Fluorescent probes in stomatology

Shuai Tang; Xiguo Wu; Tong Yang; Shan Peng; Gang Ding

doi:10.1016/j.arabjc.2022.104350

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Review article

12 2022

:15;

104350

doi:

10.1016/j.arabjc.2022.104350

Fluorescent probes in stomatology

Shuai Tang^{^a}, Xiguo Wu^{^b}, Tong Yang^{^a}, Shan Peng^{^a}, Gang Ding^{^a,⁎}

a School of Stomatology, Weifang Medical University, Weifang 261053, China

b Department of Clinical Laboratory, Yidu Central Hospital, Weifang Medical University, Weifang 262500, China

⁎Corresponding author at: School of Stomatology, Weifang Medical University, Baotong West Street No.7166, Weifang, China. dinggang@wfmc.edu.cn (Gang Ding)

Received: 2022-7-25, Accepted: 2022-10-9,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

As people pay more and more attention to quality of life, stomatology, as one of the main branches of modern medicine, has experienced rapid development. The research results of many fields, such as molecular biology, analytical chemistry, material chemistry and other disciplines, are gradually applied in the field of stomatology. Due to the advantages of fast response, flexible design, high specificity, high sensitivity and easy operation, fluorescent probe technology is widely used not only in environmental monitoring, food analysis, bioanalysis and life sciences, but also in stomatology as an increasingly powerful analytical and research tool. In this review, we will introduce the uses of fluorescent probes in stomatology for detection, diagnosis, imaging, treatment and screening from five aspects: oral and maxillofacial tumors, dental hard tissue diseases, oral soft tissue diseases, oral related ion diseases, and forensic dentistry. It is hoped that our review may contribute to the further development of fluorescent probes in terms of selectivity, sensitivity, non-toxicity, and stability, thus enhancing the pathogenesis, diagnosis and therapy of stomatological diseases, and laying the foundation for further study of oral disease mechanisms.

Keywords

Stomatology

Fluorescent probe

Detection

Oral tumor

Fluorescence imaging

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1 Introduction

With the development of the times, the research content of stomatology has long gone beyond the diseases of teeth itself, consisting of oral mucosa, saliva, salivary glands, oral microorganisms, masticatory organs, oromandibular system, etc(Zhang et al., 2016; Bhullar et al., 2019; Chung et al., 2021 ), and involves a variety of diseases of the oral and maxillofacial areas, including caries, periodontal diseases, dental defects, endodontic diseases, oral mucosal diseases, dental and maxillofacial malformations, various salivary gland diseases, oral and maxillofacial tumors, etc. Besides pain, restricting mouth opening, affecting chewing, swallowing, pronunciation, and facial appearance, stomatological diseases can affect other organs of the body and cause or aggravate systematic diseases because the oral cavity is an inseparable part of the whole body and closely related to other organs. The detection rate of Helicobacter pylori in the periodontal pockets of untreated patients with periodontitis is high, and it is well known that Helicobacter pylori can cause chronic gastritis, duodenal ulcer, and gastric cancer(Ren et al., 2016). As bacterial infectious diseases, caries and periodontitis may lead to acute or subacute infective endocarditis. When receiving oral treatment, patients with artificial heart valves could increase bacteria in the mouth and give rise to the occurrence of temporary bacteremia (Tubiana et al., 2017). And poor oral hygiene can easily cause lung infection(Huang et al., 2021). Chronic oral infections are an important pathogenic factor of cancer, and human papillomavirus (HPV) is one of the reasons of oropharyngeal cancer, as well as closely related to the development of cervical cancer(Lydiatt et al., 2017). In addition, oral infections in pregnant women are risk factors for preterm delivery and low birth weight infants(Iheozor-Ejiofor et al., 2017). A great deal of studies demonstrated that periodontal disease and diabetes have a clearer bidirectional relationship, and basic periodontal treatment not only significantly improves the periodontal condition of patients, but also improves glycemic control in diabetic patients(Genco et al., 2020). Long-term tooth loss can lead to memory loss and cause an increased incidence of Alzheimer's disease(Su et al., 2014). Oral and maxillofacial malformations affect the mental health of patients seriously and have a terrible impact on systemic health, which seriously affect human health(Koskela et al., 2021). Oral health worldwide has not improved significantly in the last 30 years and continues to be a major global public health challenge(Hugo et al., 2021).

At present, oral diseases are mainly diagnosed by clinical examination, imaging examination, hematological examination, puncture and biopsy, and some other subjective or invasive diagnostic methods(Eom et al., 2015), which require certain indications and each method has its own defects, and early misdiagnosis sometimes occurs. In addition, large instruments, such as X-ray, CT and MRI are required, which not only require special consumables but also have no specific indicators, and X-ray and CT have radioactive damages(Huang et al., 2022). With the advances in diagnostic technology, several biomarkers related to disease development and organ dysfunction have been identified, but most of these assays are based on traditional immunoassays, which are time consuming and require expensive antibodies(Han et al., 2021). Moreover, invasive inspective and therapeutic tools, such as surgery, puncture and biopsy, are required, but patients often refuse these examinations and treatments because of fear, thus apparently affecting the early diagnosis and therapy. So, although stomatology has developed rapidly in the past decades, early diagnosis and treatment of oral diseases need to be further promoted in order to obtain better diagnostic and therapeutic effects.

In recent years, fluorescent probes have increasingly become a promising analytical method, with the emergence of various methods for preparing various fluorescent biological samples, and the increasing and advanced types of instruments and equipment used for fluorescence detection. Fluorescent probes are usually composed of three parts: receptor group, fluorescent group and connector part(Wu et al., 2019). The receptor group determines the selectivity and specificity of the probe molecule, while the fluorescent group determines the sensitivity of recognition, and the linker plays the role of a molecular recognition hub with a variety of structures. Among them, the receptor group is closely related to the analyte, and the two enhance the specificity of the fluorescent probe by chemical reaction or ligand binding. Fluorescent groups with high quantum yield and small background fluorescence interference at appropriate wavelength can effectively exert the sensitivity of the probe by converting the interaction between the receptor group and the detection object into fluorescence signals, which are then detected by the instrument(Kolanowski et al., 2018). The required dose of fluorescent probe is generally small, and the information obtained is more intuitive and accurate, which can accurately reflect the structure, distribution, content, physiological function and other issues of the detection object. Therefore, fluorescence detection technology has been attracted more and more attention because of its high sensitivity, rapid response, real-time in-situ detection and tracking of biomarkers, low cost, and excellent spatio-temporal resolution, and has been gradually applied in the fields of chemistry, biology, pharmacology, medicine and other fields(Chu et al., 2021). Although fluorescent probes have been widely used in scientific research, replacing the traditional analytical methods that are time-consuming, costly and cumbersome to some extent, the main disadvantages of their toxicity cannot be ignored, which often interfere with many normal biological processes, limiting the application scope of fluorescent probes to a certain extent. Currently, there is no relatively comprehensive review on the application of fluorescent probes in stomatology, so in this review we will discuss the latest progress of fluorescent probe technology in stomatology in order to draw attention to this topic in related fields, improve the diagnostic ability of oral diseases, and seek and promote more effective treatment methods (Fig. 1).

Applications of fluorescent probes in five aspects of stomatology.

