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MOFs-Based Biosensors for the Detection of Carcinoembryonic Antigen: A Concise Review

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01 July 2023

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04 July 2023

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Abstract
Cancer has been considered one of the most serious diseases in recent decades. Early diagnosis of cancer is a crucial step for an expedited treatment. Ideally, detection of cancer biomarkers, which are usually elevated because of cancer, is the most straightforward approach to detect cancer. Consequently, the accurate, effective, and prompt detection of these compounds is an insistent need for the medical diagnosis of the disease in order to start an early therapy plan for the patients. Among these biomarkers, Carcinoembryonic antigen (CEA) is considered one of the most important tumor markers for colorectal cancer, but it has been also used as a biomarker for other types of cancers, including breast, gastric, ovarian, pancreatic, and lung cancers. Typically, conventional CEA testing depends on immunoassay approaches, which are known to be complex, highly expensive, and time-consuming. In this context, many biosensors were designed for the aim of detecting cancer biomarkers. The main prerequisites of these biosensors are high sensitivity, fast response, and low cost. Many nanostructures have been involved in the design of biosensors. Metal organic frameworks (MOFs) were found to be one of the most potential and promising materials for biosensing. MOFs are highly porous and crystalline materials that consist of metal clusters surrounded by organic linkers, where the assembly of these components gives rise to the exquisite geometric 3D structures of MOFs. Moreover, the unique structure and geometry of MOFs allow for a better tailoring of their design to provide properties that are needed by different categories of biosensors. In the past few years, researchers have extensively considered MOFs for their fabrication of biosensors that can be used for the early detection of cancer biomarkers. In this regard, MOFs were used solely or were further decorated with other nanostructures to introduce more accurate signals and lower limits of detection. This review briefly classifies and describes MOFs-based biosensors trials that have been published recently for the aim of detecting CEA.
Keywords: 
Subject: Chemistry and Materials Science  -   Materials Science and Technology

Background

Globally, cancer has been recorded to be one of the primary etiological causes of death. Cancer is described as an abnormal and uncontrolled cell growth resulted from an accumulation of specific genetic and epigenetic defects. The underlying origins of cancer are either environmental or hereditary. [1] Classically, physicians and scientists rely on methods such as centrifugation, chromatography and activated cell sorting techniques to discover cancer. Moreover, cross-sectional imaging (CT scan) and biopsy are other approaches to detect cancer. However, these methods are invasive and expensive for most of the patients. Accordingly, many efforts were carried out to explore innovative approaches for the diagnosis of cancer. Discovering cancer biomarkers has successfully contributed to the achievement of this goal. Biomarkers can be defined as specific macromolecules that are usually found in the body fluids or tissues as an indication for the development of cancer. It has been found that early detection of the cancer biomarkers has a great impact on controlling the disease in the term of treatment or even surgical interference in many incidents. [2] Biomarkers can be whole cells, biomolecules or genetic materials. There are up to160 biomarkers that have been proven to detect different types of cancers. [3] One of the most common biomarkers is carcinoembryonic antigen (CEA, also known as CEACAM5 or CD66e). CEA overexpression is related to colon, lung, ovarian and breast cancer. [4] This review outlines the various methods of the detection of CEA, with a special emphasize on the use of MOF nanomaterials in this regard.

1. Structure and Function of CEA

CEA is a glycosylated protein of a high molecular weight (180-200 KDa), as shown in Figure 1a. It is involved in the cell adhesion and recognition mechanisms (PDB entry 1E07). [5] Gold and freedman were the pioneers for describing CEA sixty years ago. They realized that CEA was related to human colon cancer tissue extracts and later to digestive system cancer. [4] CEA has immunoglobulin-like structural features and many glycosylation modification sites. [6] Particularly, CEA belongs to the immunoglobulin superfamily of cell adhesion molecules (IgCAMs). IgCAMs are highly glycosylated surface proteins whose function is fundamental in cell-cell adhesion. [2]
The function of CEA in a normal individual is not well understood. Naturally, CEA is secreted in the fetal intestinal tissue, and its serum level can also be elevated in non-malignant diseases such as inflammatory bowel diseases. In the tissues of adults, the CEA-related cell surface molecules are expressed primarily in different epithelia, vessel endothelia, and hematopoietic cells. [7] Conversely, in healthy adults CEA serum level is usually found in low concentrations. As a result, its abnormal elevation is associated to gastric, breast, ovarian, pancreatic, and most importantly in colorectal cancer. [8,9]
The family of the CEA-related cell adhesion molecules (CEACAM), which are expressed from the CEA gene family, consists of a single N-terminal domain and a maximum of six disulfide-linked internal domains. The group contains 12 proteins (CEACAM1, 3–8, 16, 18–21) as shown in Figure 1b. [10] The extracellular domains of the CEACAM group function are homophilic and heterophilic cellular adhesion molecules or receptors. Members of the CEACAM group have variable functions as they can act as dimers or oligomers with other membrane molecules. [6] Anchorage to the membrane is a characteristic property of CEACAM proteins. CEACAM5 and CEACAM6 are attached to the cell membrane through a glycosylphosphatidylinositol (GPI) linkage. A small sequence of 26 hydrophobic amino acids is involved in the CEA membrane attachment. However, phospholipase can induce the release of CEA from the cell membrane to the extracellular lumen. [10]
As a result of the ability of CEA in the cell adhesion on the surface of epithelial cells, it was found that these properties play a crucial role in the growth of tumor through the development of CEA–CEA bridges between tumor cells or tumor–normal cells, as shown in Figure 2. In tis regard, the homotypic binding between two CEA molecules takes place through the attachment between the N and A3 domains. [11] Interestingly, this feature has been found to help the immune system to recognize the presence of cancerous cells. Examining the adhesion binding domains of CEA for therapeutic intervention has led to some pertinent findings. Blocking the binding ability of CEA on purified human cells via producing monoclonal antibodies (anti-CEA-mAb), which will bind specifically to the CEA, has led to the lysis of the tumor cells. Therefore, the anti-CEA mAb, named CC4, has been recently recognized as a promising treatment for cancer. [12]

