Two-dimensional metal carbides and nitrides (MXenes): preparation, property, and applications in cancer therapy

Lu Ming Dong; Cui Ye; Lin Lin Zheng; Zhong Feng Gao; Fan Xia

doi:10.1515/nanoph-2019-0550

Artikel Open Access

Two-dimensional metal carbides and nitrides (MXenes): preparation, property, and applications in cancer therapy

Lu Ming Dong , Cui Ye , Lin Lin Zheng , Zhong Feng Gao und Fan Xia

Veröffentlicht/Copyright: 13. April 2020

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Abstract

Transition metal carbides and nitrides (MXenes), which comprise a rapidly growing family of two-dimensional materials, have attracted extensive attention of the scientific community, owing to its unique characteristics of high specific surface area, remarkable biocompatibility, and versatile applications. Exploring different methods to tune the size and morphology of MXenes plays a critical role in their practical applications. In recent years, MXenes have been demonstrated as promising nanomaterials for cancer therapy with substantial performances, which not only are helpful to clarify the mechanism between properties and morphologies but also bridge the gap between MXene nanotechnology and forward-looking applications. In this review, recent progress on the preparation and properties of MXenes are summarized. Further applications in cancer therapy are also discussed. Finally, the current opportunities and future perspective of MXenes are described.

Keywords: 2D materials; photothermal therapy; photodynamic therapy; combined therapy

1 Introduction

Two-dimensional (2D) materials, due to their electronic structures, high specific surface area, and easy-to-assemble building blocks for nanoscale architectures, have attracted considerable attention [1], [2], [3]. Graphene is considered to be a promising material in the field of nanotechnology. Other 2D materials, such as layered double hydroxides [4], transition metal dichalcogenides [5], covalent organic frameworks [6], and black phosphorus (BP) [7], have been applied in a variety of fields, including optoelectronics, energy storage, and biomedicine.

In 2011, Naguib et al. selectively etched the Al atomic layer in the ternary layered compound Ti₃AlC₂ (MAX) by hydrofluoric acid (HF), thus obtaining a 2D Ti₃C₂ material with similar structure to graphene [8]. After that, new 2D crystal compounds, such as Ti₂C, Ta₄C₃, Ti₃CN, and V₄C₃T_x, were prepared successively. Because of their unique graphene-like structure, they were named MXenes. In terms of the precursors, more than 90 MAX-phase and non-MAX-phase precursors have been reported to fabricate MXenes [9], [10]. MAX phase is a family of layered ternary carbides, nitrides, and carbonitrides consisting of “M”, “A”, and “X” layers. The general formula is M_n+1AX_n (n=1, 2, 3), where “M” represents transition metals (M=Ti, Sr, V, Cr, Ta, Nb, Zr, Mo), “A” represents major group elements (mainly Al, Ga, In, Ti, Si, Ge, Sn, and Pb), and “X” represents carbon (C) or nitrogen (N) [11] (Figure 1). MAX phase, which combines the excellent properties of ceramics and metals, has not only high modulus of elasticity, low density, remarkable thermal stability, and oxidation resistance but also excellent thermal conductivity and electrical conductivity [12], [13]. In an alternative method, non-MAX phases have also been successfully employed to prepare MXenes, including Zr₂C₂T_x, U₂CT_x, and Mo₂CT_x [14], [15], [16]. For example, Mo₂CT_x is made by etching Ga layers from Mo₂Ga₂C. Despite its similarity to Mo₂GaC MAX phase, there are two A layers (Ga) separating carbide layers [14], [15]. By selectively etching Al₃C₃ layers from Zr₃Al₃C₅ and U₂Al₃C₄ phases, Zr₂C₂T_x and U₂CT_x are fabricated, respectively [17], [18]. These discoveries may enable a novel direction for the precursor to expand the MXene family.

Figure 1:

Constituent elements of MAX and MXenes and their intercalation ions.

The blue background elements show reports only in the MXene precursor (MAX phase) and have not been synthesized in MXenes. The elements on the red background are the A element of MAX and may be selectively etched to make MXenes. The yellow background shows the cations that have been embedded in MXenes to date [11].

As a new type of 2D material, MXenes show excellent properties such as electrical properties [19], [20], optical properties [19], [20], thermal stability [21], and so on, which could be used in energy storage, catalysis, and other fields. In addition, the abundant oxygen-containing groups make MXene nanosheets have remarkable performance in the biomedical field. Compared to traditional photothermal agents, MXenes have a large specific surface area (250–1000 m² g⁻¹) [22], [23], wide ultraviolet (UV)/near-infrared (NIR) band (up to 1350 nm), and high photothermal conversion efficiency (η; ~50% under certain situations) [24], which have been successfully used in photothermal therapy (PTT). Furthermore, the NIR laser has strong deep penetration ability to target tissue, rapid and effective treatment, fast recovery, and small invasion, which highlights the application of MXenes in tumor treatment.

In this review, the latest development of MXenes in the field of biomedicine, especially in cancer therapy, is discussed from the aspects of their structure, preparation, and properties. First, the structure and preparation of MXenes are introduced. Second, the latest research of MXenes in cancer therapy is reviewed (Figure 2). Finally, the future challenges and prospects of MXenes are discussed.

Figure 2:

Applications of MXenes in cancer therapy.

We summarize the preparation methods, properties, and cancer therapy applications in this review.

2 Preparation and properties of MXenes

2.1 Structure of MXenes

Like the MAX phase (M_n+1AX_n), MXene has a hexagonal crystal structure, in which M atoms belong to hexagonal close packing. While X atoms are filled in the octahedral gap, and its general formula (M_n+1X_n) is also consistent with MAX. Due to the high chemical activity of MXene without surface terminations, it is easy to react with solution in the process of preparation of MXenes by solution etching, forming MXenes with surface terminations (M_n+1X_nT_x, T_x mainly represents -F, -OH, -O terminations) [25], [26].

As shown in Figure 3, Tang et al. modeled the microstructures of Ti₃C₂ and Ti₃C₂X₂ (X=F, OH) [27]. For the nonfunctional group Ti₃C₂, the atomic structure is mainly arranged in layers in the order of Ti(1)-C-Ti(2)-C-Ti(1) (Figure 3A). For the functional group Ti₃C₂X₂ (X=F, OH), due to the distribution of X functional groups, the atomic structure distribution is mainly divided into three types: (i) X functional groups are distributed on both sides of the Ti₃C₂ sheet, and the X group is directly above the Ti(2) atoms, at the same time close to three C atoms (Figure 3B and E); (ii) on both sides of Ti₃C₂, the X group is directly above the C atoms (Figure 3C and F); and (iii) this class can be regarded as the first two combinations, and the X group on one side is opposite to Ti(2) atoms and the other side of the X group is opposite to the C atoms (Figure 3D and G). In addition, the X groups (O, etc.) are randomly distributed on both sides of Ti₃C₂, and there is no specific order and no correlation between the groups [28], [29].

Figure 3:

Schematic diagram of Ti₃C₂ microstructure.

(A) schematic of side view of 2D material Ti₃C₂ microstructure and (B–G) side view of the microstructure of Ti₃C₂X₂ material (X=F, OH) [27].

Wang et al. observed the Ti atom arrangement of Ti₃C₂X intuitively with high-angle annular dark field [30]. The measured interval of Ti₃C₂X was 0.98 nm, which was consistent with that of X-ray diffraction (XRD). There was no observation of the atoms such as C, F, and O in the dark-field image. However, they used the annular bright-field image to find their existence and relative position with the Ti atom successfully, which was consistent with previous research [21], [31].

2.2 Synthesis of MXenes

In recent years, the synthesis methods of MXenes have been extensively established. More than 70 kinds of MXenes have been theoretically predicted, and more than 20 kinds of such MXenes have been experimentally reported, which can be fabricated by top-down approaches or bottom-up fabrication. To enhance the biocompatibility of MXenes for various biomedical applications, different surface functionalizations have been proposed. One can refer to some excellent reviews for a comprehensive summary of the related achievements of MXene synthesis and modification [10], [26], [32], [33]. A brief overview on the synthesis of MXenes is presented in the following.