2 Design strategies for oral-related fluorescent probes

Fluorescent probes used in stomatology are essentially a class of compounds that localize certain areas of the oral cavity in response to specific stimuli such as pH, specific substances, and ions. When designing oral-related fluorescent probes, an appropriate receptor group should be selected as much as possible to match the substance to be detected, to improve the binding performance of the fluorescent probe to the substance to be detected. The receptor groups with recognition function can be proteins, nucleic acids, peptides, drugs, carboxyl groups and other substances that have a biological target role in the fluorescence detection process to identify the substances to be tested such as oral diseases, oral inflammatory tissues, oral cells, etc. There are three main design strategies for fluorescent probes: bonding-signal output method substitution method, and chemometric method (Fig. 2 A-C). Most fluorescent probes in stomatology are synthesized based on the strategy of bonding-signal output method. When the receptor group combines with the detection object, the chemical environment of the fluorescent group changes, which is usually reversible. The substitution method uses the difference in the ability of the receptor group to bind to the fluorescent group and the analyte, respectively, to achieve detection of the analyte, and is commonly used to design anionic fluorescent probes. However, the principle of chemometric method is to use a specific chemical reaction between the probe molecule and the analyte to change the chemical environment in which it is located, mostly irreversible, and such oral-related fluorescent probes have high sensitivity and good specificity. In addition, the mainly used fluorophores include organic fluorescent small molecules (such as rhodamine, fluorescein, coumarin, flower cyanide dyes, etc.), and inorganic materials (for example, quantum dots) (Fig. 2 D and E). Common fluorescence mechanisms for fluorescent probes in stomatology are photoinduced electron transfer (PET), when the receptor group does not exist, and the fluorescent group is then excited by light, one of the electrons in the highest occupied molecular orbital (HOMO) transitions to the lowest unoccupied molecular orbital (LUMO) can produce fluorescence; if the HOMO or LOMO orbital of the receptor group is between the two orbital energy of the fluorescent group, the electron transfer between the receptor group and the fluorescent group can occur, resulting in fluorescence quenching (Sun et al., 2019); intramolecular charge transfer (ICT), when the receptor group is combined with the analyte, the push–pull ability of the electron donor or pull electron part of the receptor group changes, and the π electronic structure of the whole system is redistributed, resulting in changes in the absorption and emission spectra, i.e., spectral red-shift or blue-shift (Park et al., 2020); fluorescence resonance energy transfer (FRET), a fluorescent system contains two fluorophores, one acting as the energy donor D and the other as the energy acceptor A, when the fluorescent system is excited with the excitation of the donor D, a non-radiative energy transfer from D to A can occur, resulting in the emission of fluorescence from the acceptor fluorophore(Wu et al., 2020); excited–state intramolecular proton transfer (ESIPT), some fluorophores tend to produce radical conjugates in close proximity to another identical or different ground state fluorophore in the excited state (formation of radical conjugates by π-π stacking) and double fluorescence can be observed(Sedgwick et al., 2018); and aggregation-induced emission (AIE), with the typical property of “the more it gathers and glows”, then these molecules are grouped together, the mutual restraint restricts the internal motion of the molecules, so that the proportion of energy dissipated in the form of motion decreases and the proportion of energy output in the form of light increases, thus showing the phenomenon of fluorescence enhancement(Hu et al., 2018) (Fig. 3). Regardless of the design mechanism, the fluorescent probes should have the following conditions: specific binding, good biocompatibility, non-toxic or low toxicity, high fluorescence quantum yield, significant fluorescence change after binding to biological samples, and good fluorescence stability. Meanwhile, combined with fluorescence imaging technology, it can realize the imaging of oral cells and analytes in oral tissues and the visualization of related biological processes. Various research groups are still working hard to meet these requirements, which will optimize the design of oral-related fluorescent probes in the future.

A–C: Three main design strategies for fluorescent probes. D and E: Common fluorescent groups found in fluorescent probes. Fluorescent probes generate and emit fluorescence at different wavelengths by absorbing light at specific wavelengths. (A) Bonding-signal output method. The recognition group and the fluorescent group are connected by covalent bonds to design the fluorescent probe. (B) Substitution method. The binding ability of the recognition group in the probe to the analyte is stronger than the binding ability of the recognition group to the fluorescent group, so the analyte displaces the fluorescent group, which causes a change in the fluorescence intensity of the whole system. (C) Chemometric method. Upper panel, the analyte and the fluorescent probe react to form a covalent compound. Lower panel, the analyte catalyzes the reaction of the fluorescent probe to generate two new substances. (D) Organic fluorescent small molecules. (E) Inorganic materials: quantum dots.

Common fluorescence mechanisms for fluorescent probes: (A) Photoinduced electron transfer (PET). (B) Intramolecular charge transfer (ICT). (C) Fluorescence resonance energy transfer (FRET). (D) Excited–state intramolecular proton transfer (ESIPT). (E) Aggregation-induced emission (AIE).

3 Application of fluorescent probes in stomatology

The application of fluorescent probes in stomatology is summarized in Table 1.

Table 1 Fluorescent Probes in Stomatology.

Probe type	Probe name	Detection object	Detection result	Biological application	Reference
Oral and maxillofacial tumors
*Cyanine Dyes*	AF750-6Ahx-Sta-BBN	HSC-3 cells and HOK cells	Bound to the receptors in HSC-3 cells	Fluorescence imaging for OSCC	(Li et al., 2020a)
	o-BMVC	Cancer cells; head and neck patients	More o-BMVC foci in cancer cells	Clinical screening of human cancers	(Tseng et al., 2018)
	EBI-NO₂	Cal-27 cells under hypoxia	Detected NTR in oral cancer cells；monitored hypoxia in oral cells	Investigating the physiological and pathological changes in hypoxia oral cells	(Jiao et al., 2020)
	Panitumumab-IRDye800CW	Head and neck cancer patients	50 mg was the appropriate diagnostic dose	Assessment of intraoperative tumor margin	(Nishio et al., 2020; van Keulen et al., 2019b; van Keulen et al., 2019a )
	Cetuximab-IRdy800CW	471 lymph nodes	Fluorescence imaging of lymph nodes	Intraoperative imaging	(Rosenthal et al., 2017)
	Cetuximab-IRdy800CW	Head and neck cancer surgery	75 mg of unlabeled cetuximab pre-dose and 15 mg of cetuximab 800CW could be more sensitive to assess the edge of tumor resection	Intraoperative imaging	(Voskuil et al., 2020)
	Indocyanine green (ICG)	12 patients with oral cancer	0.75 mg/kg showed the highest SBR	Guided surgery in oral cancer	(Wang et al., 2019b)
	ICG-Glu-Glu-AE105	Head and neck tumors of model mice constructed by implanting OSC-19-luc2 cells	The fluorescent signal was clear on the tongues of tumor-bearing mice	Fluoresce tumors in real time and guide tumor resection	(Juhl et al., 2016; Christensen A JK, 2017)
*Fluorescein Dyes*	WGA-FITC	Two groups of subject	Malignant and dysplastic lesions were distinguished	Chairside detection of oral cancerous and dysplastic lesions	(Baeten et al., 2018)
	Fluorescein	100 subjects	Fluorescence imaging of oral cancer cases and heterogeneous hyperplasia	Large-scale oral cancer screening	(Qaiser et al., 2020)
	FAM-NP41	Mouse model of parotid carcinoma in situ	Identified and preserved facial nerves	Clinical surgery	(Hussain et al., 2016)
*NBD Dyes*	Dual-color fluorescent cyclodextrin nanogels	Cal-27 cells	Reversible light-switching two-color fluorescence was achieved	Fluorescence imaging for OSCC	(Deng et al., 2019)
*Naphthalimide Dyes*	A colorimetric and ratiometric fluorescent probe	Cal-27 cells	Intracellular alteration of GSH levels	Apoptosis of OSCCs	(Zhu et al., 2010)(Zhou et al., 2017)
*Rhodamine Dyes*	EP-HMRG	17 cases of HNSCCs	Fluorescence intensity in tumor lesions were higher than normal lesions	Detection of superficial HNSCC without a history of radiotherapy	(Mizushima et al., 2018)
	HA-FA-HEG-OA	SCC-9 oral squamous cells	Internalised through the CD44 receptor into intracellular vesicles	Imaging for oral cancer	(Ghanim et al., 2021; Paolino et al., 2019)
	gGlu-HMRG	HNC cells and oral cancer tissues	Recognize cancer cells; fluorescence imaging of patient-derived cancer frozen specimens and surgical margins	Tumour-positive resection margins	(Slooter et al., 2018)
*BODIPY Dyes*	PARPi-FL	Oral cancer biospecimens and OSCC patients	PARP1 was expressed in oral cancer	Early detection of oral cancer and mark intraoperative margins	(Kossatz et al., 2016; Kossatz et al., 2017; Kossatz et al., 2020 )
*NIR Dyes*	TQTPA	Orthotopic, Tongue tumor-bearing, nude mice.	Outlined orthotopic tongue tumors and metastatic lymph nodes	Clinical diagnosis and treatment	(Wang et al., 2019c)
	HATb–PDA–DOX	OSCC cells	The antitumor results was better	Treatment with combined chemo-photothermal therapy for OSCC	(Gu et al., 2021)
	IFP-O₂	Cal-27 cells	Responded to the change of endogenous O₂^•- concentration in living cells	Studying the relationship between ROS and apoptosis	(Jiao et al., 2021)
	HNT-NTR	HSC2 cells and Cal-27 cells	Detected tumor cells and reflected the invasiveness of tumor cells	Diagnosis of tumors with early formation and suspected metastasis	(Chen et al., 2022)
*Quantum Dot*	NCQD-HCS	FaDu cells	Thermal ablation effect in FaDu cells	Tracing the curative response during the treatment	(Das et al., 2019)
	Zwitterionic carbon dots	FaDu cells and Cal-27 cells	Improved biocompatibility with two different oral cancer cell lines	Fluorescence imaging for OSCC	(Sri et al., 2018)
	Green and Orange Fluorescent Carbon Dots	Stain oral tissue sections	Normal tissues and pathological tissues were distinguished	Detection of oral cancer	(Peng et al., 2019)
Dental hard tissue diseases
	PENA	Deformed streptoglobulin glucose transferase (GTF)	Detection of virulence factors and fluorescence imaging of pathogenic bacteria were associated with caries	Prevention, diagnosis and treatment of caries	(Feng et al., 2019a)
	Ratiometric pH-sensitive nanosensors	Oral biofilm	monitor pH changes in oral biofilms	Slowing the progression of carie	(Hollmann et al., 2021)
	TMPyP	60 tooth samples	Detected early damage lesions of tooth enamel	Clinical practice	(NouhzadehMalekshah et al., 2019)
	Fura-2 and BCECF	Enamel cell-derived HAT-7 cells	Detected Ca²⁺ and pH changed	The relevant mechanisms of tooth enamel defect formation	(Foldes et al., 2021)
	Rhodamine B	Dental adhesive resin	Obtained dentin adhesive interface images	Preparation of viscous resin samples	(Bim Junior et al., 2017)
	Rhodamine B and calcein	The blocking agent	Detection performance of the blocking agent	Dental treatment	(Generali et al., 2017)
Oral soft tissue diseases
	A novel H₂S fuorescence probe	H₂S	Diagnosis of infammatory diseases of bone	The researches about pathogenesis of periodontitis	(Lu et al., 2021)
	PxB-Cy3	Gram-negative bacteria	Fluorescence labeling	Detection of microbiota	(Wang and Chen, 2018)
	TriA	Gram-negative bacteria and peptidoglycans	Fluorescence labeling	Microbial studies	(Wang et al., 2019a)
	Fe-Tracer	Porphyromonas gingivalis	Identified and tracked iron-related proteins	Iron homeostasis in pathogens	(Jiang et al., 2018)
	CFW	228 specimens	Diagnosis of oral candidiasis	Oral disease examination	(Yao et al., 2019)
	NSCDs	Bacteria and human oral epithelial cells	Fluorescence imaging	Oral cell tagging	(Pathak et al., 2019)
	fluorescein	Parotid duct injury	Reduced damage	Surgical exploration	(Montag et al., 2016)
Oral-related ion diseases
	Mito FV	Fluoride ion	Fluorescence imaging	Monitoring fluoride ion levels	(Zhou K et al., 2018)
	Two Sn²⁺ fluorescent probes	Streptococcus mutans	Fluorescence imaging	Oral disease prevention and treatment	(Lan et al., 2014)
	A novel amino-ICAN based solvatochromic fluorophore family	Hg²⁺	Fluorescence imaging	Detecting water and dental amalgam	(Nagy et al., 2019)
Forensic dentistry
	Aridinium orange fluorescent probes and other dyes	90 pulp tissue samples	For Barr body, females were positive,while males were almost non-positive.	Identification of gender	(Hong B, 2001; KS, 2015)
	SiC@BSANPs	Streptococcus salivarius	Fluorescence imaging	Detecting bacteria in saliva	(Li et al., 2019)
	A Mn-doped ZnS quantum dots fluorescent probe	Oral fluids and serums	Evaluation of the cocaine and the metabolites	Testing for cocaine abuse	(Chantada-Vazquez et al., 2018)
	MFBPs	Salivary exosomes	Fluorescence imaging	Diagnosis of exosomes related diseases	(Wu et al., 2021)