Detection of CEA biomarker: conventional methods vs biosensors

ELISA (enzyme-linked immunosorbent assays) was the utmost used method for CEA detection. [8] Numerous approaches for the detection of CEA biomarker have been explored. These include radioimmunoassay (RIA) and immunoradiometric assay (IRMA), reverse transcriptase polymerase chain reaction (RT-PCR) [1], capillary electrophoresis and chromatographic analysis. [13] In spite of their reliable detection, most established assays are still relatively considered as complex, time consuming and expensive. In addition, most of these techniques require the availability of professionally skilled personnel to carry out their protocols. Hence, replacing these ways with other assays that are highly sensitive, highly selective, rapid, and cost-effective for the detection of CEA is highly required as an approach for the detection of human cancer. With the development of biosensor technology, biosensors have attracted great attention as a tool for the analysis and diagnosis of cancer biomarkers in a simple, selective and low-cost manner.
A typical biosensor usually consists of three main parts: firstly, a biosensing (or biorecognition) component for the selective recognition, secondly a transducer, and a signal processing unit, while the third part is the detector. The transducer can transfer the signals produced from the biorecognition part in different methods including optical, piezoelectric, electrochemical, magnetic, and thermal. [14] Several studies have reported the fabrications of CEA biosensors with good selectivity and sensitivity. [8]
The recognition parts of the CEA biosensors were frequently made-up of a broad variety of nanomaterials, such as gold nanoparticles [15] , graphene quantum dots [16] and molecular imprinted polymers (MIPs) [17]. The common objective of these sensors has been the development of highly sensitive and highly selective approaches that result in the achievement of satisfying results, as compared to the conventional methods. [18]

2. Why using MOFs for biosensors

In the same context, MOFs have recently been recognized as potential materials for enhancing the sensitivity and selectivity of biosensors for the detection of cancer biomarkers. A typical MOF structure essentially consists of metal nodes and organic linkers known as struts (Figure 3). The arrangement of metal nodes and struts in an orderly fashion in their geometrical configuration results in uniform porous crystalline structures of MOFs with tunable outstanding porosity. [19] The hierarchical structure of MOFs provides unique features, such as high surface area that facilitates the interaction with more analytes thru high selectivity, and a tunable porosity that enables the capture of biomarkers with diverse structure and reactivity. Moreover, MOF can be fabricated in various dynamic geometrical shapes (0D, 1D, 2D, 3D), hence provide more options for capturing more analytes within the framework. [20] Additionally, the facile synthesis of multifunctional MOFs has extended its applications in the fields of energy storage, waste-water treatment, photovoltaics and biosensing. [18,21]
The first attempts to design biosensors were carried out in 2008. [22] A significant exponential increase in the interest of biosensors in general and MOF-based biosensors in particular was observed since 2008, as shown in Figure 4. This was also accompanied with a consistent increase in the development of MOF nanostructures with various functionalities, morphologies and capabilities. Moreover, hybrid nanostructure involving MOFs and other nanomaterials, such as gold nanoparticle (Au NPs), Graphene oxide, carbon nanotube (CNT) have shown promising results as composite biosensors. This is attributed to the enhanced optical or electrochemical signals generated during the sensing process. [23,24]
Interestingly, the unique surface functionality and the highly interconnected porosity of MOF nanostructures can also serve as sites for the immobilization of bioactive molecules that can help in the biosensing process, such as oligonucleotides, antibodies, and enzymes. [25] Figure 5 shows typical MOF nanostructures that have been explored for the development of biosensors and as drug delivery vehicles for cancer treatment. Immobilization of these bioactive molecules usually takes place through any of the approaches shown in Figure 6. Choice of the immobilization approach depends to a large extent on the size of the molecules as well as the MOF’s surface functionalities and the average pore size. [26,27] Moreover, other materials such as polymer, carbon materials, metal nanoparticles could be considered in the design of the biosensor in order to contribute to the sensing mechanism. Recently, abundant studies have been described the biosensing applications of MOFs either as a stand-alone candidate or combined with other structures, which have shown promising potential applications. [24]
MOF nanostructures have been prepared by different methods, including hydrothermal [28], solvothermal [29], ultrasonication [30], electro-chemical [31], mechanochemical [32], and microwave assisted heating [33]. Facile methods of synthesizing MOFs provide the opportunity to optimize the composition and crystalline arrangement of metal nodes and struts in order to obtain desired porosity, surface area and reactivity for an application of interest. [19] In the following sections, examples of the most recent advances in the design and fabrication of MOF-based biosensors for the detection of CEA will be illustrated. Table 1 lists the most studied MOF nanostructures that have been developed for the detection of CEA biomarker as well as the method of structure modification, the type of sensing and the limits of detection.