2.2.1 Top-down synthesis method

HF etching is the most classical and common top-down method for preparing MXenes. The reaction between MAX and HF can be divided into two processes in the etching process. Taking Ti₃AlC₂ MAX as an example, by immersing Ti₃AlC₂ into 50% (w/v) HF solution for 2 h at room temperature, the Al atoms in Ti₃AlC₂ are stripped completely and Ti₃C₂ is obtained [34]. The reaction process is as follows:

(1)Ti3AlC2+3HF=AlF3+3/2H2+Ti3C2

(2)Ti3C2+2H2O=Ti3C2(OH)2+H2

(3)Ti3C2+2HF=Ti3C2F2+H2

The same etching principle is applied to the preparation of other MXenes (Ti₂CT_x, V₂CT_x, and Mo₂CT_x). HF is a highly toxic chemical that can penetrate through skin, tissue, and even bones, rendering its handling and disposal hazardous [35]. Different approaches have been developed to improve the etching procedure and avoid or reduce the use of HF. In 2014, the conductive “clay” (Ti₃C₂T_x) was etched by Ghidiu et al., mixing fluoride salts (e.g. NaF, KF, LiF, and CsF) with H₂SO₄ or HCl to replace the strong corrosive HF [36]. This etching approach offers a much milder way to fabricate MXenes by employing the selective etching-assisted liquid exfoliation, significantly improving its potential for practical applications. Alhabeb et al. also summarized that as low as 5 wt% HF can be successfully applied for the fabrication of Ti₃C₂T_x, noting that hazardous HF can be produced as NH₄HF₂ or HCl-LiF indirectly, in the in situ method, over an etching time of 24 h [37]. In the presence of NH₄HF₂ or HF, delamination is realized using large organic chemicals dissolved in tetramethylammonium hydroxide (TMAOH) or dimethyl sulfoxide followed by sonication. Employing HCl-LiF, delamination of Ti₃C₂T_x intercalated with Li⁺ is achieved without or with sonication (thus via minimally intensive layer delamination) depending on the concentrations of LiF and HCl [37]. Another merit of the in situ method over direct HF etching is the formation of increased interlayer spacing between water that ultimately weakens their interaction and MXene nanosheets owing to the intercalation of cations (e.g. Li⁺) [37].

The F-free etching method was also used as an alternative way to prepare MXenes. Based on the anodic corrosion of Ti₃AlC₂ in a binary aqueous electrolyte of NH₄Cl and TMAOH, carbide flakes (Ti₃C₂T_x) with a yield of more than 40% were achieved [38]. This work provides a safe way to the scalable synthesis of MXene materials. Electrochemical etching was conducted on Ti₂AlC to produce Ti₂CT_x multilayers in low concentrated HCl but with the generation of carbide-derived carbon [39]. Most recently, Cl-terminated Ti₃C₂T_x and Ti₂CT_x MXenes were derived in the presence of Lewis acidic molten salts (e.g. ZnCl₂) by a subsequent exfoliation of Ti₃ZnC₂ and Ti₂ZnC [40].

After etching, MXenes with multilayers are often obtained, which need further exfoliation. Generally, the exfoliation techniques depend on MXene composition and etching method. Energetic treatments, including shaking or sonication, can be employed to exfoliate multilayers, but most results are unsatisfied. By the intercalation of molecules, liquid exfoliation is a promising approach used to generate colloidal suspensions with high yield (up to 20 mg ml⁻¹ MXene) [32]. Introducing proper organic molecules or cations can trigger the swelling of the interlayer space and a concomitant weakening of the interlayer interactions, which is critical to exfoliate multilayers into monolayers.

Typically, etching methods are carried out at low temperatures (<60°C). However, it is also demonstrated to yield MXenes at higher temperatures. For example, Peng et al. reported that Ti₃C₂T_x can be prepared based on the hydrothermal ammonium fluoride (NH₄F) method [41]. The morphology and structure of Ti₃C₂T_x were controlled by the time of hydrothermal reaction, temperature, and the content of NH₄F. Li et al. prepared high-purity Ti₃C₂T_x without F terminations by the fluorine-free hydrothermal method, etching in NaOH solution (2.75 mol l⁻¹) at 270°C [42]. To heat MAX phase in the molten salt at high temperature and to selectively etch the A element layer in a vacuum environment can possibly obtain MXenes [8], [43]. For example, Ti₃C₂T_x with high purity was prepared by mixing 10 g Ti_n+1AlC_n powder with 30 g LiF powder, transferring to the medium platinum crucible, and heating at 900°C at ambient environment for 2 h. With the increase of temperature, the M_n+1X_n layer will be detached and a 3D M_n+1X_n rock salt structure is generated [44]. The first nitride MXenes (Ti₄N₃T_x) were achieved by heating Ti₄AlN₃ in a fluoride salt by Hantanasirisakul et al., which was not previously reported to produce MXenes from their corresponding MAX phases [45].

2.2.2 Bottom-up synthesis method

Researchers have invented a variety of methods to prepare ultrathin materials since the discovery of 2D materials. Chemical vapor deposition (CVD) has been widely used to prepare ultrathin materials with nanometer thickness [46]. Hou et al. synthesized α-Mo₂C and other transition metal carbides, such as W₂C, WC, TaC, and NbC, with a thickness of only a few nanometers by CVD [47]. As MXenes of carbide type are easier to obtain than that of nitride type, nitriding (or ammoniating) M_n+1C_n may be an effective way to prepare M_n+1N_n. Urbankowski et al. treated Mo₂CT_x and V₂CT_x with NH₃ flow at 600°C, the C atom in Mo₂CT_x and V₂CT_x was replaced by N atom, and Mo₂CT_x and V₂CT_x were successfully prepared [48]. However, V₂CT_x generated cubic V₂N and cubic VN after the above treatment. In addition, the conductivities of Mo₂CT_x and V₂CT_x obtained after ammonization were significantly increased. Peng et al. used CVD as a more efficient and safe synthesis method to prepare MXenes, which could effectively control the rate of defects in MXenes [41].

Taken together, it is important to understand the unique surface properties of MXenes for its performances and applications. To date, the synthesis of MXenes is still in the laboratory stage. For further practical application of industrialization, a large-scale process is indispensable. Considering the numerous complex factors in the process of commercialization, the optimization of synthesis methods is necessary for the breakthrough in production.

2.3 Properties of MXenes

2.3.1 Stability

The stability of the crystal structure depends on the crystal lattice energy. Generally, the crystal with large negative lattice energy has a stable structure. Seredych et al. found that the lattice energy of MXene is negative and stable through the calculation of the first principle [21]. They also studied the stability of MXene phase from two aspects of binding energy and formation energy. The binding energy (E_cho) is usually defined as follows: that is, the sum of the total energy of the compound minus the total energy of each atom. It is found that the E_cho of MAX and MXene phases increases with the increase of n value, which is caused by the increase of the number of Ti-C (N) bonds. The binding force of Ti-C (N) bonds is stronger than that of Ti-Al bonds.

The limited stability of MXene in water has important practical implications. One critical instance is that water and oxygen are not the best medium to store MXene after synthesis [49]. In addition, exposure to light can accelerate the oxidation of a few layers of MXene suspension. Thus, it is recommended to refrigerate the MXene suspension for storage in an oxygen-free dark environment. The oxidation of MXene lamellae starts from the edge, and the formed metal oxide nanocrystals TiO₂ are distributed at the edge of the lamellae and then spread to the whole surface through nucleation and growth [50]. The oxidation resistance of MXene depends on the quality of the product: higher-quality MXene nanosheets have higher stability [51].

There are few studies on the high temperature stability of MXene materials, and the understanding of this property is still under development. The composition and environment of MXenes have an important influence on its high temperature stability. At present, the transformation behavior of various MXene materials in different atmospheres (argon, air, hydrogen, etc.) is mainly studied by thermal analyzer, and their behaviors have been reported [50].

