Cooling-Induced NIR Emission Enhancement and Targeting

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Letter Cite This: ACS Macro Lett. 2019, 8, 381−386

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Cooling-Induced NIR Emission Enhancement and Targeting Fluorescence Imaging of Biperylene Monoimide and Glycodendrimer Conjugates Chun-Miao Zhao, Ke-Rang Wang,* Chong Wang, Xu He, and Xiao-Liu Li* Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China

ACS Macro Lett. Downloaded from pubs.acs.org by OCCIDENTAL COLG on 03/25/19. For personal use only.

S Supporting Information *

ABSTRACT: Under high concentrations, strong pressure, and low temperature, fluorophores usually exhibit the fluorescence quenching phenomenon. Of significance, the development of aggregation-induced emission (AIE) and pressure-induced emission (PIE) fluorophores has perfectly prevented fluorescence quenching under high concentrations and strong pressure. However, cooling-induced fluorescence quenching in water is still an urgent problem. In this paper, cooling-induced emission (CIE) enhancement based on a biperylene monoimide (BPMI) derivative, BPMI-18Lac, with a conjugated lactose-based glycodendrimer was developed. BPMI-18Lac, as a non-AIE molecule, exhibited the CIE phenomenon with a fluorescent intensity increasing 7-fold when the temperature decreased from 80 to −40 °C. The mechanism was due to the inhibition of the intramolecular electron interactions between the perylene monoimide moieties linked by the C−C single bond. In addition, BPMI-18Lac, as a multivalent glycodendrimer, showed selective fluorescence imaging for HepG 2 cells through the ASGP receptor on the cell surface. Importantly, this work developed a water-soluble CIE molecule for potential application below freezing temperature. the fluorophore backbones. Interestingly, cooling-induced emission (CIE) enhancement based on AIE molecules has been observed through inhibition of intramolecular rotations and vibrations under cooling, such as tetraphenylethene (TPE)-21−23 and 1,2,3,4,5-pentaphenylsilole (MPS)-based24 polymers and other AIE molecules.25−28 CIE enhancement based on non-AIE molecules is limited, especially for NIR fluorophores. Flavonoid-based dyes have shown CIE enhancement through inhibition of the intramolecular charge transfer (ICT) and excited-state intramolecular proton transfer (ESIPT) processes and exhibited the maximum emission band at 460 nm under a temperature of −186 °C for the locally excited state, at 510 nm under −90 °C for the excited normal form and at 575 nm under 25 °C for the excited tautomer form.29 Green fluorescent protein, as a CIE molecule, exhibited emission enhancement through inhibition of fast quenching processes upon decreasing the temperature.30 This result might be useful for the discovery of new functional proteins and RNA-fluorophore architectures.31 However, these results were obtained in an organic solution, in the solid state, or at a temperature beyond 0 °C for an aqueous solution. To date,

he designs and syntheses of novel organic fluorophores have attracted much attention due to their wide applications in biological imaging1,2 and optoelectronic materials.3,4 Good solubility, high fluorescence quantum yield, and large Stokes shift are the desirable features of fluorophores.5 Recently, the development of organic fluorophores has gained unprecedented results; the absorption and emission bands were in the visible (400∼650 nm),6,7 nearinfrared I (NIR-I, 700∼900 nm), and NIR-II (1000∼1700 nm) regions.8,9 However, the fluorescence properties of organic fluorophores are usually affected by external conditions, especially the concentration, pressure, and temperature. High concentrations, strong pressure and low temperature have resulted in fluorescence quenching because of the enhanced intermolecular π−π stacking interactions.10,11 To solve the fluorescence self-quenching problem induced by the concentration and pressure, aggregation-induced emission (AIE)12,13 and pressure-induced emission (PIE)14−17 fluorophores were developed, which possess wide potential in the fields of biomedical applications18−20 and solid materials.14−17 However, cooling-induced fluorescence quenching is still an urgent problem, especially in aqueous solution. Upon decreasing the temperature, the fluorescence intensity of organic fluorophores usually shows fluorescence quenching because of the enhanced π−π stacking interactions between

T

© XXXX American Chemical Society

Received: January 31, 2019 Accepted: March 21, 2019

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DOI: 10.1021/acsmacrolett.9b00095 ACS Macro Lett. 2019, 8, 381−386

