NML review: next-generation MXene-based smart electrochemical aptasensors for point-of-care cancer diagnosis

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Cancer is a major disease that threatens human life and health. Once it occurs, the survival rate of patients is not optimistic. Traditional diagnostic modalities, including PET, CT, X-ray, and tissue biopsy, are still the main modalities for clinical cancer diagnosis. However, none of them can provide early diagnosis of cancer. Therefore, traditional diagnostic methods are of limited help in improving patient survival. Early diagnosis is the diagnosis before the onset of the disease. Through new technologies and strategies, the disease can be detected early, the mortality rate can be reduced, and the patients life can be saved. Early diagnosis is the detection of important markers associated with the development and progression of cancer, and the quantification of these biomarkers can reflect the stage of cancer progression. Previously, PCR and ELISA methods were used to detect these biomarkers with low accuracy and sensitivity. Recently, the use of biosensors for early diagnosis has attracted great interest among researchers. These biosensors are optical, piezoelectric and electrochemical. Among them, electrochemical-based biosensors provide a highly sensitive, rapid, and cost-effective platform for early detection of cancer biomarkers. picture
Next‐Generation Intelligent MXene‐Based Electrochemical Aptasensors for Point‐of‐Care Cancer Diagnostics

Arpana Parihar, Ayushi Singhal, Neeraj Kumar, Raju Khan*, Mohd. Akram Khan, Avanish K. Srivastava

Nano-Micro Letters (2022)14: 100

https://doi.org/10.1007/s40820-022-00845-1



Highlights of this article

1. Introduced MXene-based electrochemical aptasensors for the detection of cancer biomarkers.

2. The design and synthesis strategies of biomarker-specific aptamers are introduced.

3. The electrical conductivity, chemical stability, mechanical properties, hydrophilicity and hydrophobicity of MXenes are discussed.

4. The future sensing applications and their challenges are highlighted.

brief introduction

Early diagnosis of cancer promises early detection of the disease, reducing mortality and saving the lives of patients. Recently, sensors based on 2D materials have attracted the attention of researchers for their excellent potential in early cancer diagnosis. Among them, MXene-based 2D materials exhibit the advantages of high surface area, active surface functional groups, and excellent electrical conductivity. The electrochemical aptamer sensor based on MXene synthesis can reach the lower limit of detection of cancer markers, and it is convenient to synthesize, easy to repeat, and has good stability, which has broad application prospects. Raju Khans group from CSIR-AMPRI, India, reviewed the design and synthesis of MXene-based electrochemical aptasensors, including various synthesis processes and their properties (optical, thermal, magnetic, electrical, and mechanical properties), and listed some of the MXene electrochemical aptasensor for cancer marker detection. Finally, the authors discuss future sensing applications and their challenges.

Graphical guide

Design method of I aptamers
Cancer-related biomarkers are important clinical indicators to measure the degree of cancer progression. Different cancers have different biomarkers due to tumor heterogeneity. Biomarkers for different tumor types of the same type of cancer also vary. Traditional methods of detecting biomarkers include polymerase chain reaction (PCR), immunohistochemistry, flow cytometry, etc. These methods are less sensitive and require precise instruments to operate, making them inconvenient to use. The use of biosensors for early diagnosis can achieve the purpose of rapid detection and high sensitivity. There are differences in the stability of traditional antibodies, enzymes and nucleic acids as biological recognition elements (BRE) in different environments. As a new BRE, aptamer is a good choice. Aptamers are single-stranded DNA or RNA sequences that specifically bind to target molecules. Aptamers have excellent chemical and thermal stability and are easily synthesized in large quantities. Biomarkers were selected by SELEX system to select aptamer sequences with high affinity (Fig. 1a). The comparison of aptamers and antibodies as BREs is shown in Fig. 1b.

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Figure 1. (a) Synthesis and electrochemical detection of aptamers; (b) Comparison of aptamers and antibodies as biological recognition elements.

Synthesis and Properties of II MXenes

The two-dimensional material MXene belongs to two-dimensional transition metal carbides and carbonitrides. MXenes are produced by a selective etching process in an appropriate solvent or solution. Etching is usually carried out in an acidic solution, resulting in the termination of surface functional groups, making them available for further use. MXenes have excellent hydrophilic, electrochemical, mechanical and optical properties. MXenes exhibit high surface area, surface functionality, hydrophilicity, high stability, high electrical conductivity, and innocuous properties, making them promising materials for analytical chemistry applications.