Studies have shown that Ti₃C₂T_x is stable at 500°C in argon, but some TiO₂ crystals are formed at the edge of the sheet. In argon at 1200°C, the phase transformation of Ti₃C₂T_x produces cubic phase TiC_x [50]. For 2D carbide Ti₂CT_x, it is confirmed that it is stable at 250°C under different inert atmospheres [52]. Another study showed that Ti₂CT_x (T=O) was stable at 1100°C in argon and hydrogen, which was higher than the phase stability limit of nonstoichiometric Ti₂C [53]. Although the characterization of this study is convincing, XRD or Raman analysis is required to confirm the formation of new phase. Being different from the transformation of Ti₃C₂T_x to cubic carbide at high temperature, Zr₃C₂T_x shows excellent thermal stability and maintains its 2D structure at a temperature up to 1000°C in vacuum. The reason why Zr₃C₂ has better thermal stability is that the free energy of its structure is lower than the cubic phase of ZrC. As for Ti₃C₂T_x, its structure is metastable with respect to block cubic phase of TiC_x [50].

2.3.2 Mechanical property

As for the mechanical properties of MXenes, the current research is mainly focused on theoretical calculations. Many theoretical studies have been focused on the 2D materials of graphene and other graphene-like materials, but there are few theoretical and experimental studies on the mechanical properties of MXene materials.

Kurtoglu et al. calculated the materials, such as Ti₂C, Ti₃C₂, and Ta₃C₂, which contain nonfunctional groups using the first principle [31]. The results showed that, when the Al layers were etched out, their structure changed. The elastic constants of MXene phase studied are all higher than 500 GPa, which indicates that MXenes have a high elastic modulus at least along its reference plane. The elastic constant value of MXene is much larger than that of its corresponding MAX phase, such as M₂AX phase. Compared to the corresponding MXene phase, its elastic constant value is reduced by nearly 40%. For M₃AX₂ and M₄AX₃, they are reduced by nearly 70%. The elastic constants of MXene are obviously smaller than that of graphene. However, based on the same thickness, the bending strength of multilayer MXene materials, especially Ta₄C₃ and Ti₄C₃, is one order of magnitude higher than that of graphene, and the mechanical properties are better than that of multilayer grapheme [8]. To test the elastic property of monolayer Ti₃C₂T_x, direct experimental measurement was first carried out using atomic force microscopy nanoindentation. The measured Young’s modulus for single flakes was 333 ± 30 GPa and the breaking strength of 17.3 ± 1.6 GPa was obtained for both layers [54].

2.3.3 Electronic property

MXenes reveal the properties of semiconductors or semimetals or metals influenced by the electronic structure associated with the elemental composition. Unterminated (bare) MXenes are metallic with a high density of states at the Fermi level. The electronic properties of MXenes are significant depending on the properties of M, X elements and surface terminations [11], [19], [55], [56], [57], [58], [59]. Upon surface modification, some of the MXenes are tuned from metallic to semiconducting. For instance, Ti₃C₂ is always metallic, whereas Ti₃C₂OH₂ and Ti₃C₂F₂ behave as semiconductors. The semiconducting characters of modified MXenes are derived from the coexistence of positive surfaces, and nearly free electrons produce dipole moments together with the shifting of Fermi energies triggered by “X” and “M” [60].

Depending on the synthesis method and the morphology, the electronic and electrical conductivity of MXenes can also be regulated. It is recognized that delamination and mild etching can generate flakes with minimal defects and large size. High conductivity can be achieved by the perfect contact between the absence of intercalated species and individual flakes [61]. In terms of the delamination and etching conditions, the conductivity of Ti₃C₂T_x can be observed to range from 1000 to more than 6500 S cm⁻¹, implying that MXenes have higher conductivity than graphene [61].

Noteworthy, the elemental composition of “M” layers also has a critical impact on the electronic property of MXenes [51]. Some approaches to tune the metallic to semiconducting behavior of MXenes have been demonstrated, such as changing surface termination, changing phase, doping, or changing the element of outer metal layers [60]. The binary cooperative metallic-semiconductor characters of MXenes provided potential applications in energy-harvesting materials, such as light-to-heat conversion materials [19].

In an inert environment, controlling the surface of MXenes by heat treatment results in a remarkable improvement of conductivity, owing to the elimination of surface terminations and intercalated molecules. Hart et al. reported a direct experimental evidence for the influences of temperature on the electronic properties of MXene [62]. The conductivity of Ti₃C₂T_x significantly increased (about threefold) after annealing at 100°C to 400°C. It was explained that interflake conductivity was improved by deintercalation of water and other adsorbed species and that intraflake conductivity was improved by defunctionalization of OH-termination. When the sample was heated up to 775°C, the conductivity continued to enhance because of loss of F-termination as demonstrated by electron energy loss spectra measurements.

2.3.4 Optical property

In addition to excellent electrical properties, the optical property of MXene is also worth studying. MXenes have a linear absorption loss of ~1% nm⁻¹ [45], a nonlinear absorption coefficient of about −10⁻²¹ m² V⁻² [63] and a negative nonlinear refractive index of about −10⁻²⁰ m² W⁻¹ [63]. Under low light, the Ti₃C₂T_x single-photon process has the advantage of saturation absorption. Under strong light, the process of multiphoton absorption dominates, and the saturated absorption characteristics of MXenes make them suitable for ultrafast laser field. Dong et al. studied the nonlinear optical properties by z-scan [64]. The SA behavior of Ti₃C₂T_x film at 1064 nm is due to the increase of plasma-induced ground state absorption. Importantly, the properties of nonlinear light absorption and saturation flux of the Ti₃C₂T_x film vary with film thickness. Through further research, Ti₃C₂T_x is combined with a reverse saturable absorbing material C₆₀ to realize a photonic diode, which has a high rectification ratio and can be used for optical signal filtering. When Ti₃C₂T_x is dispersed in rhodamine 101 solution, random laser generation occurs, indicating the formation of supermaterials. Research on the nonlinear optical properties of MXenes are still in the infancy, but they have shown application prospects in many fields. Jiang et al. used Ti₃C₂T_x as a mode-locked saturated absorber [63]. Under the wavelength of 1066 and 1555 nm, a broadband optical switch is realized, and a femtosecond ultrafast pulse laser is obtained.

The optoelectronic properties of MXenes are often regulated by the chemical and electrochemical intercalation of cations. The extraordinary optoelectronic characters are successfully applied to fabricate conductive transparent films with low resistivity and high electrical conductivity and transmittance, comparable or better than devices used nowadays. By etching of magnetron sputtered Ti₃AlC₂, the first transparent MXene film was produced with conductivity of ≈2000 to 5000 S cm⁻¹ and transmittance of 14% to 85% [65]. Treating with NH₄⁺ ions, films became more transparent, owing to the expansion of the c-lattice parameter; however, it showed less conductivity than those with small interlayer spacing. Using the spin-casting method, Ti₃C₂T_x films obtained a high conductivity of 6600 S cm⁻¹ with a high transmittance of more than 97% and a figure of merit (FoM) of 5 [66]. Notably, Ti₃C₂T_x films also display significant near-IR absorption, with the onset wavelength similar to the negative permittivity (ε₁), which are well matched with density functional theory predictions [67]. Moreover, storing in inert atmosphere (e.g. dry N₂) was demonstrated to remarkably improve the conductivity of the films by threefold. It was found that the conductivity and transparency were well maintained after vacuum-annealing treatment [68]. To meet a demand of transparent electrodes, FoM of more than 30 is required [69]. Improving the flake quality and size, postdeposition treatment, and deposition techniques of MXene might be helpful to fabricate films with high conductivity and transparency [19]. To date, most previous reports concentrated on Ti-based MXenes (e.g. Ti₃C₂, Ti₂C, and Ti₃CN) and Nb-based MXenes [e.g. niobium carbide (Nb₂C)] in aqueous solution, whereas the optoelectronic properties of other MXenes await further exploration.

Using the facile hydrothermal method, TiCN fluorescent quantum dots (QDs) were prepared with good aqueous dispersibility using TiCN powder as the precursor [70]. The average vertical and lateral sizes of TiCN QDs were 3.2 ± 0.3 and 2.7 ± 0.2 nm, respectively. The obtained TiCN QDs were employed for the sensitive and selective determination of ferric ion (Fe³⁺) with a low limit of detection of 1.0 μM. This work provides novel insights for the development of fluorescent MXene QDs.