3.1

3.1 Fluorescent probes for oral and maxillofacial tumors

As one of the common tumors in human body, oral and maxillofacial tumors involve a wide range of anatomic sites, including tongue, lip, gingiva, buccal mucosa, maxilla, mandible, salivary glands, etc. It is mainly divided into two categories, benign tumors and malignant tumors. Benign tumors are mostly of dental and epithelial origin(Diniz et al., 2017), followed by mesenchymal tissue tumors; malignant tumors are most frequently of epithelial tissue origin, and the most representative one is squamous epithelial cell carcinoma(Windon et al., 2021), which accounts for about 90 % of oral and maxillofacial malignant tumors(Ling et al., 2021). Advanced patients with oral and maxillofacial malignant tumors often have signs such as ulcers, plaques, pain, lumps, loose teeth, restricted mouth opening, dysphagia, anorexia, abnormal psychological changes, etc. (Maymone et al., 2019), however these signs are not obvious in early stage and are easily misdiagnosed as other oral diseases clinically, making patients miss the best time for treatment, thus leading to difficulties in late treatment and poor therapeutic effects. Currently, surgery is the most important and effective method for the treatment of oral and maxillofacial tumors, and radiotherapy, chemotherapy, biotherapy and so on are also common. However, several problems are urgently needed to be solved, such as accurate location of cancer, avoiding local recurrence, and decreasig potential metastasis. Therefore, it is important to make correct diagnosis of oral and maxillofacial tumors in early stage, and it is especially critical to find simple, sensitive, effective, non-invasive or minimally invasive tumor diagnostic tools and new treatment tools.

With the development of medical immunology, molecular biology and other disciplines, has been found that tumor patients often produced some chemicals, secreted and released by tumor cells in the body fluids, which often exist in the form of antigens(Yu and Cirillo, 2020), hormones(Hanamura et al., 2021), receptor(Harada et al., 2018), enzymes(Feng et al., 2019b), proteins(Mukherjee et al., 2021) and various oncogenes(Lesseur et al., 2016), which have aroused widespread concern. These substances may become biological targets for binding to the receptor groups of fluorescent probes, which are of great significance for the design and preparation of fluorescent probes. The dyes in the fluorescent probe for oral and maxillofacial tumors include cyanine, fluorescein, NBD, naphthalimide, rhodamine, BODIPY. Near-infrared (NIR) dyes and quantum dot (QD) are paid more and more attention during the recent years.

3.1.1

3.1.1 Cyanine dyes

Cyanine is a molecule with polymethylalkyne bridge between two nitrogen atoms with delocalization charge. Different substituents can control the different properties of fluorophores. The absorbance and fluorescence wavelength can be controlled by selecting the length of polymethylacetylene bridge: the longer anthocyanins have higher absorbance and emission wavelength up to the near infrared region(Li et al., 2020b). Many cyanine dyes are commonly used in the field of stomatology to label biomolecules such as DNA, proteins and so on.

Gastrin-releasing peptide receptor (GRPR) is highly expressed in the early stages of OSCC, which is 6 times higher than that of normal human non-cancerous tissue and 4 times higher than normal epithelial tissue paracancerum. Li et al. prepared gastrin releasing peptide receptor specific nano graphene oxide (NGO) probe according to this feature, the BBN antagonist was labeled with GRPR-specific Alexa Fluor 750 (AF750) to form AF750-6AHX-STA-BBN. Subsequently, this product reacted with NGO via hydrogen bond and π-π interaction, and finally NGO-BBN-AF750 fluorescent probe was synthesized(Li et al., 2020a). The human oral cancer cell line HSC-3 cell and normal oral HOK cells, which do not express GRPR used as a negative control, were detected by the confocal laser scanning microscope to obtain the early diagnosis of OSCC. There was no fluorescence in HOK cells, whereas stronger fluorescent signal was observed on the membrane and the nuclei of HSC-3 cells in the presence of NGO-BBN-AF750. Both AF750-6Ahx-Sta-BBN and NGO-BBN-AF750 have a strong specificity to bind to the receptor of HSC-3 cells. In addition, NGO-BBN-AF750 was taken up and internalized by HSC-3 cells, the cell viability of the NGO-BBN-AF750 group was slightly reduced, indicating that the probe may have some toxicity, but still provides a new idea for the diagnosis of oral cancer (Fig. 4 A and B).

(A) Chemical structure of AF750-6Ahx-Sta-BBN. (B) Microscopic images show cell binding of AF750-6Ahx-Sta-BBN and NGO-BBN-AF750 on HSC-3 cells. NGO-BBN-AF750 does not bind to the GRPR-negative HOK cells. Reprinted from Ref. (Li et al., 2020a). Copyright 2020, Ran Li et al. Published by Springer Nature. (C) Synthetic route of the probe EBI-NO2. (D) The docking model of EBI-NO2 binding to the binding cleft of NTR. (E) Main absorption and emission of EBI-NO2 (left) and EBI-NH2 (right). Reprinted from Ref. (Jiao et al., 2020). Copyright 2020, Elsevier B.V.