3. Progress in MOF-based biosensors for the detection of CEA

Recently, many research papers described the design of MOF- based biosensors for CEA detection via different routes, namely electrochemical, optical, photoelectrochemical, etc. The application of MOF-based biosensors for the detection of CEA using these approaches will be explained in the following sections.
(a).
Electrochemical approach
The electrochemical detection mainly depends on the transduction of the chemical reactions to electrical signal (e.g., current, voltage, impedance, etc.). By incorporating this kind of detection to biosensors, the biochemical reactions such as enzyme substrate reaction and antigen-antibody can be translated to electrical signals. Many electrochemical sensors have proven their efficiency and have been commercialized. In these biosensors, the working electrode is a key component, which is employed as a solid support for the of immobilization of biomolecules (enzyme, antibody and nucleic acid) and electron movement. [34,35] The electrochemical cell used in these sensors is composed of three electrodes submerged in an electrolyte of the required analytes. One of the electrodes is a reference electrode (such as Ag/AgCl or Hg/Hg2Cl2), which is used to maintain a constant potential when compared to a working electrode. The other electrode is known as the working electrode, where the reaction of interest takes place. The third electrode, known as the auxiliary electrode, is composed of an inert conducting substance (e.g., platinum or graphite). A considerable interest in the development MOF-based biosensors has been shown, which is attributed to the high thermal and chemical stabilities of MOFs. This results in an excellent electrochemical biosensor performance, where the MOF nanostructure is immobilized on the working electrode. [36,37] Many electrochemical analysis techniques have been used in these biosensors, such as Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV), Square Wave Voltammetry (SWV) and Electrochemical Impedimetric Signal (EIS). Examples of MOF-based biosensors are described in the following sections.
Zhang et al. presented a CEA electrochemical biosensor that was based on the modification of a glassy carbon electrode (GCE) using polyaniline nanofibers. Polyaniline nanofibers provided high surface area and good electrical conductivity. The modified GCE was investigated for the simultaneous determination of the cancer biomarkers CEA and alpha-fetoprotein (AFP) by using particles of MOFs prepared from Pb(II) or Cd(II). The MOFs nanoparticles were labeled by secondary antibodies for both biomarkers to form a sandwich assay. The respective detection limits were 0.03 pg/mL and 0.1 pg/mL, respectively. [38]
A similar sandwich-type electrochemical biosensor was proposed by Li’s group. [39] In their work, Ce-MOF was synthetized and loaded with silver nanoparticles (Ag NPs) and horseradish peroxidase to catalyze H2O2, hence amplify the current signal. This MOF-based assembly was then coated with hyaluronic acid. The designed immune-sensor further used Au NPs to enhance the ability of attaching the antibody based on the high electrical conductivity of the Au NPs. The immune-sensor assembly was tested for the detection of CEA, and showed a limit of detection (LOD) of 0.2 pg/ml. Moreover, the proposed immune-sensor was found to possess high reproducibility, selectivity, and stability. [39]
Liu and his coworkers successfully used a Ag-based MOF as a decoration of an electrode and showed that it provided stable electrochemical signals in a voltametric technique alone. Using the Ag-MOF decorated electrode, it was able to detect CEA with a low LOD of 8.0 fg/ml. It should be mentioned that the voltametric immunoassay has been proven to be stable, inexpensive, sensitive, and selective. [40] Zhou et al in 2017 fabricated a Cu-MOF to be used as an electrochemical biosensor, where EIS measurements were used for the detection. [41] The prepared Cu-MOF nanostructures were further functionalized with Pt nanoparticles, aptamer, hemin and glucose oxidase (Pt@CuMOFs-hGq-GOx). This biosensor assembly was found to mimic the peroxidase activity. Based on the cascade catalysis amplification driven by glucose oxidase, CEA was detected at a LOD of 0.023 pg/ml. as described in Figure 7. [41]
UiO-66, a well-known MOF, was also used in combination with Ag nanoclusters (Ag NCs) and CEA aptamer (AgNCs@Apt@UiO-66) for the detection of CEA. [42] The synthesized AgNCs@Apt@UiO-66 sensor was found to utilize both electrochemical and SPR techniques, as showed in Figure 8. Results showed that the proposed electrochemical AgNC@Apt@UiO-66-based aptasensor exhibits high sensitivity with a LOD of 8.88 and 4.93 pg/ml, as deduced from electrochemical impedance spectroscopy and differential pulse voltammetry, respectively. Meanwhile, the developed SPR biosensor exhibited a slightly high LOD of 0.3 ng/mL. [42]
In a novel approach, self-polymerized dopamine-decorated Au NPs that are also coordinated with Fe-MOF (Au@PDA@ Fe-MOF) was designed for the detection of CEA. [43] This nanocomposite was employed as a transducer and showed good electrochemical signals. In addition, this nanocomposite assembly was used to immobilize the recognition element (CEA-aptamer) due to abundant COOH groups embedded in Fe-MOFs, as shown in Figure 9. This sensor showed a high sensitivity and excellent selectivity. [43]
Bao et al used UiO-66 as a nanocarrier of electroactive molecules (methylene blue, MB). DNA was further immobilized onto this composite (MB@DNA/MOFs), and was used as a platform for electrochemical biosensor, as described in Figure 10. [44] The biosensor presented good performance for CEA detection ranging from 50 fg/ml to 10 ng/ml with a detection limit of 16 fg/ml. [44] In an earlier study, a type of dendritic DNA scaffold labeled with a Pb-based MOF, synthetized by hybrid chain reaction as signal tags, was used for the detection of CEA. A detection limit of 0.333 pg/ml was obtained. [45]
In a recent study by Zhang et al, both AuNPs and ordered mesoporous carbon (OMC) were incorporated with ZIF-8, and an electrochemical biosensor was prepared thereof. [46] Zif-8 served as a support nanocarrier for the immobilization and increased loading of the antibody onto its large surface area. The OMC was dropped on a glassy carbon electrode to improve electrochemical signals due to its intrinsic electrical conductivity. DPV was carried out to record the electrochemical responses. The sensor demonstrated excellent performance with a LOD of 1.3 pg/ml. [46]