The photothermal conversion efficiency and photothermal applications of MXenes have also been extensively studied. Compared to graphene, MXenes have a high absorption coefficient of ~15 to 40 L (g cm)⁻¹. Li et al. found that, by irradiating colloidal droplets of MXenes, the material absorbs light energy and converts it into heat energy [71]. For thermal energy, the photothermal conversion efficiency of Ti₃C₂T_x is close to 100% in this experiment. Within 1 min, the solution temperature increased by 17°C, and the increase in solution temperature was proportional to the absorption coefficient, droplet size, MXene concentration, and laser illuminance power of the MXene solution. It is difficult to compare the efficiency of photothermal conversion according to the change of temperature under different experimental conditions. Therefore, it can be used to compare the photothermal characteristics of different MXenes.

In addition to the photothermal conversion efficiency, thermal conductivity is also an important parameter for the thermal properties of materials. MXenes have higher thermal conductivity due to low concentration defects and large size. In 2018, Liu et al. tested the thermal properties of Ti₃C₂T_x and its films using temperature- and polarization-sensitive Raman spectroscopy [72]. The thermal conductivity of Ti₃C₂T_x and Ti₃C₂T_x/polyvinyl alcohol (PVA) was experimentally determined to be 55.8 and 47.6 W (m K)⁻¹, which is higher than that of metals and other 2D materials, such as MoS₂ [73] and BP [74].

3 Applications of MXenes in cancer therapy

Compared to other nanomaterials, MXenes possess the following attractive properties that suitable for cancer therapy. (i) In the presence of functional groups, such as -OH, -O, or -F, MXenes are hydrophilic in nature [9], [11], indicating substantial potential for surface modification. (ii) The large surface area makes MXenes host massive molecules for synergized therapy, including immune adjuvants, photosensitizers (PS), and chemotherapeutic drugs. (iii) Several compositions of MXenes, including Ti₂CT_x, Ti₃C₂T_x, Nb₂CT_x, and Mo₂C, have been tested to be nontoxic and biocompatible to biological organisms [75], [76]. The reason for excellent biocompatibility might be that the metal in the “M” layer, such as Ti, Mo, and Nb, are relatively inert to living organisms, and other major elements, including nitride and carbon, are essential in the structure of biological organisms [75], [76], [77]. Direct evidence for the biosafety and biocompatibility of MXenes is that it can be degraded and cleared from the body of mice [24]. (iv) MXenes exhibit strong plasmonic effects in the NIR region, bringing promising potential for both in vivo PTT and photoacoustic (PA) imaging at the first or second biological window.

3.1 PTT of cancer

Photothermal therapy is a method which converts light energy into heat energy via the photothermal transduction agents and kills tumor cells by generating heat. Compared to traditional tumor therapy, there are fewer side effects of the PTT [75], [78]. The combination of imaging guidance and therapy was commonly adapted for efficient tumor treatment due to following reasons: (i) Some important information of the tumor, including the size, location, and shape, can be visualized by imaging. (ii) The accumulation of MXenes can be acquired by imaging to evaluate the optimal time point for cancer treatment and monitor therapeutic feedback. MXene-based therapy can be easily integrated with multimodality imaging approaches, including PA imaging, magnetic resonance imaging (MRI), and computed tomography (CT).

Typical representatives of MXenes, such as Ti₃C₂, Nb₂C, Ta₄C₃, and Ti₂C, are proven to have excellent photothermal properties and have been used in PTT. Lin et al. applied MXenes to PTT of tumor for the first time [79]. Using Ti₃AlC₂ powder as the raw material, the 2D nanosheets of Ti₃C₂ were functionalized by soybean phospholipid (SP) for high-efficiency PTT of tumor. The introduction of SP enhanced the stability of Ti₃C₂ nanosheets in various dispersions and improved their applicability in tumor diagnosis and treatment. The composite nanosheet Ti₃C₂-SP had excellent PTT performance, as the Ti₃C₂-SP in the low concentration of 72 μg ml⁻¹ could be heated to above 55°C in 6 min (Figure 4A), which fully satisfied the temperature requirements of PTT for the ablation of tumor tissue. The results showed that its photothermal conversion efficiency was as high as 30.6%, which was higher than that of gold nanorods (21%) [82], copper selenide nanocrystals (22%) [83], and copper sulfide nanocrystals (25.7%) [84]. Dai et al. initiated a simple redox reaction on the surface of ultrathin Ti₃C₂ nanosheets to synthesize Ti₃C₂ matrix composite MnO_x/Ti₃C₂, which was further successfully served as a multifunctional therapeutic agent for MRI/PA imaging-guided PTT anticancer therapy (Figure 4B) [80]. Those MnO_x/Ti₃C₂ composites were further modified with SP to obtain the MnO_x/Ti₃C₂-SP, which can be used in in vitro and in vivo antitumor applications. It was found that the tumor temperature in the MnO_x/Ti₃C₂-SP NIR group increased from about 25°C to 60°C under laser irradiation for 10 min, which was enough to destroy the cancer cells. In contrast, there was no significant temperature increase in the NIR group, indicating that MnO_x/Ti₃C₂-SP nanocomposites had a high photothermal effect. Importantly, after photothermal ablation, the tumor growth of the MnO_x/Ti₃C₂-SP NIR group was significantly inhibited (Figure 4C and D). The reason for this high tumor inhibition efficiency is that MnO_x/Ti₃C₂-SP has high photothermal conversion efficiency and can effectively remove the tumor and induce tumor death. In addition, the MnO_x/Ti₃C₂ composite has high biocompatibility, which can ensure its further potential clinical transition. Liu et al. reported the application of magnetic functionalization of Ti₃C₂ in tumor therapy [85]. Based on the specific surface chemistry, they produced magnetic Fe₃O₄ nanocrystals on the surface of Ti₃C₂ [Ti₃C₂-iron oxide nanoparticles (IONPs)], which had a high efficiency of photothermal conversion (48.6%) to forcefully ensure their photothermal killing of cancer cells and ablation of tumor tissue. Using systematic in vivo and in vitro tests, it has been proven that the Ti₃C₂-IONPs have no obvious toxicity to cells and mice, indicating its high biocompatibility and promising potential for further clinical application. Hussein et al. synthesized two kinds of plasma-shaped Ti₃C₂T_x-based nanocomposites (Au/MXene and Au/Fe₃O₄/MXene) by chemical methods and studied the potential of combining Au and Fe₃O₄ nanoparticles with Ti₃C₂T_x as PTT agents [81]. They studied dose- and power density-dependent responses to tumor ablation by increasing the concentration of nanocomposites or the power density of laser diodes, respectively. As shown in Figure 4E and F, the highest power density (1.5 W cm⁻²) led to the best cell killing due to the enhancement of photothermal activity and temperature. As PTT reagents, Au/MXene and Au/Fe₃O₄/MXene both show high cell-killing effect. At the same time, the photothermal ablation activity of two kinds of MXene nanocomposites on human breast cancer cells (MCF-7) was also studied. Compared to pure Ti₃C₂T_x, the new nanocomposites based on MXene are safer and more suitable.

Figure 4:

Ti₃C₂-based PTT of cancer.

(A) Photothermal heating curves of pure water and different concentrations (72, 36, 18, and 9 ppm) of Ti₃C₂ nanosheets dispersed in water suspension under irradiation with 808 nm laser (1.5 W cm⁻²) [79]. (B) Effective PTT ablation of tumors guided by MRI/PA imaging with MnOx/Ti₃C₂-SP composite nanosheets [80]. (C) Infrared thermographs of 4T1 tumor-bearing nude mice under intravenous irradiation of MnOx/Ti₃C₂-SP composite nanosheets, irradiated with 808 nm laser (1.5 W cm⁻²) at different time intervals [80]. (D) Digital images of tumors in each group after different treatments [80]. (E) Relative viability of MCF-7 cells after incubation with different concentrations of Au/MXene and Au/Fe₃O₄/MXene at a power density of 1.0 W cm⁻², irradiated with MXene and NIR 808 nm laser for 5 min [81]. (F) Relative effectiveness of MCF-7 cells after incubation with Au/MXene and Au/Fe₃O₄/MXene for 5 min after exposure to NIR 808 nm laser at different laser power densities [81].