The G-quadruplex (G4) is another possible cancer target. Tseng and his colleagues reported that the G-quadruplex fluorescent probe 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC) can be used for the clinical detection of head and neck cancer(Tseng et al., 2018). After testing 50 head and neck cancer (HNC) specimens and 20 normal oral specimens, it was found that the number of o-BMVC foci detected in cancer cells was significantly 8 times higher than in normal cells, while it was almost undetectable in normal oral epithelial cells.

Nitroreductase (NTR) is an important fatty acid enzyme that can cause a large amount of intracellular nitroreductase expression when tumor cells are hypoxic(Wang and Chen, 2021). Jiao’s research team designed a nitroreductase fluorescent probe with simple preparation and excellent performance, that is, 3-ethyl-1,1-dimethyl-2-(4-nitrostyrenyl)-1H-benzo[e]indole-3-ium iodide (EBI-NO₂) for monitoring NTR levels in cells(Jiao et al., 2020) (Fig. 4 C-E). The fluorescent probe showed high sensitivity and good specificity to NTR. The hypoxia of oral cells is capable of being judged by intracellular fluorescence imaging, which provides a new tool for the diagnosis and treatment of oral tumors.

Fluorescent labeled antibodies to target epidermal growth factor receptor (EGFR) and the nuclear enzyme Poly (ADP-ribose) Polymerase 1 (PARP1) are commonly used for imaging when performing tumor surgery. EGFR is highly expressed in tumor tissues of patients with HNSCC, and Nishio’s research group investigated the optimal dose of panitumumab-IRDye800CW fluorescent probe labeled with the antibody EGFR in surgery to 24 patients with primary tumors. Imaging analysis was performed, and fluorescence intensity was assessed(Nishio et al., 2020). For successful surgical fluorescence imaging, 50 mg Panitumumab-IRDye800CW is the appropriate diagnostic dose. Van Keulen et al. found that the use of the panitumumab-IRDye800CW fluorescent probe allowed for rapid and accurate real-time assessment of OSCC margins(van Keulen et al., 2019b), and subsequently detected and analyzed tumor samples excised from head and neck cancer patients injected with anti-EGFR antibody panitumumab-IRDye800CW (maximum excitation/emission light: 774/789 nm)(van Keulen et al., 2019a). A strategy was developed to quickly and accurately assess the intraoperative tumor margin by peaking in fluorescence intensity. Although this ex-vitro imaging strategy can be applied to all patients who can perform tumor resection with fluorescent contrast agents, it is not suitable for patients with bone involvement. Rosenthal and her colleagues evaluated 12 patients with head and neck cancer who had received a whole-body injection of cetuximab-IRdy800CW fluorescent probe 3 to 7 days before surgery, using fluorescent imaging to analyze 471 lymph nodes and compare them with the gold standard for histopathological diagnosis. The sensitivity was 97.2 % in positive lymph nodes and 92.7 % in negative lymph nodes. The fluorescent probe has high sensitivity and specificity for fluorescence imaging of lymph nodes(Rosenthal et al., 2017). Voskuil et al. studied the optimal dose of cetuximab-800CW fluorescent probe in head and neck cancer surgery, and found that 75 mg of unlabeled cetuximab pre-dose and 15 mg of cetuximab 800CW can be more sensitive to assess the edge of tumor resection with high safety(Voskuil et al., 2020). These findings give hope to clinical diagnosis and treatment, but the drawbacks are also obvious: intravenous injection may lead to adverse infusion reactions or other harmful side effects and require relatively high doses of fluorescent probes.

Indocyanine Green (ICG) is a small molecular dye with the molecular formula C₄₃H₄₇N₂NaO₆S₂ and a relative molecular mass of 774.96. Near-infrared fluorescence (NIF) imaging of ICG has been reported to detect tumor foci during surgery and improve surgical resection rates. Wang et al. found that when using ICG to detect tumor boundaries of oral cancer, the appropriate intravenous dose range is 0.50 to 1.00 mg/kg, and the dose of 0.75 mg/kg is the best(Wang et al., 2019b). This finding provides a basis for the promotion of ICG-NIF image-guided oral cancer surgery. Urokinase receptor (uPAR) is over expressed in head and neck cancer and is associated with tumor progression and metastasis. Juhl et al. designed and developed a new uPAR-targeted fluorescent probe ICG-Glu-Glu-AE105(Juhl et al., 2016). Through the binding of ICG to the uPAR agonist (AE105), it has a targeted effect on uPAR receptors in vivo. Subsequently, their research team used the probe for image-guided surgery of head and neck tumors of model mice constructed by implanting OSC-19-luc2 cells, human OSCC metastatic cell line, and after 12 h of injecting the probe, the fluorescent signal was clear on the tongues of tumor-bearing mice, demonstrating that ICG-Glu-Glu-AE105 can fluoresce tumors in real time and help guide tumor resection(Christensen A JK, 2017).

3.1.2

3.1.2 Fluorescein dyes

Fluorescein is one of the most widely used fluorescent dyes, mainly in the form of fluorescein amidite (FAM) and fluorescein isothiocyanate (FITC). It has the characteristics of high quantum yield, good water solubility, no precipitation when coupled with protein, poor photostability, strong green fluorescence in alkaline solution and weak fluorescence in acidic condition(Negm et al., 2016; Turnbull et al., 2021).

Abnormal salivary acidification is a carcinogenic biomarker. Baeten et al. used a fluorescent probe WGA-FITC, that is, wheat germ agglutinin (WGA)-FITC, to analyze the fluorescence images of 55 subjects(Baeten et al., 2018). Forty-four individuals with clinically suspicious oral lesions showed 53 suspicious oral lesions after WGA-FITC staining, and subsequent biopsy and histopathology confirmed 15 cancers, 21 dysplasias, and 17 benign lesions. Normal WGA-FITC staining patterns were seen in all but one false-positive result in 11 subjects with normal oral mucosa, indicating a direct correlation between WGA-FITC staining patterns and malignancy. The probe is highly sensitive, strong specificity, and could be used to distinguish malignant or atypical hyperplasia lesions occur in the oral mucosa, and provide rapid chairside detection, thereby promoting the early detection and treatment of oral cancer.

Qaiser and his research group, for the first time, used fluorescein and blue light to detect 100 subjects (42 patients with oral potentially malignant disorders, 40 patients with OSCC and 18 controls), 95 % of oral cancer cases and all cases of heterogeneous hyperplasia showed fluorescence, while only 47.6 % of cases without heterogeneous hyperplasia showed fluorescence. The team believes that topical fluorescein can quickly and sensitively distinguish malignant lesions in patients, suggesting that fluorescein is a simple and cost-effective screening method and may be used in large-scale oral cancer screening in developing countries(Qaiser et al., 2020).

Hussain et al. designed and synthesized the fluorescent labeled neural probe, FAM-NP41, the fluorescent dye carboxylfluorescein is combined with the C-terminal lysine, which is then formed Ac-SHSNTQTLAKAPEHTGK (5,6FAM)-amide for evaluating parotidectomy in a mouse model of parotid carcinoma in situ. The results showed that the probe could identify and preserve facial nerves, which could be used in clinical surgery in the future to reduce the risk of iatrogenic injury(Hussain et al., 2016).

3.1.3

3.1.3 NBD dyes

The compounds containing nitrobenzoxadiazole (NBD) skeleton have excellent properties, such as environmental sensitivity, strong reactivity to amines and biological mercaptan, obvious fluorescence change and small volume(Jiang et al., 2021).

Deng et al prepared a two-color fluorescent probe, a novel nano-gel, containing two fluorophore groups, 4-amino-7-nitro-1,2,3-benzoxadiazole (NBDNH2) and β-cyclodextrin (β-CD-SP)(Deng et al., 2019). The spiropyran in β-CD will quench or restore the fluorescence of NBDNH2 by ultraviolet or visible light, that is, the interconversion between two isomers, the non-fluorescent closed ring (SP) and fluorescent open ring (MC), achieving reversible switch bi-color fluorescence (Fig. 5 A - C). When the ratio of NBDNH2/β-CD-SPH was 1:2 (mol/mol), the fluorescence intensity of nano-gel (NG-N2) was the highest. Then the cell imaging effect of human tongue squamouscell carcinoma cells (Cal-27 cells) was observed. After Cal-27 cells were irradiated with visible light, the NBD part of the probe showed bright green fluorescence. Subsequently, the cells were then exposed to ultraviolet light (60 s) and the green fluorescence diminished, while the MC part of the probe showed red fluorescence. This fluorescent probe has the characteristics of long-term photostability, good cytocompatibility, high sensitivity and clear imaging of cancer cells, which can be widely used for biomedical purposes.