Liu et al revealed the synthesis of Cu-MOFs by a hydrothermal method for establishing a sandwich-type sensor, as shown in Figure 11. [47] Toluidine blue (TB) loaded mesoporous Cu-MOFs with PDA coating were employed as a signal transducer probe. The suggested sensor was fabricated by Cu-MOFs-TB/PDA, chitosan and multiwall carbon nanotubes (MWCNTs) on a glassy carbon electrode with a large surface area to immobilize primary antibodies (Ab1). [47] An excellent conductivity was achieved, and CEA was quantitatively detected with LOD of 3.0 fg/mL under optimal conditions. [47]
A platform for the ultrasensitive detection of three analytes: thrombin, kanamycin, and CEA, was also established by Zhang et al. [23] A series of Zr-based MOF composites embedded with three kinds of aptamer strands were achieved by a one-step de novo synthetic approach. [23] The label-free electrochemical aptasensors based on Zr-MOF@Apt composites demonstrated high stability, repeatability, applicability and showed an excellent sensitivity to these analytes with detection limits of 0.40, 0.37, and 0.21 pg/mL for CEA, thrombin, and kanamycin, respectively. [23]
In another study, three Sm-based MOF nanostructures were synthesized with different organic linkers, resulting in three different morphologies including rod-shaped, cubic consisting of stacked 2D layers, and spherical made of small cubic structures. [48] These Sm-MOFs were used to fabricate immunosensors for the detection of CEA, where the CEA antibodies were immobilized onto the working electrode. [48] The exhibited reproducibility and selectivity of the immunosensors were proven with low limit of detection. They were tested with human serum samples, proving the promising results. [48]
(b).
Chemiluminescence Approach
Chemiluminescence (CL) has grown into a well-established luminometry method in analytical chemistry and has been widely applied to liquid phase samples for over 30 years. CL is defined as the production of light through a chemical reaction that is accompanied by energy release. It has numerous advantages such as superior sensitivity, rapidity, safety and controllable emission rate. However, CL-detection acquires extra facilities, such as on-line sample processing and in-line multi-detector installment. [49] For CL-based biosensors the most utilized design is a flow-through biosensor one. [50]
A novel preparation of MIL-88B (Fe) by hemin a metalloporphyrin Fe-based MOF, called as hemin@MIL-88B (Fe), has been reported in 2020 by Han et al [51] to be used for the CL biosensing of CEA. The hemin@MIL-88B (Fe) was conjugated with CEA aptamer1 (hemin@MIL-88B (Fe)-apt1) as the large signaling strategy. The ssDNA was immobilized on the surface of Fe3O4@SiO2 magnetic material, and hemin@MIL-88B (Fe)-apt1 was adsorbed on the Fe3O4@SiO2 by the complementary pairing of the partial bases between ssDNA and CEA apt1. The luminol CEA aptamer2 (L-apt2), which can generate the CL signal, was separately prepared, and was adsorbed on magnetic carbon nanotubes (M-CNTs) by an electrostatic adsorption. Interestingly, hemin@MIL-88B (Fe)-apt1, L-apt2 and CEA formed by sandwiched-like ternary complexes. The positively charged hemin@MIL-88B (Fe) easily accumulated near the hydroperoxide anion (HO2−) through electrostatic adsorption, thereby catalyzing the luminol transient chemiluminescence system. LOD was successfully reported to be 1.5 × 10-3 ng/ml. [51]
(c).
Electrochemiluminescence Approach
On the other hand, electrochemiluminescence (ECL), which is defined as electrogenerated CL, possesses high sensitivity and broad dynamic range. [52] ECL differs from most other electrochemical techniques. [52] In fact, ECL relies on the generation of high energy electro-active species in the vicinity of electrode surface. As a result, ECL techniques have been widely used in the immunoassays as a direct optical readout of electrochemical reactions. The ECL intensity of the targeted nanomaterials considerably depends on the corresponding electrocatalytic activity. In recent years, extensive research has been performed on ECL in combination with various nanomaterials, including MOFs. The brilliant features of MOFs, make them promising candidates in ECL bioanalysis. [53] In a unique study, Hf-based 2D MOF was fabricated and used in CEA detection, as described in Figure 12. The proposed 2D nanostructure exhibited higher ECL intensity and efficiency and was used to load aptasensor for the ultrasensitive detection of CEA. A detection limit of 0.63 fg/ml was achieved. It should be mentioned that these findings strongly provide new prospects for the development of novel ECL materials and will provoke more interests in the use of 2D MOF nanostructures for ECL sensing. [54]
Graphene oxide (GO)-doped ZIF-8 were also used for the fabrication of an ultrasensitive sandwich-type ECL immunosensor. The pyrolyzed nanocomposites were loaded with Au NPs, which were immobilized with antibodies. These nanocomposites were further loaded onto ruthenium (Ru)-labelled silica nanoparticles (RuSi NPs), and were used as ECL signaling units as it provided numerous luminophores that enhanced the ECL as shown in Figure 13. [55]
Through the combination of MIL-101 and CdSe quantum dots (QDs), an ECL sensor has been successfully synthesized, as described in Figure 14. The as-prepared nanocomposites were applied to immobilize the antibody of the CEA, and a high ECL activity and sensing selectivity were obtained, where a detection limit of 0.33 fg/ml was observed. [56]
(d).
Fluorescence Approach
Fluorescence is by far the most commonly used method in the design of biosensors, as described in many studies. Peculiarly, fluorescent MOFs were used in in these research directions. The fluorescence properties of MOFs are generated by metal ions and organic ligands. Moreover, other fluorescent molecules are encapsulated within the MOF channels and can produce emission fluorescence. [57] These characteristics make MOF materials suitable candidates for the fabrication of MOF-based fluorescence sensors for specific targeted species such as metal ion, anion and small molecule. [58]