For a long time, Nb₂C has two key problems: surface engineering and multifunction. On the surface of Nb₂C-MXenes, Han et al. synthesized a uniform silica coating based on sol-gel chemistry and constructed “therapeutic mesoporous” (Figure 5A) [86]. The photothermal conversion ability of Nb₂C in NIR-II biological window was 28.6%, which could be used to enhance PTT (Figure 5B and C). This study not only broadens the biomedical application of Nb₂C-MXene in tumor intensive therapy but also provides an effective strategy for surface engineering of MXenes. Lin et al. developed a biodegradable Nb₂C nanosheets for PTT of tumor [24]. The size of the Nb₂C nanosheets was about 150 nm. Excellent photothermal performance was shown in the first and second biological windows (Figure 5D), and the photothermal conversion efficiency was 36.4% and 45.65%, respectively. After polyvinylpyrrolidone (PVP) modification, Nb₂C-PVP showed excellent biocompatibility and low toxicity and could realize the biodegradation of peroxidase response. Both in vitro cell experiments and in vivo mouse experiments have proven that Nb₂C-PVP had no noticeable toxicity and was able to effectively kill tumors in the first and second biological windows.

Figure 5:

Non Ti₃C₂-based PTT of cancer.

(A) Synthesis steps and surface PEGylation/targeting modification scheme of CTAC@Nb₂C-MSN [86]. (B) Heating curves of CTAC@Nb₂C-MSN dispersed in water during three laser on/off cycles under 1064 nm laser irradiation (1.5 W cm⁻²) [86]. (C) Photothermal properties of CTAC@Nb₂C-MSN dispersed in aqueous solution under NIR radiation [86]. (D) Visible-NIR absorbance spectra of aqueous suspensions of dispersed Nb₂C NSs at various concentrations (2.5, 5, 10, and 20 μg ml⁻¹). Inset: First NIR biowindow (NIR-I; 750–1000 nm) and second NIR biowindow (NIR-II, 1000–1350 nm) [24]. (E) Schematic diagram of Ta₄C₃ nanosheets synthesized by in vivo PA/CT dual-mode imaging combined with PTT [78]. (F) Tumor growth curve over time in four groups (control group, NIR laser group, MnO_x/Ta₄C₃-SP group, and MnO_x/Ta₄C₃-SP+NIR laser group) after receiving different disposes [87]. (G) Transmission electron microscopy (TEM) images of V₂C QDs. Inset: Fast Fourier transform pattern of V₂C-QDs [88]. (H) High-resolution TEM images of V₂C QDs [88]. (I) XRD spectra of V₂C-QDs [88]. (J) X-ray photoelectron spectroscopy of V₂C-QDs [88].

In addition, Lin et al. successfully synthesized 2D ultrathin Ta₄C₃ nanosheets by two-step liquid phase stripping (Figure 5E) [78]. The photothermal conversion efficiency of this material was 44.7%. When the nanosheets were modified with biocompatible SP, a remarkable effect of photothermal killing tumor was observed. All these works have laid a solid foundation for the application of MXene in biomedical field. Dai et al. reported tantalum carbide (Ta₄C₃)-based composite nanochip, which could be used for multitarget photothermal tumor ablation [87]. The redox reaction was activated on the surface of Ta₄C₃ to grow manganese oxide nanoparticles (MnO_x/Ta₄C₃). Because Ta₄C₃ possesses a high photothermal conversion capacity, MnO_x/Ta₄C₃ composite nanosheets had similar photothermal conversion performance in potential PTT (Figure 5F). Under the irradiation of NIR laser, they evaluated the photothermal properties of MnO_x/Ta₄C₃ nanocomposites with different concentrations in vitro and found that MnO_x/Ta₄C₃ showed the photothermal properties of concentration/laser power dependence. The results showed that MnO_x/Ta₄C₃ composite nanotablet had high photothermal conversion ability, which could ensure the further ablation of tumors in vivo. They also modified the surface of MnO_x/Ta₄C₃ composite nanosheets with SP to make MnO_x/Ta₄C₃ composite nanosheets with excellent stability and high dispersion.

When the lateral dimension of a 2D material is less than 100 nm, QDs can be generated due to the quantum confinement effect. The 2D QDs maintain the characteristics of their 2D structure to some extent. More importantly, they have more novel physicochemical properties, such as better dispersibility in the aqueous and nonaqueous phases, ease of modification or doping, and photoluminescence [70]. Their unique and diverse nature determines the better application of 2D QDs in different research fields, including bioimaging, cancer therapy, optoelectronics, catalysis, and so on. Cao et al. synthesized a 2D vanadium carbide QD (V₂C-QDs; Figure 5G–J), which has strong absorption in the second NIR region [88]. On the surface of V₂C-QDs, the nuclear targeted polypeptide segment TAT (V₂C-TAT) was modified and loaded into the engineered exosomes of arginine-glycine-aspartic acid (Ex-RGD). The tumor cell membrane/nucleus double targeted nanodiagnosis and treatment carrier V₂C-TAT@Ex-RGD was obtained. V₂C-TAT@Ex-RGD nanodiagnosis and treatment carrier has excellent biocompatibility, excellent immune escape ability, and long blood circulation time under the inclusion of exosomes. The modification of RGD endows the tumor cell targeting ability of the nanodiagnostic and therapeutic carrier. V₂C-TAT-QDs can enter the tumor cell nucleus and destroy the genetic material directly to achieve low temperature PTT. After 1064 nm laser (0.96 W cm⁻²) irradiation, V₂C-TAT@Ex-RGD could cause significant cell death at a relatively low temperature (45°C). Therefore, the prepared V₂C-TAT@Ex-RGD nanodiagnosis and treatment carrier can realize the nuclear targeting low temperature PTT in the NIR-II region guided by multimode imaging, which has a great prospect in the clinical application of biomedicine. Yu et al. prepared Ti₃C₂-MXene QDs with high NIR photothermal properties by the method of fluorine-free mechanical force-assisted liquid-phase stripping [89]. The prepared MXene QDs had strong absorption in the NIR region, with extinction coefficient as high as 52.8 L g⁻¹ cm⁻¹ and photothermal conversion efficiency as high as 52.2%. MXene-QDs can obtain PA imaging and PTT effect simultaneously and show great biocompatibility in vitro and in vivo without causing obvious toxicity, indicating its high clinical application potential.

Recently, Szuplewska et al. explored Ti₂C as a new, efficient, and selective PTT reagent [90]. The surface of Ti₂C was modified by polyethylene glycol (PEG), and Ti₂C was obtained by etching from layered Ti₂AlC with concentrated HF. It was found that, in a different concentration range, Ti₂C film coated by PEG has good photothermal conversion efficiency and biocompatibility. Through in vitro study, PEG-modified Ti₂C showed significant NIR-induced ablation ability of cancer cells, with the smallest effect on normal cells, reaching 37.5 μg ml⁻¹. Compared to other MXene-based PTT agents, the application dose of Ti₂C-PEG was even 24 times lower. The work is expected to lead to the development of a new phototherapy drug. Besides, a new type of Mo₂C hybrid was prepared by Zhang et al. The obtained Mo₂C has a typical chemical composition, but it has a spherical structure at about 50 nm, which makes it have MXene-like structure and photophysical properties [91]. According to the previous work, they calculated the photothermal conversion efficiency by recording the heating-cooling process of Mo₂C dispersion. The photothermal conversion efficiency was determined to be 24.95%, which showed that Mo₂C had a remarkable photothermal effect for cancer therapy.

Feng et al. also reported a new 2D molybdenum carbide MXene for photon tumor hyperthermia [92]. It was revealed that Mo₂C MXene has strong NIR absorption characteristics, covering the first and second biological transparent windows (NIR-Ⅰ and NIR-Ⅱ). The surface modification of PVA confirmed that Mo₂C-PVA nanoflakes had excellent absorption band in regions I and II and had ideal photothermal conversion efficiency. This study broadens the application of MXene in nanomedicine through the preparation of new material components (Mo₂C). Meanwhile, it provides an excellent biodegradability and therapeutic performance for the inorganic multifunctional biomedical nanoplatform. Table 1 summarizes the recent progress in MXenes with different compositions, wavelength, biocompatibility, photothermal conversion efficiency, and performance of PTT.

