New High-Performance Fluorescent Dye Scaffolds: Applications for Bioimaging and Biosensing

Abstract

Fluorescence imaging in the shortwave infrared region (SWIR, 850–2500 nm) window has become an indispensable tool in biomedical research because it has weaker absorption, less light scattering, and less background fluorescence in this window. As we know, the design and synthesis of fluorescent dyes and fluorescent probes are the cores of fluorescence imaging and biosensing. Thus, their photophysical mechanisms exploring and bioanalytical applications are multidisciplinary and cutting-edge research topics. In this regard, we have been working on high-performance fluorescent dyes and fluorescent probes for years. In short, we have developed a series of bright, stable, aggregation-resistant, SWIR fluorescent dyes ECXs, based on a carbon-bridged spiro ring strategy. We also developed a series of high-performance SWIR fluorescent dyes CXs and Chrodols, which combine the structural advantages of cyanine and xanthenoid dyes. Based on these new SWIR scaffolds, we further constructed some activatable SWIR fluorescent probes with OFF-ON or ratiometric properties for biosensing in vivo. Therefore, the main line of our work is to gain an in-depth understanding of the photophysical mechanisms of fluorescent dyes, to create high-performance luminescent dyes, and to further develop fluorescent probes for bioimaging and biosensing.

1 Introduction

2 ECX Dyes Based on a Carbon-Bridged Spiro Ring Strategy

3 Fluorescent Dyes and Fluorescent probes Combining the Structures of Cyanine and Xanthenoid Dyes

3.1 CX Series Dyes

3.2 A Functionalized Modified CX probe NRh

3.3 CX-like Dyes with a Secondary Amino Py-2

3.4 Chrodol Series Dyes

4 Conclusion and Future Prospects

Key words

fluorescence imaging - short-wave infrared - new scaffolds - fluorescent dyes - fluorescent probes

Biographical Sketches

Zuhai Lei received his PhD (2017) from East China University of Science & Technology (ECUST) followed by two years of postdoctoral experience at Fudan University. He is currently a tenure-track PI at Fudan University, where his research interests focus on the design and synthesis of NIR-I/II fluorescent dyes for bioimaging and biosensing.

Junfeng Cheng was born in 1998 in Sichuan Province, China. He obtained his Bachelor’s degree at Fudan University, Shanghai, China in 2022. He is now studying for a master’s degree in the group of Prof. Zuhai Lei at Fudan University, focusing on the design and synthesis of NIR-I/II fluorescent probes for bioimaging and biosensing.

1

Introduction

With the advantages of high spatial and temporal resolution, no radiation, real-time detection, non-invasiveness, and low cost,[1] [2] fluorescence imaging has become an indispensable tool in biomedical research. Current research focus on how to see deeper and more clearly by fluorescence imaging, which depends heavily on the brightness of fluorescent dyes, the tissue penetration ability of the excitation and emission light, and the background fluorescence.[3] However, tissue penetration depth and background fluorescence interference remain challenges for bio-fluorescence imaging and sensing. Light experiences less absorption and scattering by biological tissues at longer wavelengths in the shortwave infrared region (850–2500 nm), and there is less background fluorescence, which makes this optical window a promising choice for biomedical studies in vivo.[4–6] Therefore, the design and synthesis of fluorescent dyes and fluorescent probes are the cores of fluorescent imaging and sensing. Their photophysical mechanisms and bioanalytical applications are multidisciplinary and cutting-edge research topics.[7] [8]

We have been working on high-performance fluorescent dyes and fluorescent probes for years. To address the problems of penetration depth and background interference in fluorescent imaging in vivo, we have done systematic work on chemical and biological sensing. For example, we created several fluorescent dyes with exceptional brightness and stability for biological imaging. We also proposed a ‘covalent assembly’ probe design strategy[9] with zero background interference, and so on.

This account focuses on our important work for new, high-performance fluorescent dye scaffolds published in high-quality papers, including bright, stable, aggregation-resistant, shortwave infrared fluorescent dyes ECXs based on a carbon-bridged spiro ring strategy, and a series of high-performance shortwave infrared fluorescent dyes and fluorescent probes (CXs, NRh, Py-2, and Chrodols) combining the structural advantages of cyanine and xanthenoid dyes. In general, our work has focused on gaining a deeper understanding of the photophysical mechanisms of fluorescent dyes, to create high-performance luminescent dyes, and further to develop fluorescent probes for bioimaging and biosensing.