A promising fluorescence-based microfluidic sensor for the quantification of CEA was developed by Zhao et al, as schematically represented in Figure 15. [59] In this work, a synergetic fluorescence enhancement strategy based on micro/nanostructure optimization of ZnO nanorod arrays and the in situ ZIF-8 coating was proposed. A glass capillary was chosen as the microfluidic channel, and controllable construction of ZnO nanorod arrays on the inner wall of the microchannel was conducted via the intermittent reaction method. The fluorescence enhancement characteristics of ZIF-8 towards organic fluorescence labels were investigated and were successfully applied to protein marker detection. The LOD reached was as low as 0.01 pg/ml. [59]
In a different study, an innovative and powerful visible fluorescence immunoassay method was fabricated through a wet NH3- triggered structural change of NH2-MIL-125(Ti) impregnated on paper for the detection of CEA. [60] Au NPs heavily functionalized with glutamate dehydrogenase and secondary antibody were used for the generation of wet NH3 with a sandwiched immunoassay format. Paper-based analytical device (PAD) coated with NH2-MIL-125(Ti) exhibited good visible fluorescence intensity through wet NH3-triggeried structural change with high accuracy and reproducibility. Moreover, the NH2-MIL-125(Ti)-based PAD displayed two visual modes of fluorescence color and physical color with the naked eye and allowed for the detection of CEA at a concentration of as low as 0.041 ng/ml. Importantly, the PAD-based assay provides a promise for the mass production of miniaturized devices and opens new opportunities for protein diagnostics and biosecurity. [60]
(e).
Photoelectrochemical Approach
The photoelectrochemical (PEC) process is a promising low-cost approach to convert chemical energy to electricity under light illumination and applied potential. PEC biosensing has attracted huge attention because of its ability to detect biomolecules through the photocurrent generated from a biomolecule oxidation. The ability to couple the photoexcitation process with electrochemical detection renders PEC sensors unique. Moreover, the separation between the sources of excitation (light) and detection (photocurrent) in the PEC process offers high sensitivity with low background signal. [61]
Liu et al proposed a photoelectrochemical biosensor based on UiO-66 MOF. [62] This work established an immobilization-free PEC biosensor based on the DNA-functionalized MOF. Here UiO-66 served as a nanocarrier for the efficient encapsulation of electron donors, while a designed probe was employed as the recognition element (Figure 16). The proposed biosensor was found capable of ultrasensitive and highly selective determination of CEA with a detection limit down to 0.36 fg/ml. [62]
A recent PEC immunosensor based on Yb-MOF was designed for the high performance determination of CEA. [63] The surface of the Yb-MOF was integrated with AuNPs to improve the photoelectric conversion efficiency of the Yb-MOF in the near infrared region. Subsequently, this nanocomposite became a photoelectrochemical platform for loading the CEA antibody (anti-CEA). After exposing it to CEA, the photogenerated electron-hole pairs transfer was blocked thus leading to a decrease in the photocurrent response. The photocurrent variation can be used for determining CEA quantitatively. The range of detection was measured from 0.005 to 15 ng/ml. [63]
(f).
Colorimetric Approach
Colorimetric sensors and biosensors exhibit promising potential due to their simplicity and reliability as potential low-cost platforms. The main prospect of colorimetric sensors is based on the interaction of light and metal nanomaterials. In particular, the color is created by the change in absorbance due to the optical properties of the material. The change in absorbance can be measured as a function of the different concentrations of clinical biomarkers. [64] For CEA colorimetric detection, a group of researchers synthetized a novel biosensor based on PCN-222 MOF, which was prepared by grafting CEA aptamer incorporated DNA tetrahedral (TDN) nanostructures. [65] The synthesized CEA aptamer-TDN-MOF showed a high detection stability due to the iron porphyrin ring in the PCN-222 MOF which possess a significant horseradish peroxidase mimicking activity, which leads to a colorimetric reaction upon binding toward antibody-captured CEA. Ultra-sensitive detection of CEA can be achieved with a limit of detection as low as 3.3 pg/ml. In addition, they demonstrated a great potential upon the analysis of clinical serum samples. [65] In a latest study, Zeng and his colleagues have designed and fabricated a colorimetric immunosensor by taking advantage of 2D-MOF nanomaterials as enzyme mimics. [66] The nanomaterial showed a strong peroxidase mimetic activity, and good selectivity after being modified with a specific aptamer. They reported a CEA detection performance with a linear range from 1 pg/ml to 1000 ng/ml and LOD of 0.742 pg/ml. [66]
ELISA has been identified as a gold standard and is the most widely used immunoassay technique for detecting and measuring disease biomarkers. However, there are some inevitable limitations in the use of ELISA, including limited sensitivity, which requires novel strategies to improve the ELISA limit of detection. For the enhancement of ELISA researchers have introduced MOFs during the fabrication of an ELISA platform. The MOF-based ELISA provides large surface-to-volume ratios which promote the efficient immobilization of antibodies on the nanoscale surface that consequently increase the capture efficiency of substrate surfaces.
In one of the most interesting studies, ZIF-8 doped with carbon dots (CDs) and thymolphthalein was used as a platform for CEA detection via ELISA technique, as shown in Figure 17. In this nanocomposite sensor, the strong fluorescence intensity of CDs could be observed directly to achieve the sensitive detection of the target. After stimulation of alkaline solution, TP was released from ZIF-8 carriers and generated a color change with an obvious absorption, which was beneficial for an increased sensitivity of this ELISA due to the high loading of the thymolphthalein. [67]