Table 1:

Recent progress in MXenes with different composition, wavelength, biocompatibility, photothermal conversion efficiency (η), and highlights of PTT.

Composition	Wavelength	η	Biocompatibility	Strategy	Highlights	Ref.
Ti₃C₂-SP; PLGA/Ti₃C₂	808 nm	30.6%	No obvious in vitro and in vivo toxicity; no leakage of implanted components into body circulation	PTT	First-time report of Ti₃C₂ MXenes as PTT agent	[79]
Ti₂C-PEG	808 nm	87.1%	Viability of cells up to 70% as high as 500 μg ml⁻¹	PTT	Notable NIR-induced ability to cancerous cells’ ablation	[90]
Mo₂C	1064 nm	24.95%	>75% cell viability at 2 mg ml⁻¹	PTT; PDT	“Four-in-one” theranostic agent; PA imaging and CT	[91]
CTAC@Nb₂C-MSN-PEG	1064	28.6%	No noticeable cytotoxicity at 300 μg ml⁻¹	PTT; chemotherapy	“Therapeutic mesopore” coating; enhanced therapeutic efficacy	[86]
Nb₂C-PVP	808 nm; 1064 nm	36.4% (808 nm); 45.65% (1064 nm)	No noticeable in vitro and in vivo toxicity	PTT	Photothermal ablation of mouse tumor xenografts at both NIR-I and NIR-II windows	[24]
Ti₃C₂	808 nm	52.2%	Almost no cytotoxicity at 100 ppm; no obvious tissue damage in the main organs	PTT	PA imaging; fluorine free	[89]
MnOx/Ti₃C₂-SP	808 nm	22.9%	No obvious cytotoxicity at 160 μg ml⁻¹; no notable toxicology profiles to mice	PTT	MRI and PA imaging; pH responsive	[80]
MnOx/Ta₄C₃-SP	808 nm	34.9%	Negligible cytotoxicity to cells; no noticeable histological abnormalities or lesions in the main organs	PTT	TME responsive; MRI/CT/PA imaging	[87]
Ta₄C₃-IONP-SP	808 nm	32.5%	No significant in vitro toxicity (200 ppm) and no significant damage or acute inflammation in the main organs	PTT	Superparamagnetic MXenes; MRI and CT	[93]
Ta₄C₃-SP	808 nm	44.7%	Negligible effect on the survival of breast 4T1 cancer cells; no adverse, significant chronic pathological toxicity and acute effects to mice	PTT	Nanoscale lateral size and atomic scale thickness; enhanced CT contrast	[85]
GdW₁₀@Ti₃C₂	808 nm	21.9%	No negative effects to cells up to 500 ppm; no obvious cell necrosis in the tumor tissues	PTT	Contrast-enhanced CT and MRI	[94]
Ti₃C₂-DOX	808 nm	58.3%	No significant damage in all the organs	PTT; PDT; chemotherapy	Stimuli-responsive drug release; enhanced biocompatibility and tumor specific accumulation	[95]
V₂C-PEG-TAT@Ex-RGD	1064 nm	45.05%	High cell viability (>90%) to NHDF, MCF-7, and A549 at 200 μg ml⁻¹; no significant side effect or damage for in vivo test	PTT	Low temperature, nucleus targeted; MRI and PA imaging	[88]
Mo₂C-PVA	808 nm; 1064 nm	24.5% (808 nm); 43.3% (1064 nm)	No appreciable cell apoptosis up 400 μg ml⁻¹; no significant bodyweight loss or tissue damage in the major organs	PTT	High biocompatibility; highly efficient photothermal tumor ablation; fast biodegradability	[92]
Nb₂C-MSNs-SNO	1064 nm	39.09%	Negligible toxicity to 4T1 and HUVEC cells; no acute or chronic reactions in vivo; desirable excretion behavior	PTT	Photonic/thermal-responsive nanoreactor	[96]
Ti₃C₂-bioactive glass scaffold	808 nm	–	No obvious in vitro and in vivo toxicity		3D printing; photonic bone tumor killing and bone tissue regeneration	[97]
V₂C	808 nm	48%	Little cytotoxicity for MCF-7 cells at 200 μg ml⁻¹; good biodistribution in key organs and the tumor	PTT	Highly enhanced NIR absorption; good structural integrity	[98]
TiC@Au-PEG	808 nm; 1064 nm	34.3% (808 nm); 39.6% (1064 nm)	No apparent toxic side effect for 1 month	PTT	Core-shell structure; PA/CT dual-modal imaging	[99]
Ti₃C₂/DOX@cellulose	808 nm	–	Excellent biosafety at cellular level; no obvious in vivo toxicity	PTT; chemotherapy	Hydrogel-type nanoplatform; PTT/drug release system	[100]

3.2 PDT of cancer

In the past few decades, PDT has made tremendous progress as a treatment for diseases. Light with a specific wavelength activates a PS that accumulates at the tumor site [101]. The activated PS transfers energy to the surrounding oxygen molecules, leading to oxygen reduction and production of reactive oxygen species (ROS), which oxidizes the biological macromolecules leading to tumor reduction, vascular damage, localized acute inflammation, and immune response [102].

Compared to traditional treatment methods, PDT has laid a solid foundation for its clinical application due to its weak invasiveness, ideal convenience and flexibility, effective efficacy, and high acceptance of patient [103]. In addition, due to the lack of effective PS, appropriate light doses, and effective PS delivery, there are still many limitations to PDT as a first-line clinical treatment.

In drug delivery systems, light is a common external stimulus used to trigger drug release. Compared to complex and uncontrollable internal stimulus, light can regulate drug release for more time and space. Based on the process of PDT oxygen consumption and ROS production, PDT can be combined with nanodrugs and has tumor microenvironment (TME) sensitivity, such as ROS and hypoxia, to achieve a positive feedback and synergistic treatment. Due to the unique electronic structure and photoelectric properties of MXene, theoretical studies have shown that MXene itself can be used as PS for PDT. In 2017, Liu et al. studied the capability of Ti₃C₂ nanosheets to generate ROS under irradiation using 1,3-diphenylisobenzofuran (DPBF) as oxygen detector (Figure 6A and B) and the potential as a new PS for photodynamic therapy [95]. It was found that the absorption of DPBF at 420 nm decreased by 80% after NIR irradiation of Ti₃C₂ nanosheets at 808 nm for 10 min, indicating the formation of ¹O₂ (Figure 6C and D). The author further explained the possible causes. On the one hand, due to the energy transfer of photoexcited electrons from Ti₃C₂ to triplet oxygen, ¹O₂ is produced, which is similar to the photodynamic behavior of BP and graphene QDs. On the other hand, due to the high specific surface area of Ti₃C₂, it has an excellent localized surface plasmon resonance (LSPR) effect and plays a role in ¹O₂ production. The LSPR effect of Ti₃C₂ may also play a role in the generation of ¹O₂. According to previous reports, the ability of gold nanoparticles to produce living oxygen under visible light irradiation depends on their LSPR effect. The energy transfer efficiency of low energy surface state and aggregation state particles is particularly high. The large surface area of Ti₃C₂ is also conducive to the formation of LSPR. PDT triggered by NIR laser is an ideal choice for deep tissue penetration. Therefore, Ti₃C₂ nanosheets are considered as a new PS, which can be used in photodynamic therapy.

Figure 6:

PDT of cancer.

(A) Schematic illustration of the preparation of Ti₃C₂-based nanoplatform and PTT/PDT synergy of tumors [95]. (B) UV-visible spectra of Ti₃C₂ nanoplatelets dispersed in water at various concentrations. Inset: Absorbance plot of Lambert-Beer’s law at 808 nm [95]. (C) Normalized absorbance of DPBF in the presence of Ti₃C₂ or Ti₃C₂-DOX under 808 nm radiation (0.8 W cm⁻²) [95]. (D) Using DCFH-DA as a probe to detect intracellular ROS production under 808 nm laser irradiation (0.8 W cm⁻², 10 min) [95].