(A) Schematic illustration of novel nanogels via covalently combining NBDNH2 and β-CD-SP, and (B) the photo-switchable dual color behavior of nanogels under UV and visible light irradiation, and (C) photo-switchable dual-color cancer cell imaging of nanogels. Reprinted from Ref. (Deng et al., 2019). Copyright 2019, Elsevier ltd. (D) Chemical structure and (E) optical properties of HA-FA-HEG-OE. Reprinted from Ref. (Ghanim et al., 2021). Copyright 2021, Magda Ghanim et al. Published by Springer Nature.

3.1.4

3.1.4 Naphthalimide dyes

Naphthalimide fluorophores have been widely used in the field of fluorescence sensing because of their high fluorescence quantum yield, moderate fluorescence emission wavelength, large Stokes shift, good light stability and easy structure modification(Fueyo-Gonzalez et al., 2020).

Glutathione (GSH) is an important intracellular regulatory metabolic substance, synthesized in the cytoplasm, distributed in organelles such as mitochondria, nuclei and endoplasmic reticulum, which can help maintain normal immune system function, and has antioxidant effects, integration and detoxification effects, and its abnormal levels can lead to certain cancers. Zhu and his colleagues selected 4-aminonaphthalimide as the fluorophore and a disulfide group as the thiol receptor to design and synthesize a naphthaleimide-like colorimetric fluorescent probe based on internal charge transfer mechanisms. Upon reaction with thiol, the color of the probe solution changes from colorless to green, could be seen more visually. And the probe was used to quantitatively detect the physiological levels of glutathione and related thiols in living HeLa cells(Zhu et al., 2010). Subsequently, Zhou et al. used GSH selective fluorescent probes for the first time to detect living OSCC cells(Zhou et al., 2017). After incubating the probe with Cal-27 cells (human tongue squamous carcinoma cells) for 20 min, it showed an intense blue fluorescence at an excitation wavelength of 340 nm, indicating a high GSH level and a low reactive oxygen species (ROS) level. At the same time, the research team used a variety of fluorescent probes such as DCF-DA (2,7-Dichlorodihydrofluorescein diacetate), annexin V–fluorescein isothiocyanate probe, JC-1 probe, Mitotracker red CM-H₂XRos probe, to observe the oxidative stress and apoptosis induced by exogenous H₂O₂ and EA under the laser confocal fluorescence microscope. The conversion of phosphatidylserine and the mitochondrial membrane potential (DJm) were evaluated. The data demonstrated that GSH selective fluorescent probes can sensitively, real-time and quantitatively detect cell GSH and mtGSH depletion during oxidative stress caused apoptosis of cells, which undoubtedly brings good news to cancer patients undergoing chemotherapy or radiation therapy, and it is very promising to avoid the emergence of drug resistance during treatment.

3.1.5

3.1.5 Rhodamine dyes

Rhodamine dyes belong to basic dyes, whose aqueous solution has larger molar absorptivity and molecular structure has a large rigid plane, so its monomer aqueous solution can produce strong fluorescence(Lavis, 2017).

Mizushima et al found that superficial head and neck squamous cell carcinoma (HNSCC) without a history of radiation therapy can be rapidly detected by spraying glutamyl prosyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probes, which could be cut by dipeptidyl peptidase-IV (DPP-IV)(Mizushima et al., 2018), resulting in turn-on fluorescence. Meantime, they used the probe to image HNSCC cell lines (HSC2, HSC3 and HSC4) and head and neck squamous cell carcinoma cases, respectively. DPP-IV was expressed in HNSCC cells and activated the EP-HMRG fluorescent probe, which was weakly expressed in tumor cases with a history of radiation therapy but not expressed in normal mucosa, resulting in green fluorescence in all three cell lines and lesions without a history of radiotherapy several minutes later.

The cluster of differentiation 44 (CD44) receptor is a marker of cancer stem cells that is highly expressed in oral cancer cells. Ghanim et al. reported the synthesis of a water-soluble fluorescent probe based on these properties, namely HA-FA-HEG-OE (Ghanim et al., 2021)(Fig. 5 D and E). Later, this research group improved the previous research product HA-FA-HEG-OA(Paolino et al., 2019), the proparyngyl group of propargylated ferulate fluorophores (HA-FA-Pg) derivative is bound to the oleic acid (OA) residue by a biocompatible hexa(ethylene glycol) (HEG) spacer, the amide bond connecting the ferulic and oleic portions was replaced by an ester bond, thus forming HA-FA-HEG-OE. The hyaluronic acid (HA) part of the probe can be recognized by CD44 receptor, and the ferulic acid (FA) part of the probe is the fluorescent active group. It showed blue-green fluorescence under ultraviolet light excitation and also provided a method for real-time intraoperative fluorescence imaging of oral cancer.

A novel concept probe, γ-glutamylhydroxymethyl rhodamine green (g-Glu-HMRG) is a fluorescent tracer activated by γ-glutamyl transpeptidase (GGT) that is highly sensitive to the detection of OSCC in vitro(Shimane et al., 2016). The Slooter’s research team demonstrated that the gGlu-HMRG fluorescent probe, which is sensitive and accurate in imaging, can detect the tumor margin after oral cancer surgery, and can direct resection in the case of tumor positivity(Slooter et al., 2018). It has great clinical significance for patients with oral cancer during surgery.

3.1.6

3.1.6 BODIPY dyes

Boron dipyrromethene (BODIPY) dyes has attracted great attention of researchers because of its high absorption coefficient, high fluorescence quantum efficiency, good biocompatibility and stability(Zhang et al., 2021).

Kossatz et al used the fluorescent probe PARPi-FL to confirm that the nuclear enzyme Poly (ADP-ribose) Polymerase 1 (PARP1) is a promising target in OSCC fluorescence imaging. By using this probe to fluorescent image of oral cancer biospecimens, FaDu and Cal-27 tumor cell lines, and normal tissues, they found that PARP1 was sensitively and specifically expressed in oral cancer and produced a strong fluorescent signal, yet there was almost no fluorescence in normal tissues(Kossatz et al., 2016) (Fig. 6). PARPi FL fluorescent probe has good membrane permeability, high affinity, and spatial resolution(Kossatz et al., 2017). After analyzing 60 biological samples, preoperative biopsies from 12 patients and a dataset of 84 patients, the researchers found significant differences in PARP1 expression in tumor and normal tissue regions, and that PARP1 expression could be used for early detection of oral cancer and to mark intraoperative margins. Although in-human clinical trials are ongoing, topical use of PARPi FL mouthwash was found to be more effective. These findings further confirm that PARPi FL can be used as mouthwash to detect oral cancer in patients, with high sensitivity and specificity when distinguishing new biopsy samples of oral tumors and surgical resection edges(Kossatz et al., 2020). In the subsequent phase I clinical study, the results of malignant lesions after gargling with the solution in 12 OSCC patients were consistent with the histopathological results, i.e., the patients showed no adverse effects, the malignant lesions showed significant differences, and the maximum increase in fluorescence signal occurred when the probe was at the highest dose level (1000 nM), which again confirmed the advantages of PARPi-FL fluorescent probe solution in terms of simple operation, fast sensitivity, non-invasiveness, and promising clinical applications(Demetrio de Souza Franca et al., 2021).

(A) PARPi-FL accumulation in OSCC xenografts in mice. (B) Oral cancer delineation after topical application of PARPi-FL. Reprinted from Ref. (Kossatz et al., 2016). Copyright 2016, Susanne Kossatz et al. Published by Springer Nature.

3.1.7

3.1.7 NIR dyes

Near-infrared (NIR) fluorescent probes have the characteristics of less light damage to cells or tissues, strong penetrability and less background interference and so on(Chen et al., 2017). Wang et al. designed and synthesized a new NIR-II probe TQTPA, [4,4′-((6,7-bis(4-(hexyloxy)phenyl)-[1,2,5]thiadiazolo [3,4-g]quinoxaline-4,9-diyl)bis(thiophene-5,2-diyl))bis(N,N-diphenylaniline)], and combined with oral cancer chemotherapy drug cis-dichlorodiammine platinum (CDDP) to prapare nanoparticles (NPs) (HT@CDDP)(Wang et al., 2019c). After inoculating human OSCC cells HSC3 on the tongue mucosa of nude mice to establish an in-situ xenograft model of OSSC, the investigators treated the model with the probe and found that the tumors in the HT@CDDP group of nude mice were slow-growing and small by histological analysis. Thus, the probe has excellent imaging capabilities and anti-tumor efficacy and can be used for fluorescence imaging of tongue cancer and metastatic lymph nodes in combination with chemotherapy and photothermal therapy in the diagnosis and treatment of OSCC.