2

ECX Dyes Based on a Carbon-Bridged Spiro Ring Strategy

When propagating through the biological tissue, the light will be absorbed and scattered, resulting in light loss, which is the main reason for the limitation of tissue penetration depth in fluorescent imaging. Compared to visible light, biological tissues have weaker absorption of shortwave infrared light, as well as reduced scattering. Therefore, redshifted wavelengths of fluorescent dyes can enable deep-tissue fluorescent imaging and sensing. Typically, an effective strategy is to increase conjugation, but this could decrease the fluorescence quantum yield, brightness, stability, and dispersion of dyes,[10] which are key challenges in the development of high-performance shortwave infrared fluorescent dyes.

Fluorophores with planar structures can easily aggregate, leading to fluorescence quenching.[11] [12] The introduction of spatially site-resistant groups to the molecule can prevent it from aggregating, thereby improving its dispersibility. But at the same time, the introduction of site-resistant groups also brings a certain degree of flexibility. The larger the steric hindrance group is, the more difficult it is to introduce. In nature, things with plane structures are easy to pile up, but those with irregular three-dimensional structures are not easy to stack. Inspired by this, we originally introduced the spiral ring structure to realize the stereochemistry of dyes, while ensuring the push-pull electron conjugation system of dye molecules, which can greatly improve the comprehensive performance of fluorescent dyes. Based on this, we designed a series of high-performance shortwave infrared fluorescent dyes (ECXs).[13]

ECXs were conveniently synthesized in six linear steps. Then, different chemical handles or functional groups could be readily installed onto the skeleton of ECXs through a post-synthetic procedure (Figure [1]).[13] Benzaldehyde 2 was obtained through Vilsmeier–Haack formylation of 3-bromojulolidine (1), and then condensed with ethylene glycol to yield 3 in 75%. The latter was lithiated with nBuLi at –78 °C in THF to furnish benzaldehyde 4 in 97% yield. The dibenzylideneacetone 6 was prepared in 95% yield through aldol condensation of 4 with 1,4-cyclohexanedione monoethylene acetal (5). Compound 8 was obtained by reacting 6 with lithiated diphenyl ether (7) followed by an acid-promoted six-step cascade, in an overall 67% yield. Alternatively, compound 6 could be treated with MeSO₃H to give pentacenedione 9. Subsequent addition of mono-lithiated diphenyl ether (7) to 9 occurred regioselectively to generate 10, acid-catalyzed cyclization of which also led to 8. Finally, reactions between 8 and various Grignard reagents (11a–f) afforded ECXa–f in a good yield, ranging from 61 to 72%. In addition, ECXg, bearing a readily derivatized benzylic bromide moiety, was prepared in 84% yield by reacting ECXe with BBr₃. The azido-substituted analog ECXh was obtained in 73% yield by stirring ECXg with sodium azide in DMF at room temperature. Furthermore, ECXf was easily sulfonated in concentrated H₂SO₄ at 0 °C in 64% yield to give ECXi. ECXj, with three sulfonyl chloride groups, was also synthesized analogously in 68% yield. In a word, the benzyl bromide in ECXg, the azide in ECXh, and the sulfonyl chloride in ECXj, together offer diverse opportunities for further functionalization of the ECX core.[13]

Figure 1 Design, synthesis, and derivatization of ECXs[13]

The diphenyl ether structure in ECX is perpendicular to the push-pull electron system of the dye and plays a very important role in the performance enhancement of the molecule, which is the core of ECX. To be specific, the bridging atom of the spiro ring is sp³ hybridized, and the diphenyl ether is perpendicular to the parent nucleus of ECX through the spiro ring form, which increases the rigidity and fluorescence quantum yield of the dye. Besides, the diphenyl ether is a site-blocking group that can effectively shield the nucleus of the dye from nucleophilic reagents, which greatly improves the stability and dispersion of ECX, avoiding the quenching and aggregation of the dye. Finally, the oxygen atom of diphenyl ether is a readily modified reactive site, which increases the modifiability of the dye and facilitates the practical application of ECX.

Figure 2 Optical properties and cellular level, in vivo imaging applications of ECXs[13]

The maximum absorption and emission wavelengths of these fluorescent dyes are around 880nm and 920nm, respectively. Furthermore, they exhibit very good chemical stability, photostability, and dispersion. With an absolute fluorescence quantum yield of 13.3%, they are still one of the brightest shortwave infrared fluorescent dyes reported to date, showing superior imaging performance in cellular and in vivo biological imaging studies (Figure [2]).

