOF is 1.7 times that of PCN-224, and its IC50 is far less than that of PCN-224 (Fig. 9)[94]. At a very low dose (2 μg/mL), cell viability was only 8%, and tumors in mice were completely eliminated without recurrence.

3.2.2 PTT-PDT-CDT

The increase of tumor local temperature can improve the therapeutic effect of Fenton reaction and PDT, and CDT can improve the therapeutic effect of PDT. PTT-PDT-CDT is not only better than the combination of PTT-PDT-CDT, but also avoids the drug resistance and toxicity caused by chemotherapy. It is a non-invasive, efficient and low-toxicity cancer treatment method. Yin research group prepared Mn/Cu/Zn-MOF@MnO2 hollow porous structure loaded with ICG, the aggregated ICG had photothermal properties and was released at the tumor site to show PDT performance, Cu2+/MnO2 reacted with GSH to produce Fenton reaction catalyst Cu+/Mn2+, and reacted with H2O2 to produce · OH and O2, PTT-PDT-CDT combined therapy was carried out under 808 nm laser irradiation, the survival rate of U87 cells was 12%, and the tumor growth of U87 tumor-bearing nude mice was effectively controlled[95].

4 Summary and Prospect

NMOFs have the advantages of tunable structure and morphology, large specific surface area, high porosity, high crystallinity, high loading rate, good thermal stability, high chemical stability and variable affinity, and are a class of promising biomedical nanomaterials. Table 1 provides a comprehensive summary of the latest applications of NMOFs in CT, PTT, PDT, CDT and various combination therapies.
At present, NMOFs have shown great application potential in the field of cancer therapy, but there is still a long way to go before their clinical application, and they still face many challenges, mainly including the following three aspects:
(1) The toxicity of NMOFs itself
In biomedical applications, it is essential to systematically evaluate the biosafety issues of materials. NMOFs are a class of porous coordination polymers, which are prone to aggregation, resulting in difficulties in entering cells and additional toxic side effects. Although many studies have used physical and chemical means to functionalize the surface of NMOFs to improve their dispersion and stability, they have not yet achieved the desired results. Therefore, it is still urgent to solve the problem of aggregation of NMOFs. The toxicity of NMOFs is not only related to the composition, morphology, size and stability, but also to the complex physiological environment. At present, the toxicity research of NMOFs mainly focuses on the short-term toxicity or acute toxicity in vivo, while the long-term toxicity research is rarely reported.
(2) Problems of NMOFs in PDT and PTT
The application of NMOFs in phototherapy has been proposed and developed in the past decade, and has attracted more and more attention from researchers. Although many NMOFs systems have been designed to achieve good therapeutic effects in vivo and in vitro, the research on NMOFs in phototherapy is still in its infancy. Limited laser penetration is a huge challenge in phototherapy. Although researchers have improved the penetration depth by combining NMOFs with upconversion nanoparticles, the treatment of deep tumors has not achieved the desired effect, and there is also a risk of infection.
(3) Problems of NMOFs in CDT
In 2016, NMOFs were applied to CDT, and many studies have shown that CDT is a promising cancer treatment, but there are still some problems to be solved: 1) tumor endogenous H2O2 is not enough to maintain the CDT treatment process; 2) Most of the studies on CDT focus on performance and lack of analysis of molecular and genetic mechanisms; 3) There are few studies on the targeting ability of CDT reagent nanocarriers.
In a word, although there are still many problems in the clinical application of NMOFs, in recent years, the research on NMOFs in the field of cancer treatment has gradually increased, and scientists are full of confidence in it.It can be predicted that there are broad development prospects in the following aspects: (1) When constructing NMOFs, bioactive molecules or endogenous molecules are used as organic ligands, and transition metal cations with high biocompatibility are used as metal nodes, which can largely avoid the toxicity of NMOFs; (2) Monotherapy and dual-mode combination therapy have achieved certain efficacy, and the establishment of multi-mode combination therapy will achieve better therapeutic effect; (3) At present, many active targeted drug delivery systems have been prepared, and different aptamers will be further developed as targeting agents for precise targeted therapy of tumors in the future; (4) Most of the reported PDT belongs to type II oxygen-dependent treatment, so it is largely affected by the hypoxia of tumor cells. Therefore, it is necessary to develop type I oxygen-independent PDT in the future to improve its efficacy.

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Funding

National Natural Science Foundation of China(21975146)

Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(2021L368)

Cultivate Scientific Research Excellence Programs of Higher Education Institutions in Shanxi(2020KJ023)

Shanxi Scholarship Council of China(2020-133)

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