However, the mechanism of PDT for Ti₃C₂ nanosheets still needs further study and recognition. In addition, the application of PDT based on MXene is still in its infancy, and there is still a lot of work to be done, such as long-term toxicity assessment and biocompatibility. Zhang et al. studied the feasibility of Mo₂C as a PS and determined the content of ROS in aqueous solution [91]. A DPBF active oxygen indicator having a typical light absorption at 420 nm was employed. It was found that, after encountering ROS generated by Mo₂C, DPBF was oxidized, in which significant light absorption loss at 420 nm was observed. The level of active oxygen was measured indirectly, which is inversely proportional to the characteristic absorption intensity of DPBF. It was proven that Mo₂C was a qualified PS to produce ROS.

At present, the mechanism of the role of PDT in tumor therapy is still in its infancy. As a result, there have been few reports on the application of PDT in tumor therapy, and most of them have been combined with chemotherapy and PTT in the diagnosis and treatment of tumors.

3.3 Combined therapy

To improve the efficiency of cancer therapy, researchers have combined two or more treatments to achieve synergistic treatment. As early as the middle of the 20th century, researchers have proposed a method of synergistic treatment of chemical drugs and radiation therapy, but its shortcomings are very obvious, especially for the human body. After 100 years of exploration, this kind of synergistic treatment has still not significantly reduced the damage to human tissues. Nowadays, in the era of new cancer treatment methods, such as PTT and PDT, how to combine the advantages of various new treatment methods to achieve the goal of synergistic therapy has become a hotspot for researchers.

3.3.1 Chemotherapy and PTT

As a new type of 2D functional nanomaterial system, MXenes have been widely used in many fields. Similar to 2D structures, such as graphene, manganese dioxide, and BP, MXenes with a large specific surface area make it sufficient to provide functionalized material modification.

Han et al. reported the drug loading capacity of 2D Ti₃C₂ as a drug delivery vehicle and its potent synergistic therapeutic effect with PTT (Figure 7A) [104]. As a drug delivery vehicle, Ti₃C₂ had a drug loading rate up to 211.8% (Figure 7B) and exhibited a pH response and a laser-targeted response-release drug characteristic throughout the drug release process. It is worth mentioning that, based on the high-efficiency photothermal conversion efficiency of Ti₃C₂, it acts as a synergistic PTT and chemotherapeutic drug carrier and exhibits a powerful tumor-killing effect in vivo and in vitro. In addition, Ti₃C₂ has also been proven to be an ideal PA imaging contrast agent, which can simultaneously achieve targeted treatment during the entire synergistic treatment process. At the same time, the biocompatibility of Ti₃C₂in vivo and its ability to be easily removed from the body are also evaluated and confirmed in this work. The higher biosafety further indicates that Ti₃C₂ can be obtained during clinical transformation. MXenes as both a diagnostic probe and a chemotherapeutic drug carrier provide new ideas for the integration of cancer diagnosis and treatment and at the same time extend the biological application in the field of nanomedicine, especially after functional structure improvement. It has huge potential in chemotherapy treatment and synergistic photothermal treatment of tumors.

Figure 7:

Chemotherapy and PTT of cancer.

(A) Schematic of a Ti₃C₂-based drug delivery system for in vivo synergistic photothermal and chemotherapy for cancer, including intravascular transport, accumulation into tumors, controlled drug release, and NIR-triggered photothermal ablation of tumor tissue [104]. (B) Schematic for surface modification of Ti₃C₂ nanosheets by SP, further surface drug loading, and stimulant-responsive drugs released by internal or external irradiation [104]. (C) Schematic illustration of the detailed mechanism of sequential catalytic processes based on IONP as a Fenton reaction nanocatalyst and an MIG nanoplatform for natural GOD [105]. (D and E) Fading curves of experimental group, control group 1, and control group 2 using methylene blue as chromogenic agent within (D) 1 h and (E) 7 days [105]. (F) Schematic illustration of pH/photothermal-triggered drug release from DOX-loaded Ti₃C₂@mMSNs-RGD [105]. (G) Cumulative DOX release from DOX-loaded Ti₃C₂@mMSNs-RGD in phosphate-buffered saline (pH 7.4) as triggered by 808 nm NIR lasers at elevated power density [106].

Furthermore, Han et al. synthesized the 2D-Nb₂C-MXene with “therapeutic mesopore” layer. It is beneficial to the surface engineering of 2D-MXene, and it also improves the effect of PTT by adjuvant chemotherapy [86]. These nanocomposites have high therapeutic biosafety and easy excretion. This work provides an effective strategy for the surface engineering of 2D-MXene to satisfy the needs of multipurpose applications. At the same time, it greatly expands the biomedical application of 2D-Nb₂C-MXene in tumor intensive therapy, such as PTT and chemotherapy.

Endogenous reaction and TME-specific nanocatalysis have become one of the most representative methods of low toxicity and cancer specific treatment. The ultimate goal of chemokinetic therapy based on Fenton catalytic reaction is to kill the toxic substances of cancer cells. Liang et al. reported that Fenton-based nanocatalytic reaction was initiated on Ti₃C₂ nanosheets [105]. As a photothermal conversion nanoagent, the efficiency of nanocatalytic killing cancer cells was further improved. Glucose oxidase (GOD) and superparamagnetic IONPs (Fe₃O₄-IONPs) were loaded on the surface of ultrathin Ti₃C₂ nanosheets, which was a new 2D nanoplatform of Maxceramics with high biocompatibility. The loaded GOD can catalyze the tumor to produce plentiful hydrogen peroxide molecules over glucose (Figure 7C). They are further catalyzed by Fe₃O₄ nanoparticles to produce enough hydroxyl radicals to kill cancer cells. The 2D-Ti₃C₂-MXene matrix effectively converts NIR light energy into heat energy. The NIR-triggered light heat conversion further enhances and accelerates the catalytic reaction and synergistically improves the catalytic efficiency of this chain reaction to obtain a high synergistic cancer treatment effect, which has been systematically verified in cells and in vivo (Figure 7D–F).

Hepatocellular carcinoma is one of the most common and deadly gastrointestinal malignancies. Because of its insensitivity to traditional systemic chemotherapy, new effective treatment strategies are urgently needed. Li et al. reported a new 2D-MXene composite nanoplatform for high-efficiency synergistic chemotherapy and photothermal hyperthermia for liver cancer (Figure 7G) [106]. The surface nanopore engineering method is used to realize the multifunctionality of Ti₃C₂-based MXene, and a thin layer of mesoporous silica is uniformly coated on the surface of 2D-MXenes. An in vitro and in vivo evaluation of the system indicated that Ti₃C₂@mMSNs-RGD is highly targeted to tumors, whereas synergistic chemotherapy (caused by mesopores) and photothermotherapy (caused by Ti₃C₂-MXene) are fully capable of eradicating tumors and nonobvious recurrence. At the same time, in vivo biocompatibility and excretion analysis showed that these composite MXene-based nanosheets are highly compatible and easy to excrete. This work has greatly expanded the biomedical applications of MXene-based nanoplatform for anti-liver cancer through fine surface nanopore engineering.

A composite hydrogel with cellulose and Ti₃C₂ MXene as raw materials was synthesized by Xing et al. [100]. Using its excellent photothermal properties and controlled release of doxorubicin (DOX), cellulose/MXene hydrogel was used as a multifunctional nanoplatform for intratumoral injection therapy. The results showed that PTT combined with the long-term adjuvant chemotherapy of the nanoplatform had high efficiency in the immediate killing of tumor and the inhibition of tumor recurrence, which showed the application potential of the nanoplatform in tumor treatment. Their work not only opens the door for manufacturing smart nanocomposites based on MXenes but also paves the way for the application of other inorganic 2D composites in the biomedical field.

3.3.2 PTT and PDT

The photoactive substance is the most important part of phototherapy. Generally, photoactive substances only play a single role, either producing living oxygen (PS) or generating heat (photothermal agent). Therefore, in most cases, the use of a single photoactive substance can only achieve a single effect of phototherapy. The combination of PS and photothermal agents to form a multicomponent system can realize the synergistic treatment of PTT and PDT. However, there are influencing factors, such as mutual interference between PS and photothermal agents, absorption mismatch, premature disintegration risk, and uneven distribution of photoactive substances. One of the effective ways to solve this problem is to find multifunctional nanomaterials with both photothermal effect and active oxygen generation characteristics under NIR radiation. In terms of those, MXenes have become a new candidate for research due to its unique properties.