3

Fluorescent Dyes and Fluorescent Probes Combining the Structures of Cyanine and Xanthenoid Dyes

The maximum absorption wavelength of ECX series dyes obtained from our previous work is around 880 nm, so we hope that we can further redshift the wavelength of dyes to meet the requirements of practical applications such as in vivo multicolor imaging and biosensing. For the structural analysis, while the conjugation is simply extended, the dye will have too many aromatic rings, leading to poor solubility and instability. Therefore, new strategies need to be further developed to construct fluorescent dyes with longer wavelengths, greater brightness, higher stability, and biocompatibility.

Notably, polymethyl cyanine dyes have become an indispensable class of fluorescent dyes for chemical and biological research due to their high molar absorbance coefficients and flexible wavelength tunability.[14] [15] [16] However, the long flexible conjugated chains also cause some problems, including insufficient fluorescence brightness, poor molecular stability, and unsatisfactory biocompatibility.[17] Nevertheless, xanthenoid dyes usually have high brightness and excellent stability,[18] with maximum emission wavelengths redshifted to the near-infrared window by using some structural modification strategies, such as π-conjugation extension, replacement of the oxygen atom with other atoms, and cyclization,[19] although the wavelengths often remain below 800 nm.[20]

Figure 3 A series of high-performance shortwave infrared fluorescent dyes and fluorescent probes that combine the structural advantages of cyanine and xanthenoid dyes: CX, Chrodol, NRh, Py-2[21] [22] [23] [24]

Based on these observations, we have designed a series of shortwave infrared fluorescent dyes CX[21] and Chrodol,[22] with adjustable wavelengths, by creatively combining the respective advantages of cyanine and xanthenoid dyes. We further constructed two fluorescent probes (NRh[23] and Py-2[24]), based on the structure of CX dyes, which can be used to achieve superior biologically specific sensing and imaging (Figure [3]). Importantly, CX and Chrodol series dyes are expected to become classic biological shortwave infrared fluorescent dyes (Table [1]). Firstly, they are simple to synthesize and produce on a large scale, and it is easy to modify their structures so that the fluorescence can be adjusted. Secondly, they have large extinction coefficients and high brightness. In addition, they are stable both in vitro and in vivo, which is convenient for practical application, transportation, and preservation.

Table 1 Photophysical Properties of CX-3 in CHCl₃, NRhH⁺ Micelle in H₂O, Chrodol-3 in Methanol, and Py-2 in DCM

	CX-3	NRhH+	Chrodol-3	Py-2
λ abs (nm)	1089	986	870	965
log ε	5.02 ± 0.01	–	4.60	5.06
λ em (nm)	1140	1026	902	1010
Φ (%)	0.091 ± 0.014	–	0.34	0.47

3.1

CX Series Dyes

Small-molecule fluorescent dyes are powerful tools that enable fluorescent imaging and sensing technologies to play an important role in biomedical research. NIR-II (1000–1700 nm) fluorescence imaging technology has brought a major technological change to the fluorescent imaging field. Compared to conventional techniques with short wavelengths (400–700nm), NIR-II fluorescence significantly reduces scattering and autofluorescence interference in biological tissues, thus revolutionizing the resolution and depth of imaging.[25] However, an important bottleneck limiting the further development of this technology is the lack of suitable and biocompatible small-molecule fluorescent dyes. Existing NIR-II fluorescent dyes are generally unstable, especially in aqueous solutions, and their fluorescence also lacks suitable ways to be modulated, limiting the application in biosensing analysis.[26]

To address these issues, we have developed a series of wavelength-tunable and highly stable NIR-II fluorescent dyes (CXs), based on the structural rigidity of xanthenoid dyes and the wavelength tunability of cyanine dyes. CXs were synthesized via a one-step condensation reaction between compound 1 and electrophile 2, 3, or 4 in good yields, ranging from 51 to 61% (Figure [4]).[21] Their structures are symmetrical. The conjugated structure of xanthene at the end is not fully aromatized, and both ends are connected by a conjugated chain for available wavelength adjustment. The incompletely aromatized structure also ensures good solubility of the dye.

Figure 4 (A) The design and synthesis, (B) optical properties, and (C) applications for non-invasive drug-induced liver injury detection of CX dyes[21]

Compared to traditional cyanine dyes, CXs have shorter flexible chains, longer wavelengths (880–1100 nm), and higher stability. At the same time, this series of dyes retain a spiro-loop switch of xanthene, which can be regulated between the spirolactam and cation state, thus realizing specific biosensing in vivo. Compared with conventional dyes, CXs have superior photostability and chemical stability in aqueous solutions, and their lymphatic imaging results are far superior to those of the gold-standard dye (indocyanine green). At the same time, we have also successfully constructed the first FRET-based NIR-II OONO^– sensing probe by studying in-depth the photophysical properties of the dye, which was applied to the noninvasive detection of drug-induced liver injury. In comparison with traditional ‘OFF-ON’ fluorescent probes for qualitative detection, FRET-based ratiometric fluorescent probes provide a self-corrected ratiometric signal for quantitative detection. In combination with the simulated tissue calibration curve in vitro, they can offer a new strategy for fluorescent quantitative analysis in vivo.