Gu et al. reported a fluorescent probe called terbium-doped hydroxyapatite (HATb) nanoparticles for precision chemotherapy guided by NIR fluorescence imaging(Gu et al., 2021). The probe contains three parts, the first part is hydroxyapatite nanoparticles used as a drug carrier because of its good performance, the second part is polydopamine used as a near-infrared photothermal agent with high photothermal conversion efficiency, which is easy to bind to the third part, i.e., the anti-cancer drug doxorubicin, thereby promoting the drug release in near-infrared radiation (Fig. 7 A). This probe is highly innovative not only non-invasive for diagnosis, but also in the fluorescent image-guided treatment of cancer, possessing a broad clinical application prospect in the combination therapy of OSCC patients.

(A)Schematic illustration of the fabrication of the HATb–PDA–DOX nanotheranostic agent for imaging-guided synergistic chemophotothermal OSCC therapy. Reprinted from Ref. (Gu et al., 2021). Copyright 2021, The Royal Society of Chemistry. (B) The synthesis route of IFP-O2. (C) The fluorescence properties of IFP-O2 (5 μM) were determined under simulated physiological conditions (10 mM PBS buffer, pH 7.4). Reprinted from Ref. (Jiao et al., 2021). Copyright 2020, Elsevier B.V. (D) Schematic representation of synthesis of NCQD-HCS. (E) FTIR spectrum of NCQD-HCS and NCQD-HCS-COOH, high-resolution scan of C 1s、 N 1s and O 1s region. (F) Confocal images of FaDu cells after being treated with 50 μg mL-1 NCQD-HCS-800 nanoparticles. Reprinted from Ref. (Das et al., 2019). Copyright 2019, American Chemical Society.

Jiao’s research team designed and synthesized a near-infrared (NIR) fluorescent probe IFP-O_2, to monitor O₂^•- concentrations in the mitochondria of Cal-27 cells of oral cancer and analyze ROS change during the pathological process (Fig. 7 B and C). The results showed that IFP-O₂ had good cell membrane permeability, low detection limit, and cationic indole groups as were able to improve the mitochondria targeting ability(Jiao et al., 2021). Chen Y and his colleagues combined 4-hydroxy-3-nitrobenzaldehyde and active 2-(3,5,5-trimethylcyclohex-2enylidene)malononitrile to construct a novel nitrofluoroprobe, HNT-NTR(Chen et al., 2022), which can specifically and sensitively detect the NTR level of human oral squamous cell carcinoma-2 (HSC2) cell lines and Cal-27 cell lines in 2D monolayer and 3D spherical states, and even solid tumors in nude mouse tumor models, and reflect the hypoxia state of tumors. It can be used to distinguish tumor cells from normal cells. In addition, by observing the near-infrared fluorescence intensity, it is found that the probe has stronger fluorescence intensity in detecting HSC2 cell line than Cal-27 cell line, which confirms that HSC2 cell line has higher invasiveness than Cal-27 cell line and provides a new strategy for clinical pathological diagnosis.

3.1.8

3.1.8 Quantum dot

With excellent optical properties such as large Stokes shift, long fluorescence time, broad excitation spectrum and small spatial potential resistance, quantum dots (QDs) have broad application prospects in biochemistry, molecular biology, drug screening and other fields(Lu et al., 2019).

Das’s research team reported a novel fluorescent nanoprobe called NCQD-HCS with fluorescent imaging properties and photothermal therapy, which showed significant thermal ablation effects on oral cancer cells when exposed to a 980 nm NIR laser (Das et al., 2019)(Fig. 7 D - F). This probe is prepared by carbonization of polyaniline-co-polypyrrole polymer as raw materials, laying the foundation for further exploration of photochemical therapy tumors.

Carbon dots (CDs) are a kind of fluorescent nanomaterials that have emerged in recent years(Devi et al., 2019). As the latest member of the “quantum dot family”, carbon dots have attracted great interest because of their small size, strong photostability and high biocompatibility. Sri et al. designed and synthesized a new type of amphoteric CDs, which were microwaved pyrolysis of citric acid and l-cysteine to synthesize CDs with good biocompatibility and high quantum yield(Sri et al., 2018). The probe can be excited in the ultraviolet region (360 nm) and for the first time used in fluorescent imaging of two oral cancer cell lines, FaDu (human pharyngeal squamous carcinoma cells) and Cal-27 (human tongue squamous carcinoma cells), and it was found that CDs can be rapidly entered or excreted in the cytoplasm, providing a sensitive and stable early monitoring method.

Peng and his research team mixed nitric acid (NA) and formic acid (FA) with ethylenediamine (ED), respectively, and a new type of nanofluorescent dye CDs could be prepared by microwave method(Peng et al., 2019). Depending on the raw material, the excitation wavelength and the emission wavelength are also different. The excitation and emission wavelengths of fluorescent probes (n-CDs) prepared with NA and ED as raw materials are 430 nm and 500 nm, respectively, and the fluorescent probes (f-CDs) prepared with FA and ED as raw materials are 480 nm and 570 nm, respectively. Observation after staining oral tissue sections showed that CDs staining was highly selective for cell nuclei, and the staining effect was superior to the conventional hematoxylin-eosin (H&E) staining. It was observed that the squamous cells in pathological tissues showed invasive growth, and keratin beads formed in the center of cancer nests. This probe is water-soluble, easier to operate, has strong photoluminescence performance, is clearer under fluorescence microscopy, and is more sensitive for oral cancer tissue biopsy. Moreover, the preparation method is highly feasible, safe and economical.

3.2

3.2 Fluorescent probes for dental hard tissue diseases

Dental caries is one of the highest-occurring dental hard tissue diseases. Different treatment methods will be adopted according to the different degree of dental caries. Early enamel caries can be treated non-surgically, and once tissue defects appear, restorative treatment should be adopted. Early prevention, early diagnosis and early treatment of dental caries are the key issues for dentists. Caries will not only lead to inflammation of the root tip and tooth loss, but also make it difficult for patients to chew food and aggravate the burden of gastrointestinal tract. Feng et al. designed and synthesized a naphthaleimide ratio fluorescent probe PENA, which can be used for real-time detection of deformed streptoglobulin glucose transferase (GTF). GTF is the main caries-causing factor of streptococcus pyogenes, which can use sucrose to synthesize extracellular glucan and play a key role in the process of dental caries development(Feng et al., 2019a). The fluorescent probe N-phenethyl-4-hydroxy-1,8-naphthalinmide (PENA) is guided by GTFs to form 4-O-β-d-glucopyranosyl-N-phenethyl-1,8-naphthalimide (PENA-G) in the presence of uridine-diphosphate glucose (UDPG). PENA and PENA-G fluorescent probes can show strong fluorescence at 560 and 440 nm, respectively, enabling efficient detection of virulence factors and fluorescence imaging of pathogenic bacteria associated with caries, which contribute to the prevention, diagnosis and treatment of caries. Oral bacteria adhering to the tooth surface can form oral biofilm and metabolize carbohydrate food to produce acid, and lower the pH value of the tooth surface, resulting in enamel demineralization and eventually tooth decay (Fig. 8 A - B). Hollmann's research group described a ratiometric fluorescence pH-sensitive nanosensor for changes in oral biofilm(Hollmann et al., 2021). The fluorescent probe used a pH-insensitive fluorophore 5(6)-carboxytetramethylrhodamine (TAMRA) and two pH-sensitive fluorophores of Oregon green (OG) and 5(6)-carboxylfluorescein (FAM) encapsulated in nanoparticles of polyacrylamide, which can monitor pH changes in oral biofilms in real time, providing a strategy for slowing the progression of caries.

(A) Glucosylation of PENA by GTFs in the presence of UDPG (300 μM), and the interaction between PENA and GTFs molecule. （B）Fluorescence images of various bacteria in the presence of PENA (50 μM). Reprinted from Ref. (Feng et al., 2019a). Copyright 2019, The Royal Society of Chemistry. (C and D): Schematic of the methodology of tracking the iron-associated proteome in live P. gingivalis. Reprinted from Ref. (Jiang et al., 2018). Copyright 2022, Oxford University Press.