Szuplewska et al. synthesized Ti₂C modified by PEG [90]. The activity of Ti₂C decreased after treatment, accompanied by oxidative stress. It is important that the “photothermal” conversion performance causes efficient ablation of cancer cells and shows relatively good selectivity to malignant cells. The observed phenomenon may be caused by the generation of active oxygen in malignant cells induced by MXenes, which certifies the synergistic PTT/PDT effect. Zhang et al. prepared Mo₂C as tumor phototherapy and image contrast agent. Mo₂C has wide and strong absorption in visible and NIR bands [91]. Meanwhile, it could produce high heat and ROS under laser excitation, which induced obvious apoptosis. The results showed that PDT/PTT combined with PDT was superior to PDT or PTT alone in killing tumor cells.

As mentioned above, Liu et al. reported a kind of ultrathin Ti₃C₂ nanosheets [95]. They added alumina anion group to Ti₃C₂ to enhance surface plasmon resonance and finally obtained stable ultrathin Ti₃C₂ containing Al(OH)₄^-. The key problem is that the aluminum oxide anion group is removed in the etching process, which directly affects the photothermal effect of the nanosheet. To solve this problem, they developed a surface modification process to compensate for the loss of Al by providing Al³⁺. The prepared ultrathin Ti₃C₂ nanosheets have excellent extinction coefficient, excellent photothermal conversion efficiency (about 58.3%), and effective singlet oxygen generation (¹O₂) under 808 nm laser irradiation. Based on these Ti₃C₂ nanomaterials, the surface of Ti₃C₂ was modified by DOX and hyaluronic acid (HA), and the multifunctional nanoplatform of Ti₃C₂-DOX was established. In vitro and in vivo experiments showed that Ti₃C₂-DOX had enhanced biocompatibility, tumor-specific aggregation, and stimulated drug release behavior and achieved effective tumor cell-killing and tumor tissue destruction through PTT/photodynamic therapy/chemical synergistic therapy.

3.3.3 Other combined therapy strategies

Tang et al. successfully prepared 2D core-shell Ti₃C₂@Au nanocomposites using the simple seed growth method [99]. Due to the growth of Au on the surface of Ti₃C₂, the stability of MXene was greatly improved by mercaptan chemistry, and the absorbance of nanocomposites in the window of NIR-I and NIR-II was significantly improved. The synthesized Ti₃C₂@Au nanocomposite has been successfully used as a good contrast agent for PA/CT dual-mode imaging via strong absorption and high X-ray attenuation ability of NIR-II window. It is important that the mild photothermal effect of nanocomposites in the NIR-II window also improves tumor oxygenation, which can significantly enhance radiotherapy (RT; Figure 8A). Moreover, 1 month after the injection of Ti₃C₂@Au nanocomposites, no significant toxic side effects were found (Figure 8B). In a word, the 2D core-shell Ti₃C₂@Au nanocomposites can be used to realize the combined treatment of phototherapy and RT.

Figure 8:

Other combined therapy strategies of cancer.

(A) Tumor volume growth curves of mice after various treatments (n=5). NIR irradiation was conducted by 1064 nm laser at 0.75 W cm⁻² for 10 min, whereas the dose for RT was 6 Gy [99]. (B) Photographs of tumors harvested from mice 14 days after the treatments [99]. (C) Detailed mechanism diagram of 2D-Nb₂C-MXene as a radiation protective agent [107]. (D) In vivo evaluation of radiation protection by Nb₂C-PVP on IR-induced multiple organ degeneration [107].

Ionizing radiation (IR) is widely used in industry and RT. However, IR caused by nuclear accident or radiation accident often has serious health impact on the irradiated people. The application of IR in RT will inevitably cause adverse damage to normal tissues. Ren et al. developed the ultrathin 2D-Nb₂C-MXene as radiation protection agent (Figure 8C) and discussed its application in eliminating free radicals and anti-IR [107]. Nb₂C-PVP was prepared by surface modification to improve its biocompatibility and physiological stability and reduce its toxicity in vivo (Figure 8D). Moreover, Nb₂C-PVP has excellent biocompatibility and biosafety in vivo and has no obvious cytotoxicity in vitro.

4 Outlook

Since its first report in 2011, MXenes have become a hotspot and frontier in the field of 2D materials and received much attention. In terms of material preparation, the reported preparation method of MXenes is mainly developed around the idea of etching the MAX phase precursor. Although MXenes can be prepared on a large scale by etching, heteroatom functional groups or structural defects are inevitably introduced, which affects the electrochemical properties of MXenes. According to the preparation route of graphene and other 2D materials, the development of a bottom-up method such as CVD for atomic growth is the future direction for the preparation of high-purity MXenes. In addition, there are more than 70 different compositions of MXene phase, but only 20 kinds of MXenes have been successfully synthesized, and most of them have not yet been synthesized. With the change of metal element composition, MXenes will show different properties. The exploration of additional metals or bimetallic transition metals or multiple transition metal-based MXene materials is expected to open another window for the research of 2D materials. Combined with excellent photoelectric properties, high specific surface area, and unique 2D structure, MXenes have excellent application prospect in the biomedical field. Meanwhile, experimental work still needs to be carried out to further understand the basic problems of MXene materials, as a lot of research work is focused on theoretical calculation and prediction of MXenes.

MXenes have attractive and tunable properties, but several challenges are faced to be overcome for clinical applications. (i) To gain insight into the health hazards that MXenes may pose, biocompatibility using cells and animal models is vital to systematic investigation. Generally, three main methods are expected to explore the long-term biocompatibility of MXene, including biodegradability, biodistribution, and toxicity. Recent reports discovered that the surface modification, concentration, and structure obtained via different formation processes effectively influence the biocompatibility as well as photothermal conversion efficiency and tumor ablation therapy [77], [78]. (ii) The interaction between MXenes and biological organisms, especially the interaction between the immunological effect of MXenes and the immune system in vivo, needs to be further clarified to optimize the shape, size, surface physical, and chemical properties of MXene carriers. (iii) The preparation of MXene as drug carriers needs strict control conditions. Therefore, one of the key points is how to control the MXene with high drug loads in cancer therapy applications. (iv) MXenes have been experimentally found sensitive to neurotransmitters [108], [109], which can serve as a field-effect transistor and conductive microelectrode. It provides intriguing opportunity for probing neural activity and cancer therapy in brain in the future. (v) Various MXene-based organic/inorganic hybrid composites might be interesting to researchers working on this field. To evaluate the shape of MXenes, such as nanosheets, QDs, fiber, and films, influence on cancer therapy performance also needs to be explored.

In summary, we have witnessed the rapid development of MXenes for cancer therapy in recent years. More collaboration among interdisciplinary scientists, such as chemists, photophysicists, biologists, and materials researchers, will promote MXene nanomaterial for successful applications in cancer diagnosis and treatment. We hope this review can inspire insightful perspective and innovations for future biomedical sciences.

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 31800829

Award Identifier / Grant number: 21904116

Funding statement: This work was supported by the National Natural Science Foundation of China (grants 31800829 and 21904116, Funder Id: http://dx.doi.org/10.13039/501100001809), the Natural Science Foundation of Shandong Province (grant ZR2018BB054, Funder Id: http://dx.doi.org/10.13039/501100007129), and the Ph.D. Research Foundation of Linyi University (grant LYDX2018BS005).

Compliance with ethical standards: The author(s) declare that they have no competing interests.

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Received: 2019-12-26

Revised: 2020-02-23

Accepted: 2020-03-12

Published Online: 2020-04-13

This work is licensed under the Creative Commons Attribution 4.0 Public License.

Artikel in diesem Heft

https://doi.org/10.1515/nanoph-2019-0550

Schlagwörter für diesen Artikel

2D materials; photothermal therapy; photodynamic therapy; combined therapy

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