3.2

A Functionalized Modified CX probe NRh

Non-oxidative breakdown of glucose in tumor cells leads to an increase in extracellular H⁺ concentration and a decrease in pH.[27] Therefore, a weakly acidic microenvironment, as one of the most important and common physiological features of tumors, is widely used for the detection of solid tumors.[28] In recent years, with the development of ratiometric fluorescent imaging and multispectral photoacoustic imaging, non-invasive tumor visualization has been achieved in vivo.[29] [30] However, most fluorescent probes have a fixed pH-detection transition point (pHt) and a narrow pH response interval, resulting in pH detection with a narrow range, which hinders highly sensitive monitoring of the pH of tumors during dynamic changes in different microenvironments. If the pHt is to be adjusted, the structures of probes need to be redesigned and synthesized, which greatly increases the workload.

One of the most important properties of xanthenoid dyes is the balance between the states of non-fluorescent spironolactone and fluorescent amphoteric ions, which is available in the visible region but difficult to achieve in the NIR-II window.[31] Inspired by this unique balancing property, we have constructed a functionally modified CX dye (named NRh)[23] that has a balance between the non-fluorescent spirolactam and NIR-II fluorescent cation states. We further encapsulated NRh and an aza-BODIPY dye (NAB) into micelles to obtain NIR-II pH-ratiometric fluorescent probes. Different sensors (pTAS) with adjustable pHt (6.11–7.22) were established by varying the ratio (NAB to NRh). In vitro and in vivo experiments have shown that pTAS are sensitive and accurate pH sensors that can also offer a long imaging time (Figure [5]).

Figure 5 Structural transformation between NRh and pH-activated NRhH⁺, pH response and pHt regulation of pTAS, and dynamic pH monitoring in tumors[23]

In this work, we made full use of the stable aza-BODIPY dye (NAB) and functionally modified CX dye (NRh) to construct a series of NIR-II FRET-based pH-responsive ratiometric fluorescent probes, which effectively avoids excessive organic synthesis while achieving the tunable pHt. At the same time, this method can be further extended to other responsive energy donors and receptors to construct NIR-II ratiometric fluorescent probes, which can broaden the pH detection range while maintaining the high sensitivity of biosensors in vivo.

3.3

CX-like Dyes with A Secondary Amino Py-2

Current ‘off-on’ fluorescent probes in the NIR-II region can be selectively activated by specific substrates to give signals. However, most of them can only achieve a ‘yes/no’ signal. ‘Off-on’ fluorescent probes allow the qualitative visualization of specific substrates such as enzymes and ROS/RNS in the tumor microenvironment, but they are of little use for quantitative detection. In contrast, ratiometric fluorescent probes are self-calibrated and can be used for quantitative analysis and monitoring because they can collect signals through multiple channels and these signals can be correlated. However, to date, NIR-II ratiometric fluorescent probes and their related design strategies are relatively few, and substrates used for detection are mainly reactive small molecules[32] that cannot meet the demand for the detection of enzymes and other biomolecules.[33]

By combining the rhodamine 6G scaffold with polymethylene, we designed and developed a molecular platform Py-2 with an emission spectrum in the NIR-II region. Based on Py-2, a series of ratiometric fluorescent probes can be constructed (Figure [6]).[24] It has been found that acetylation of the amino group on Py-2 could result in a blueshifted absorption spectrum but still maintain ideal NIR-II fluorescent emission. Therefore, ratiometric fluorescent probes can be constructed by modulating the intramolecular charge transfer (ICT) properties of the amino groups. To verify the universality of this platform, ratiometric fluorescent probes (Rap-N and Rap-R) were synthesized in response to nitroreductase and ROS/RNS, respectively. These probes show good ratiometric fluorescent responses to specific substrates. Notably, Rap-N can be used to achieve semi-quantitative monitoring of nitroreductase in different tumors, and Rap-R enables real-time monitoring of liver injury and peritonitis to be realized in vivo.