Non-carious diseases in the tooth hard tissues are also common, such as abnormal tooth development, tooth trauma and dentin sensitivity. Nouhzadeh et al. developed tetramethylpyridine porphyrin (TMPyP) fluorescent probes to detect early damage lesions of tooth enamel of 60 tooth samples. The diagnostic results of TMPyP fluorescent dye are not only significantly correlated with the gold standard, but also can measure in real time and have high sensitivity, providing a powerful auxiliary means for future clinical practice(NouhzadehMalekshah et al., 2019). Földes et al. used fura-2 and BCECF fluorescent probes to detect Ca²⁺ and pH changes in enamel cell-derived HAT-7 cells by microfluorescence, thereby studying the relevant mechanisms of tooth enamel defect formation(Foldes et al., 2021).

As a class of dental marerial with properties of aesthetic, easy to operate, and high hardness, resin is usually used for restoring the tooth defects. Bim et al. added Rhodamine B (RB) to the dental adhesive resin, determined the minimum range of 0.1–0.02 mg/ml of fluorescent dye RB concentration, and obtained acceptable dentin adhesive interface images. The researchers found that the use of fluorescent probes in resin-based materials improved resin properties and provided a basis for the later preparation of viscous resin samples containing low concentration(Bim Junior et al., 2017). Generali's research group, for the first time, used two fluorescent probes, rhodamine B and calcein, to study root canal blockers. The authors labeled the blocking agent with rhodamine B and added calcein fluorescent dye to the water, and then measured the permeability of the blocking agent to the dentin tubules, thus offering a double staining technique for filtration test of dental materials(Generali et al., 2017).

3.3

3.3 Fluorescent probes for oral soft tissue diseases

Oral soft tissue diseases are commonly known as periodontal-related diseases, whose symptoms including red and swollen gums, bleeding gums, gum recession, loose and displaced teeth, periodontal pocket formation, and reduced alveolar bone height. The occurrence of diseases is closely related to the accumulation of oral plaque, so effective removal of plaque is of great significance to the prevention and treatment of oral soft tissue diseases. Bacteria and their products in the plaque are indispensable starting factors for causing periodontal disease, so understanding its pathogenesis is of great significance for the prevention and treatment of periodontal disease(Yamamoto and Aizawa, 2021).

Periodontitis is related to hydrogen sulfide (H₂S), an endogenous gas transmitter, which is difficult to detect because of its low concentration. Lu et al synthesized a novel fluorescent probe capable of detecting H₂S in vitro, consisting of 1,8-naphthylimide as a fluorophore and azide moiety as the identification site(Lu et al., 2021). The probe itself is almost no fluorescence, and hardly affects cell viability at a concentration of 10 μM. However, it can respond H₂S quickly with high sensitivity and selectivity, and can be used to diagnose bone inflammatory diseases, which promote the study of the pathogenesis of periodontitis.

In the non-attached plaque located below the gingival margin, the dominant bacteria are Gram-negative bacteria, such as Porphyromonas gingivalis, Tannerella forsythia, and Fusobacterium nucleatum. Wang et al. designed and developed a PxB fluorescent probe PxB-Cy3, which is based on the specificity of the antibiotic polymyxin B (PxB) and can be used to label Gram-negative bacteria directly(Wang and Chen, 2018). PxB contains five primary amine groups, which can react with fluorophore NHS separately, resulting in product confusion and affect the labeling results of bacteria. Subsequently, his research group reported a new Gram-negative specific fluorescent probe TriA(Wang et al., 2019a), a narrow-spectrum antibiotic thirteen peptide A1 based on solid phase peptide synthesis. Compared with PxB containing cyclic peptides, the chemical structure of TriA is more explicit, with a single linear structure and higher marker selectivity. In addition to label Gram-negative bacteria, it also could be used to study the synthesis of peptidoglycans.

Jiang’s research team designed and developed an iron fluorescent probe, Fe-Tracer, which can be used to specifically identify and track iron-related proteins in Porphyromonas gingivalis (ATCC 33277)(Jiang et al., 2018). The probe was synthesized by conjugating the aniline triacetic acid (NTA) fraction with coumarin fluorophore.When the aromatic group was light-activated, the iron-related protein was labeled. It was reported to be capable of identifying 17 iron-related proteins in Porphyrin monastic bacteria gingivalis, providing a solid foundation for studying iron homeostasis in pathogens (Fig. 8 C and D).

In addition to periodontal tissues, oral soft tissues also include the tongue, oral mucosa and glands, etc. Oral candidiasis is the most common oral fungal infection in humans. Yao's research group evaluated the efficacy of carbon fluorescent white (CFW) fluorescent probe for the diagnosis of oral candidiasis. They analyzed 228 specimens using fungal culture and Iodate Schiff reagent staining as the gold standard for diagnosis. The results showed that the fluorescent antibody of the probe can be specifically combined with the dextran and the characteristic chitinous layer of the oral candida cell wall, indicating that it is a relatively safe, rapid and reliable diagnostic method(Yao et al., 2019). Pathak et al. designed and synthesized a fluorescent probe, nitrogen and sulfur co-doped carbon dots (NSCDs)(Pathak et al., 2019), which is prepared by microwave-assisted hydrothermal synthesis using thiourea and ethylenediamine triacetate (TAE) as raw materials. NSCDs showed high quantum yield and superior fluorescence signal and could be applied to the study of bacteria and human oral epithelial cells (HBEC), providing a better selection choice for medical diagnosis. However, under the maximum excitation wavelength of 340 nm UV light, the fluorescent probe is susceptible to interference from biological materials, so how to weaken or even shield interference is still need in the future. Montag et al. described a case report, in which fluorescein can be used to improve the sensitivity of parotid duct injury detection and reduce the additional damage associated with surgical exploration(Montag et al., 2016). This fluorescent dyes-mediated new technique is easy to perform and reduces costs, deserving further study and dissemination.

3.4

3.4 Fluorescent probes for oral-related ion diseases

For the negative or positive ions involved in oral-related ion diseases, choosing an appropriate dose is beneficial to the human body, otherwise it is harmful. It is difficult to monitor the ion level effectively by using traditional detection methods such as serum and urine, however, the fluorescent probe has been proved to be a good choice.

Fluoride ions are widely distributed in nature and are mainly found in bones and teeth in the human body. Maintaining a certain low fluoride level in the oral cavity can effectively prevent and treat caries. Excessive intake of fluoride can cause fluorosis, leading to diseases such as dental fluorosis(Yuan et al., 2020), skeletal fluorosis(Srivastava and Flora, 2020), loss of mental capacity(Yu et al., 2021), and thyroid disorders(Wang et al., 2020). At the cellular level, high levels of fluoride can cause mitochondria inactivation(Zhao et al., 2019). Therefore, there is an urgent need to find a way to accurately detect fluoride ions in mitochondria. Zhou et al. prepared a novel mitochondrial targeted fluorescent probe (Mito FV) based on intramolecular charge transfer, which was synthesized by benzene ring-linked imidazole (donor, D) and hemicyanine (receptor, A), and used for monitoring fluoride ion levels by intracellular fluorescence imaging (Fig. 9 A). The results found that the probe has strong specificity, good stability, high sensitivity, and good mitochondria targeting(Zhou K et al., 2018).

(A) Synthesis route of probe Mito-FV (left). Proposed response mechanism of Mito-FV to F− (right). Reprinted from Ref. (Zhou K et al., 2018). Copyright 2018 Published by Elsevier B.V. (B) Synthesis of R1 and R2. Reprinted from Ref. (Lan et al., 2014). Copyright 2014, The Royal Society of Chemistry. (C) Schematic illustration of MFBP constructing process and sensing principle of MFBP-based one-step quantification of exosomes. Reprinted from Ref. (Wu et al., 2021). Copyright 2020, Elsevier B.V.

Effectively inhibiting Streptococcus mutans, Sn²⁺ is often added to toothpaste and has the effect of preventing caries and reducing plaque formation(Zero et al., 2018). Lan et al. designed and synthesized two Sn²⁺ rhodamine B derivative fluorescent probes R1 and R2 by linking different amide moiety of N, N-bis(2-hydroxyethyl)ethylenediamine (R1) and tert-butyl carbazate group (R2), respectively(Lan et al., 2014) (Fig. 9 B). This probe has high sensitivity and high selectivity to detect Sn²⁺ in Streptococcus mutans, which points out the direction for studying the bacteriostatic mechanism of Sn²⁺ and the prevention and treatment of oral diseases.