2.1 Structure and synthesis of MXene

The general formula of MXene is Mₙ₊₁Xₙ, and the general formula of MAX phase is Mₙ₊₁AXₙ, where n = 1, 2, or 3. M is a transition metal (Ti, V, Nb, Mo, Cr, Ta, Hf), A is a Group 13 or 14 element (Si, Ge, Al, Sn, etc.), and X is mainly C and/or N. In the MAX phase, Mₙ₊₁Xₙ is the stable layer, while the A layer consists of weaker bonds. Etching the A layer from the MAX phase (Ti₃AlC₂) yields Ti₃C₂ (MXene). The M and A layers are interposed between phases with a hexagonal structure, and the X atoms occupy the octahedral sites created by the M element (Fig. 2a). The removal of A element from the MAX phase resulted in the creation of multilayer MXenes (Fig. 2b). Recent studies have demonstrated the OD, 1D, 2D and 3D dimensions of MXenes (Fig. 2c). 2D MXenes exhibit a large specific surface area, thus ensuring high sensitivity for the detection of target analytes. The MAX phase has high hardness, low density, and high corrosion resistance, along with high electrical and thermal conductivity and enhanced processability. The desirable properties of MXene are shown in Figure 2d.

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Figure 2. (a) Structure of MXene; (b) Synthesis of MXene; (c) Dimension-based classification of MXene; (d) Properties of MXene.

High-temperature synthesis of MAX phases from binary elements is the most commonly used method due to low cost, simplicity, and scalability. In this method, TiC, Ti, and Al powders are mixed in a ball mill (Fig. 3a and b), annealed at 1400 °C for 2 h in a tube furnace under inert gas (argon) conditions, with a heating and cooling rate of 3 °C min⁻1 (Fig. 3c). The powder was washed with hydrochloric acid (HCl) to remove impurities (metals and intermetallic compounds) before screening (Fig. 3d).

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Figure 3. Steps associated with MAX stage production (a) ball milling; (b) oxidative passivation; (c) high temperature synthesis; (d) acid wash to remove interferences.

According to literature, several methods for MXene synthesis can be classified into top-down, wet chemical etching, and bottom-up methods (Fig. 4a–c). Proper handling of the PPE kit, gloves, fume hood, and proper use of acid should be performed when synthesizing MXenes (Figure 4d).

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Figure 4. MXene synthesis methods (a) top-down method; (b) wet chemical etching method; (c) bottom-up method, (d) precautions for MXene synthesis.

An ultrafast polyaniline@MXene cathode was created by casting a uniform polyaniline layer onto a 3D porous Ti₃C₂Tiₓ MXene. Proposed by Li et al., PS spheres and Ti₃C₂Tiₓ MXene films with the same negative surface charge were uniformly dispersed in water, which could then be vacuum-assisted filtration into flexible PS@Ti₃C₂Tiₓ films (6 m), and the Ti₃C₂Tiₓ MXene films were wrapped on the surface of PS spheres (500 μm). nm), the film exhibits a conductivity of 600 S cm⁻1 (higher than 12 S cm⁻1 for a 3D graphene film with a similar structure) (Fig. 5a). Lipatov et al. describe a new synthesis method for high-quality monolayer Ti₃C₂Tiₓ flakes, using which two kinds of Ti₃C₂Tiₓ flakes were fabricated (Fig. 5b). The first method is to soak the Ti₃AlC₂ powder in LiF-HCl solution, the molar ratio of LiF to MAX is 5:1, and there is ultrasound. The second method is to increase the molar ratio of LiF to MAX to 7.5:1, which provides an excess of Li⁺ ions for intercalation. Alhabeb et al. utilized multiple etchants and layered processes to produce titanium carbide (Ti₃C₂Tiₓ), the most studied MXene. XRD showed that for Ti₃C₂Tiₓ, the (002) peak of Ti₃AlC₂ shifted from 9.5° to 9.0°, whereas 5, 10 and 30F–Ti₃C₂Tiₓ after etching had no residual Ti₃AlC₂ peak (Fig. 5c). The characterizations of the enumerated MXenes and MXene QDs are shown in Figure 5d–j.


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Figure 5. (a) Schematic diagram of the preparation of 3D macroporous PANI@M-Ti₃C₂Tiₓ framework using PS spheres as template, the inset is the SEM of the 3D PANI@M-Ti₃C₂Tiₓ film; (b) Ti₃C₂Tiₓ synthesized by two different routes, with or without Ultrasound, inset shows AFM of the as-synthesized Ti₃C₂Tiₓ flakes; (c) XRD of Ti₃AlC₂ powder and Ti₃C₂Tiₓ MXene powder; (d) SEM of MXenes; (e) HR-TEM of Ti₃C₂Tiₓ@FePcQDs hybrid structures; (f) various hybrid structures FTIR spectra of samples; (g) XPS spectra of various samples; (h) Raman spectra of bulk MXene and MXene QDs; (i) UV-Vis absorption spectra of MXene QDs, the inset shows the fitted bandgap values; (j) Excitation and emission spectra of MXene QDs.

2.2 Characteristics of MXenes

High Youngs modulus, tunable band gap, thermal and electrical conductivity are some of the unique properties of MXenes. The hydrophilic surface and high electrical and thermal conductivity of MXene differentiate it from most 2D materials. Ultimately, the specific composition of M and X elements for different transition metals, as well as the different functionalization of surfaces through chemical and thermal processes, lead to structural and morphological changes that can be used to tune their properties and application performance.

2.2.1 Mechanical properties of MXene