Conclusion and Future Perspectives

As one of the common tumor markers, CEA has important clinical values in the differential diagnosis, disease monitoring and therapeutic evaluation of malignant tumors. In the past few decades, advances in the biosensor technology has led to the evolution of simple, fast, low-cost detection, high sensitivity and good selectivity biosensors for various diseases. Compared with other nanostructures, MOFs provide high surface area, high functionality, tunable porosity, non-expansive and versatile fabrication procedures. These features have made them appropriate choices for the establishment of a wide variety of CEA sensors. Generally, this mini-review thoroughly discussed the most recent advances in the design and fabrication of MOF-based biosensors for the detection of CEA cancer biomarker. The optical and electrochemical properties of MOF nanostructures have shown an outstanding ability to detect analytes at low concentrations. Moreover, these can be further enhanced through the development of hybrid nanostructures via the inclusion of other nanomaterials. For example, using luminescent scaffolds such as QDs or fluorescent dyes would result in the development of more accurate and sensitive optical devices. On the other hand, the integration of MOF with conductive polymers would significantly enhance the electrochemical sensing characteristics.
Despite the pronounced features of MOFs as a core material for the development of biosensors, more research is still needed to tackle the arising limitations of MOF nanostructures, such as their stability, reproducibility, toxicity, and biocompatibility. One of the primary restraints is their low water stability, which tends to cause the breakdown of the framework when exposed to moisture. In addition, more attention should be given to the validation of the MOF-based biosensors in the analysis of real biological samples, with a more emphasize given to any possible interferences that may affect the sensing results. Addressing these issues is crucial before the implementation and commercialization of the MOF-based biosensors.

Acknowledgements

This study was financially supported by the UAEU research office (Grant # 31R236). The authors acknowledge the UAEU at large and the research office in particular for their support.

List of Abbreviations

CEA Carcinoembryonic antigen
MOFs Metal organic frameworks
ELISA Enzyme-linked immunosorbent assays
RIA Radioimmunoassay
IRMA Immunoradiometric assay
RT-PCR Reverse transcriptase polymerase chain reaction
MIPs Molecular imprinted polymers
AuNPs Gold Nanoparticles
CNT Carbon NanoTubes
CV Cyclic Voltammetry
DPV Differential Pulse Voltammetry
SWV Square Wave Voltammetry
EIS Electrochemical Impedance Spectroscopy
GCE Glass Carbon Electrode
AFP Alpa FetoProtein
AgNPs Silver Nanoparticles
LOD Limit of Detection
PDA PolyDopamine
OMC Ordered Mesoporous Carbon
MWCNTs Multiwall Carbon Nanotubes
CL Chemiluminescence
ECL Electrochemiluminescence
GO Graphene Oxide
QDs Quantum Dots
PAD Paper-based analytical Device
PEC Photoelectrochemical
TDN DNA tetrahedral
CDs Carbon Dots