Mercury (Hg), the only liquid metal at room temperature, atmospheric pressure, can form a highly toxic mercury vapor and react with many metals to form alloys, such as silver amalgam, which once used as the main material of stomatology to fill caries. Nagy's research group designed and synthesized a novel amino-isocyanonaphthalene (ICAN)-based rationive fluorescent probe for the detection of Hg²⁺. The ICAN fluorescent probe is prepared by a one-step reaction of 1,5-diaminonaphthalene. When the isonitrile fraction is reduced to an amine by Hg²⁺, a large Stokes shift occurs, resulting in fluorescence appears(Nagy et al., 2019). This probe has high sensitivity, low molecular weight, strong interference resistance, non-toxicity and easy preparation, which is not only effective in water detection, but also practical in detecting newly prepared dental amalgam.

3.5

3.5 Fluorescent probes for forensic dentistry

Forensic dentistry is a subdiscipline of forensic anthropology. Traditional forensic dentistry often uses general measurement, observation and laboratory methods, while modern forensic dentistry also combines radiology, infrared spectroscopy and other methods. Teeth in the mouth are resistant to almost all chemical, biological and physical degradation or destruction, so they are of great significance on the way to forensic medicine(Sehrawat and Singh, 2020). Sex identification, as one of the important contents of forensic science, is often identified by observing the presence of chromosomal or Barr body in somatic cells. Khanna used aridinium orange fluorescent probes and other dyes to analyze 90 pulp tissue samples, and found that the dental pulp samples from females were positive for Barr body, whereas the dental pulp samples from males were almost non-positive for Barr body, suggesting that Barr body is specific to female somatic cells and the use of fluorescent probe on dental pulp samples to identify sex is effective and reliable(Hong B, 2001; KS, 2015).

In addition to teeth, there are oral fluids such as saliva secreted by the parotid, submandibular and sublingual glands that can be used for screening and identification. Saliva identification is an increasingly useful forensic test in crime investigations. Li’s research team synthesized a fluorescent nanoprobe SiC@BSANPs with a maximum of 320/410 nm, which used to detect bacteria in saliva instantly through fluorescence imaging based on its specific binding with the antimicrobial peptide GH12 of Streptococcus salivarius. The data demonstrated that the probe has good stability and high sensitivity and has broad prospects in forensics(Li et al., 2019).

Chantada-Vázquez and his colleague prepared a Mn-doped ZnS quantum dots (QDs) fluorescent probe, which is modified with cocaine and polyethylene glycol (PEG) on the surface- of ZnS quantum dots. Molecularly imprinted polymers (MIPs) was selected as the fluorescence sensing materials, which can be used to assess cocaine and metabolites in complex samples such as oral fluids and serums, and screen for cocaine abuse(Chantada-Vazquez et al., 2018). Wu et al. have developed a novel magnetic and fluorescent bio-probes (MFBPs), which are prepared by integrating aptamers, magnetic microspheres (MMs), DNA concatamers and QDs. This probe can be used for one-step quantitative detection of salivary exosomes (Fig. 9 C). It has the advantages of no prelabeling, short time consuming, high sensitivity, low detection limit and strong anti-interference, which is of great significance for the diagnosis of exosomes related diseases(Wu et al., 2021).

4 Conclusion & perspective

Fluorescent probes have been widely used in biochemistry, environmental science, medicine and other fields due to their high sensitivity, good selectivity, real-time detection, rapid fluorescence imaging, small dosage of reagents required, and economic safety. In recent years, fluorescent probes have been gradually used to study the genesis and development of soft and hard tissues in teeth and the surrounding oral and maxillofacial regions, as well as the etiology, pathogenesis, diagnosis and treatment of oral diseases. At the same time, it does not need pretreatment, is not easy to be affected by external electromagnetic fields, and can emit light from a long distance, which makes it easier for researchers and medical professionals in the field of stomatology to use fluorescent probes. Oral-related fluorescent probes are based on spectrochemistry and optical waveguide and measurement technology. We can use molecular measuring devices for fluorescence signals to transform the pathological changes or biochemical processes of oral cancer cells and oral tissues into easily measurable signals or intuitive information, so that researchers can have a deeper understanding of the occurrence and development of oral diseases. Although some progress has been made in fluorescent probes in stomatology, there are still many shortcomings that need to be improved. Among them, oral-related fluorescent probes for the study of oral and maxillofacial tumors are more common, involving fluorescence imaging at the cellular level (organelle dyes, reactive oxygen species, reactive nitrogen species, cell viability, etc.), detection of biochemical processes and labeling of biomolecules such as proteins, nucleic acids, biofilms, etc., focusing more on early detection, diagnosis and intraoperative imaging of oral cancer cells and diseased tissues, while fluorescent probes related to oral and maxillofacial tumors still need further development. It is the direction of future efforts to fully combine fluorescent probes with photothermal therapy, photodynamic therapy, sonodynamic therapy and oral cancer drug therapy by making full use of light effect(Broadwater et al., 2021; Yang et al., 2022; Zhang et al., 2022 ), heat effect and pressure effect, and develop fluorescent probes that are selective and targeted, less painful and easy to be accepted by patients.

In addition, oral-related fluorescent probes are mostly used for experimental research in vitro, but there are still some problems to be solved when used in vivo: ① Tissue autofluorescence generated by in situ excitation should be avoided as much as possible(Jiang and Pu, 2021), and fluorescent probes with low background interference and high signal-to-noise ratio should be developed. ② When conducting fluorescence experiments on deep oral tissues, the quenching of fluorescence due to pH, solvent, temperature and photolysis should be fully considered to improve the stability of fluorescent probes. ③ When developing fluorescent probes with high oral histocompatibility, the toxicity of the probes should be reduced as much as possible(Wang et al., 2013), which not only affects the activity of oral cells, but also interferes with the normal physiological process to a certain extent. Therefore, more fluorescent probes with excellent performance should be developed to provide more choices for the application of stomatology, so as to obtain better fluorescence effect. In this paper, the design strategy, fluorescence mechanism and application progress of fluorescent probes in the field of stomatology are reviewed, hoping to bring new ideas for the diagnosis and treatment of oral diseases and providing some references for the development and design of fluorescent probes with low background interference, strong tissue penetration and non-toxicity in the future.

Author contributions

Shuai Tang designed the study, searched literature, analyzed data and wrote the article. Xiguo Wu, Tong Yang and Shan Peng searched literature and analyzed data. Gang Ding designed the study, wrote the article and supervised the study.

Acknowledgement

We express our sincere gratitude to Dr. Jin Zhou, School of Pharmacy, Weifang Medical University, for his suggestions, and Dr. Xiangjun Liu, Institure of Chemistry, Chinese Academy of Sciences, for his critical reading of this article. This work was supported by grants from the Natural Science Foundation of Shandong Province, China (No. ZR2021MH051 to Gang Ding), the National Natural Science Foundation of China, China (No.81570945 to Gang Ding), the Postgraduate Education Quality Improvement Plan of Shandong Province, China (No. SDYAL21150 to Gang Ding), and 2021 Youth Innovation Talent Introduction and Education Program of Shandong Province Universities (The innovative team for molecular epidemiology of oral cancer based on multiomics), China. Figure 1 was created by using Figdraw (www.figdraw.com).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Introduction

Design strategies for oral-related fluorescent probes

Application of fluorescent probes in stomatology

Fluorescent probes for oral and maxillofacial tumors
Fluorescent probes for dental hard tissue diseases
Fluorescent probes for oral soft tissue diseases
Fluorescent probes for oral-related ion diseases
Fluorescent probes for forensic dentistry

Conclusion & perspective

Author contributions

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Fluorescent probes in stomatology

Abstract

Keywords

Stomatology

Fluorescent probe

Detection

Oral tumor

Fluorescence imaging

1 Introduction

2 Design strategies for oral-related fluorescent probes

3 Application of fluorescent probes in stomatology

3.1 Fluorescent probes for oral and maxillofacial tumors

3.1.1 Cyanine dyes

3.1.2 Fluorescein dyes

3.1.3 NBD dyes

3.1.4 Naphthalimide dyes

3.1.5 Rhodamine dyes

3.1.6 BODIPY dyes

3.1.7 NIR dyes

3.1.8 Quantum dot

3.2 Fluorescent probes for dental hard tissue diseases

3.3 Fluorescent probes for oral soft tissue diseases

3.4 Fluorescent probes for oral-related ion diseases

3.5 Fluorescent probes for forensic dentistry

4 Conclusion & perspective

Author contributions

Acknowledgement

Declaration of Competing Interest

References

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