Figure 6 Optical properties of ratiometric fluorescent probes based on the Py-2 platform and ratiometric fluorescent imaging in the tumor[24]

In this work, we designed a molecular platform with emission in the NIR-II region named Py-2, which is universal and can be easily developed into a series of NIR-II ratiometric fluorescent probes for various research purposes in biomedical detection.

3.4

Chrodol Series Dyes

Maintaining the balance between the acid and base is essential for basic life activities, and different tissues or organs have their pH ranges. For example, the bladder in the urinary system and the colon in the digestive system are typical alkaline tissues.[34] [35] Recent studies have shown an association between lesions of tissues or organs and pH changes in their metabolites.[36] The inflammation of tissues or organs can also lead to high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS).[37] Therefore, technologies that enable real-time biosensing in vivo in the microenvironment could offer new assistance to the pathological study of these tissues or organs. NIR-II fluorescent imaging can be used for biosensing in vivo because of its low light scattering, minimal autofluorescence, and deep tissue penetration.[38] To date, many fluorescent probes have been developed to achieve imaging in the acidic microenvironment.[39] However, noninvasive diagnosis of reactive species in alkaline tissues, like ROS or RNS, is still a great challenge.

Based on our previous work on CXs, we created a series of new NIR-II fluorescent dyes (Chrodol)[22] by replacing the symmetric rhodamine-like structure with an asymmetric Rhodol-like structure (Figure [7]). Chrodols are asymmetric in structure, retaining the functional hydroxyl group on the parent nucleus, and keeping properties of the xanthene-like spiro ring. On one hand, the pK _a of the hydroxyl group can be adjusted to realize biological applications for different purposes. On the other hand, fluorescence modulation and fluorescent biosensing can be achieved by switching the spiro ring.

The electron-donating ability of Chrodol series dyes is different when the hydroxyl group is alkylated or in the oxygen anion state. Therefore, the optical properties of these dyes could be distinctly different. Chrodol has no NIR-II fluorescence emission when its hydroxyl group is alkylated, and when the hydroxyl group is in the oxygen anion state the dye emits strong NIR-II fluorescence. Therefore, fluorescent probes can be constructed by modulating the intramolecular charge transfer (ICT) properties of hydroxyl groups. After a series of tests, Chrodol-3 was selected for probe construction. Benzyl phenylborate was attached to the hydroxyl group of Chrodol-3 to obtain the NIR-II fluorescent probe PN910, which can respond to alkalis and ROS/RNS. When it reacts with relevant substrates, ‘off-on’ regulation of NIR-II fluorescence can be achieved. The results show that PN910 has excellent pH dependence in response to H₂O₂ and ONOO^–, and it also enables real-time monitoring of cystitis and enteritis in vivo.

Figure 7 Optical properties of NIR-II fluorescent probes based on Chrodol dyes, and colitis monitoring in vivo[22]

Our work realized the specific deep-tissue detection of inflammation in an alkaline environment in vivo, by constructing the PN910 probe, which can respond to alkalis and ROS/RNS. In addition, Chrodol series dyes can be used as a platform to detect other biomarkers through different functional modifications in the future.

4

Conclusion and Future Prospects

In summary, we have been working on high-performance fluorescent dyes and fluorescent probes for years. Based on a carbon-bridged spiro ring strategy, we have developed bright, stable, and aggregation-resistant shortwave infrared fluorescent dyes ECXs. We have also created a series of shortwave infrared fluorescent dyes CXs and Chrodols with adjustable wavelengths, by creatively combining the respective advantages of cyanine and xanthenoid dyes. Further, we constructed two fluorescent probes, NRh and Rap, based on the structure of CX, which can achieve superior specific biosensing and imaging. In general, we have aimed to gain an in-depth understanding of the photophysical mechanisms of fluorescent dyes, which could help to create high-performance luminescent dyes and fluorescent probes based on these dyes for bioimaging and sensing analysis.

Of course, current small-molecule fluorescent dyes and fluorescent probes still have some limitations, such as their instability and short imaging time. Besides, the properties of long wavelength and ideal fluorescence brightness are often not available at the same time.[40] [41] In addition, fluorescent imaging results are always better in small animals than in humans. Therefore, we will move on to balancing the properties of wavelength and fluorescence brightness, and strive to build stable and bright fluorescent dyes and fluorescent probes with low background interference and large penetration depth in the future, to provide ideal optical diagnosis strategies for practical clinical uses, such as real-time imaging of tumors and detection of specific biomarkers.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 16 January 2023

Accepted after revision: 13 February 2023

Accepted Manuscript online:
13 February 2023

Article published online:
05 April 2023