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Preprints 78276 g001
Figure 1. 3D representation of CEACAM5 (figure modified from https://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi ) (a) and Schematic representation for the CEA Family (b) (Graph modified from http://www.carcinoembryonic-antigen.de).
Figure 1. 3D representation of CEACAM5 (figure modified from https://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi ) (a) and Schematic representation for the CEA Family (b) (Graph modified from http://www.carcinoembryonic-antigen.de).
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Preprints 78276 g002
Figure 2. shows homotypic binding between two CEA molecules. (CEA structures are modified from the CEA Site http://cea.klinikum.uni-meunchen.de).
Figure 2. shows homotypic binding between two CEA molecules. (CEA structures are modified from the CEA Site http://cea.klinikum.uni-meunchen.de).
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Preprints 78276 g003
Figure 3. Scheme for the preparation of a MOF.
Figure 3. Scheme for the preparation of a MOF.
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Figure 4. a) Number of publications of sensor based-MOFs in the period 1995-2019 based on Google Scholar, b) Articles published from the year 2010–2022 with the keyword “MOF and Biosensors” and “Cancer embryonic Antigen Biosensors” obtained and compiled from the Google Scholar database on the 07th of February 2023.
Figure 4. a) Number of publications of sensor based-MOFs in the period 1995-2019 based on Google Scholar, b) Articles published from the year 2010–2022 with the keyword “MOF and Biosensors” and “Cancer embryonic Antigen Biosensors” obtained and compiled from the Google Scholar database on the 07th of February 2023.
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Preprints 78276 g005
Figure 5. Illustration of nonporous structures of different MOFs members synthesized by different research groups. (Several names are being given to the synthetized MOFs by different groups of research) Reproduced from Reference 19, with permission from the Royal Society of Chemistry.
Figure 5. Illustration of nonporous structures of different MOFs members synthesized by different research groups. (Several names are being given to the synthetized MOFs by different groups of research) Reproduced from Reference 19, with permission from the Royal Society of Chemistry.
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Figure 6. Schematic representation of different immobilization methods. Reproduced from Reference 26, with permission from Elsevier.
Figure 6. Schematic representation of different immobilization methods. Reproduced from Reference 26, with permission from Elsevier.
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Preprints 78276 g007
Figure 7. Example for Cu-MOF electrochemical sensor. Reproduced from Reference 41, with permission from Elsevier.
Figure 7. Example for Cu-MOF electrochemical sensor. Reproduced from Reference 41, with permission from Elsevier.
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Preprints 78276 g008
Figure 8. Schematic of silver nanocrystal with UiO-66 as a platform for CEA detection. Reproduced from Reference 42, with permission from American Chemical Society.
Figure 8. Schematic of silver nanocrystal with UiO-66 as a platform for CEA detection. Reproduced from Reference 42, with permission from American Chemical Society.
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Preprints 78276 g009
Figure 9. Schematic for the Fe-MOFs based biosensor. Reproduced from Reference 43, with permission from American Chemical Society.
Figure 9. Schematic for the Fe-MOFs based biosensor. Reproduced from Reference 43, with permission from American Chemical Society.
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Preprints 78276 g010
Figure 10. Schematic for the UiO-66 loaded with MB for electrochemical biosensing. Reproduced from Reference 44, with permission from American Chemical Society.
Figure 10. Schematic for the UiO-66 loaded with MB for electrochemical biosensing. Reproduced from Reference 44, with permission from American Chemical Society.
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Preprints 78276 g011
Figure 11. Schematic diagram for Cu-MOFs biosensor. Reproduced from Reference 47,with permission from Elsevier.
Figure 11. Schematic diagram for Cu-MOFs biosensor. Reproduced from Reference 47,with permission from Elsevier.
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Preprints 78276 g012
Figure 12. Schematic for MOL for CEA detection. Reproduced from Reference 54, with permission of Royal Society of Chemistry.
Figure 12. Schematic for MOL for CEA detection. Reproduced from Reference 54, with permission of Royal Society of Chemistry.
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Preprints 78276 g013
Figure 13. The procedure for preparing AuNP@NPCGO, the fabrication of the RuSiNP-Ab2 probe (Ab2 bioconjugates) and the stepwise preparation of the immunosensor. Reproduced from Reference [55] with permission of Royal Society of Chemistry.
Figure 13. The procedure for preparing AuNP@NPCGO, the fabrication of the RuSiNP-Ab2 probe (Ab2 bioconjugates) and the stepwise preparation of the immunosensor. Reproduced from Reference [55] with permission of Royal Society of Chemistry.
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Preprints 78276 g014
Figure 14. Electrochemiluminescence MOFs based biosensor have been successfully synthesized by combining CdSe QDs and MIL-101. Reproduced from Reference 56, with permission from Elsevier.
Figure 14. Electrochemiluminescence MOFs based biosensor have been successfully synthesized by combining CdSe QDs and MIL-101. Reproduced from Reference 56, with permission from Elsevier.
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Figure 15. Microfluidic channels for fluorescence detection of CEA. Reproduced from Reference 59, with permission from Elsevier.
Figure 15. Microfluidic channels for fluorescence detection of CEA. Reproduced from Reference 59, with permission from Elsevier.
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Preprints 78276 g016
Figure 16. Zr-MOF (UiO-66) as a carrier for electron donor. Reproduced from Reference 62, with permission from Elsevier.
Figure 16. Zr-MOF (UiO-66) as a carrier for electron donor. Reproduced from Reference 62, with permission from Elsevier.
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Preprints 78276 g017
Figure 17. ZIF-8 For ELIZA detection of CEA. Reproduced from Reference 67, with permission from Elsevier.
Figure 17. ZIF-8 For ELIZA detection of CEA. Reproduced from Reference 67, with permission from Elsevier.
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Table 1. MOF-based CEA biosensors.
Table 1. MOF-based CEA biosensors.
# MOFs Metal used Organic Ligand Surface Modifications & added materials Types of Sensing LOD/Detection range Reference
1 Pd/Cd-MOFs Pd/Cd 2- aminoterephthalic acid Immobilization of labels for secondary anti-CEA and secondary anti-AFP antibody Electrochemical 0.03 pg/mL and 0.1 pg/mL [38]
2 Ce-MOF Ce 1,3,5-benzenetricarboxylic acid hyaluronic acid was coated on the surface of Ce-MoF, which loaded with silver nanoparticles (AgNPs) and horseradish peroxidase Electrochemical 0.2 pg / mL [39]
3 Ag-MOF Ag Terephthalic acid Ag-MOF was dopped by gold nanoparticles and labelled by anti-CEA Electrochemical 8.0 fg/mL [40]
4 Cu-MOF Cu 2-amino terephthalic acid Platinum nanoparticles (PtNPs) was linked to Cu-MOF then, CEA aptamer loaded onto Pt@CuMOFs, finally, this was bound with hemin to form hemin@G-quadruplex (hGq) with mimicking peroxidase activity Electrochemical 0.023 pg /mL
[41]
5 UiO-66 Zr 2-Aminoterephthalic acid MOF embedded with silver nanoclusters (AgNCs) using the carcinoembryonic antigen (CEA)-targeted aptamer as template A. Electrochemical
1-Impedance
8.88
Pg/mL


 [42]
2-Differential pulse voltammetry 4.93 pg/mL
B. SPR 0.3 ng/mL
6 Fe-MOF Fe 1, 4-dicarboxybenzene self-polymerized dopamine-decorated AuNPs was loaded on Fe-MOF and attached to CEA aptamer Electrochemical 0.33 fg /mL [43]
7 UiO-66-NH2 Zr 2-Aminoterephthalic acid By using MOF as nanocarrier of electroactive molecules (methylene blue, MB) and functionalized by the assembled DNA Electrochemical 16 fg/mL [44]
8 Pd-MOF Pd 2- amino-1,4-benzenedicarboxylic acid (H2N-BDC) dendritic (Hybridization chain reaction) HCR-triggered DNA nano structure was labeled with Pb-MOF Electrochemical 0.333 pg /mL [45]
9 Zif-8 Zn Methyl Imidazole It is based on the use of Au NPs modified ZIF-8 and ordered mesoporous carbon (OMC) Electrochemical 1.3 pg/mL [46]
10 Cu-MOF Cu Terephthalic acid Toluidine blue (TB) loaded mesoporous Cu-MOFs with polydopamine (PDA) coating were employed as a signal probe Electrochemical 3.0 fg/mL [47]
11 Zr- MOF Zr 4′,4‴,4′′′′- nitrilotris[1,1′-biphenyl]-4-carboxylic acid (H3NBB) Aptamers of
CEA, thrombin, and kanamycin were separately immobilized on the MOF		 Electrochemical 0.40 pg/ mL
0.21pg/mL
0.37pg/mL		 [23]
12 Sm-MOF Sm trimesic acid (TMA), meso-tetra(4-carboxyphenyl)porphine (TCPP), and 1,3,6,8-tetra(4-carboxylphenyl) pyrene(TBPy) Anti-CEA immobalization Electrochemical SmTMA, SmTBPy, and
SmTCPP MOF-based immunosensors are determined to be
0.001, 0.05, and 0.01 U /mL, respectively		 [48]
13 MIL-88B Fe 2-aminoterephthalic acid Hemin modified Mil-88B
Immobilization of CEA aptamer		 CL 1.5 × 10-3 ng/mL [51]
14 Hf-ETTC-MOL Hf H4ETTC (H4ETTC = 4',4''',4''''',4'''''''-(ethene-1,1,2,2-tetrayl)tetrakis(([1,1'-biphenyl]-4-carboxylic acid))) two-dimensional (2D) ultrathin metal-organic layer (MOL) was used as a platform for CEA detection ECL 0.63 fg/mL [54]
15 Zif-8 Zn Methyl imidazole ZIF-8 and graphene oxide (GO) to form a ZIF-8@GO composite
Then, the in situ growth of AuNPs due to the p–p interaction between AuNPs and Zif-8@GO take place		 ECL 0.003 ng/mL [55]
16 MIL-101 Cr Terephthalic acid prepared MIL-101-CdSe nanocomposites
antibodies for CEA was linked		 ECL 0.33 fg /mL [56]
17 Zif-8 Zn Methyl Imidazole formation of sandwich immunoassay by using Zif-8 coated with the ZnO/PAA (Polyacrylic acid) nanorod arrays Fluorescence 0.01 pg /mL [59]
18 NH2-MIL-125(Ti) Ti 2- amino-1,4-benzenedicarboxylic acid (H2N-BDC) Gold nanoparticles heavily functionalized with glutamate dehydrogenase (GDH) and secondary antibody were used for generation of wet NH3 Fluorescence 0.041 ng /mL [60]
19 UiO-66-NH2 Zr 2-Aminoterephthalic acid MOF Loaded with lactic acid and attached to dsDNA PEC 0.36 fg /mL [62]
20 Yb-MOF Yb 1,1′-(1,5-dihydropyrene-2,7-diyl)bis(3-(4-carboxybenzyl)-1H-imidazol-3-ium) bromide [DDPDBCBIm(Br)2] ionic liquid Combined with Gold Nanoparticles PEC 0.005-15 ng/mL [63]
21 PCN-222 Zr and Fe-based MOF meso-tetra (4-carboxyphenyl) porphine ferric chloride (Fe-TCPP) CEA Aptamed was immobilized on the PCN-222 Colorimetric 3.3 pg/mL [65]
22 Cu-TCPP Cu-MOF TCPP Gold Nanoparticles immobilization and aptamer Colorimetric 1pg/mL to 1000 ng/mL [66]
23 Zif-8 Zn Methyl Imidazole ZIF-8 used as the carrier to deliver the tracer agent carbon dots (CDs) and the “drug” thymolphthalein (TP) ELIZA 10 pg/mL [67]
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