Letter

ACS Macro Letters water-soluble CIE molecules exhibiting CIE below the freezing temperature have not been reported. In this paper, a novel CIE molecule based on a biperylene monoimide (BPMI) derivative, BPMI-18Lac (Figure 1), with

Figure 2. Concentration-dependent fluorescence spectra of BPMI18Lac (a, λex = 540 nm) and PMI-9Lac (b, λex = 495 nm) in water.

intermolecular π−π stacking interactions. The concentrationdependent fluorescence spectra of BPMI-18Lac and PMI9Lac exhibited similar changes (Figure 2), which increased from 1 × 10−5 M to 2 × 10−5 M at first and then quenched with the increase in concentrations. The solvent-dependent UV−vis and fluorescence spectra of BPMI-18Lac and PMI9Lac exhibited a similar result in various ratios of DMSO and H2O (Figure S20). The absorption and emission intensities decreased with the increase in the water ratio. Moreover, solvent-dependent UV−vis and fluorescence spectra of BPMI18Lac in various ratios of DMSO and CH3OH (Figure S21) were studied. CH3OH is the poor solvent. Increasing of the CH3OH ratio, the absorption intensities increased with hypsochromic shift from 529.5 to 528.5 nm. However, the fluorescence intensities decreased. These results indicated that BPMI-18Lac and PMI-9Lac as non-AIE molecules possessed similar optical properties. On the other hand, temperaturedependent UV−vis spectra of BPMI-18Lac under 1 × 10−5 M and 1 × 10−4 M were used to investigate the changes of the solubility and the aggregation formation (Figure S22). Upon decreasing the temperature from 80 °C to −40 °C, the maximum absorption band was bathochromic shift from 545 to 550 nm with weak absorption intensity changes. These results indicated that the solubility and the aggregation formation showed no obvious changes. By examining the optical properties, we know that BPMI18Lac and PMI-9Lac showed maximum excitation bands at 540 and 495 nm and emission bands at 720 and 600 nm, respectively. BPMI-18Lac exhibited a large Stokes shift of 180 nm, which was larger than that of PMI-9Lac (Stokes shift of 100 nm). Through the above results, we can conclude that BPMI-18Lac possessed more advantages than PMI-9Lac with a large Stokes shift and a near-red emission. Furthermore, the temperature-dependent fluorescent behaviors were studied. To investigate the optical properties below the freezing temperature, a water solution containing 39.7 g of CaCl2 in 100 g of H2O was used, which can antifreeze below −40 °C. Interestingly, it was found that BPMI-18Lac exhibited cooling-induced emission (CIE). Upon decreasing the temperature from 80 to −40 °C, the fluorescence of BPMI-18Lac increased approximately 7-fold (Figure 3a,b). Especially, when the temperature was lower than 0 °C, the enhancement trend of the fluorescence was enhanced. As the control molecule, PMI-18Lac showed cooling-induced quenching (Figure 3c,d). Furthermore, temperature-dependent solid-state fluorescence spectra of BPMI-18Lac were investigated. Upon decreasing the temperature from 20 to −80 °C, the fluorescence of BPMI-18Lac increased approximately 3.3-fold (Figure S23a,b). It is well-known that fluorophores usually show aggregationcaused quenching because of the enhancement of the π−π

Figure 1. Structures of the BPMI derivative BPMI-18Lac and the PMI derivative PMI-9Lac.

a conjugated lactose-based glycodendrimer, was developed. BPMI-18Lac showed CIE between 80 °C and −40 °C, with an emission enhancement of 7-fold. BPMI derivatives, with two perylene monoimide backbones linked with a C−C single bond. Compared with perylene bisimide derivatives, BPMI derivatives show a larger Stokes shift and weaker π−π stacking interactions because of the twisted π-plane.32,33 The lactose moiety is responsible for the selectivity of the recognition and water solubility. The compound BPMI-18Lac was synthesized through four steps (Scheme S1). BPMI-1 was synthesized according to the reference’s method.34,35 The dianhydride intermediate BPMI2 was obtained through hydrolysis of BPMI-1 in NaOH. Then, BPMI-3 was synthesized by reacting the dianhydride intermediate BPMI-2 with the tripropargylated compound M1 in the presence of Zn(OAc)2 in a solution of pyridine. After that, the acetyl-protected compound BPMI-18AcLac was produced by the click reaction of BPMI-3 with the carbohydrate derivative M-2, followed by the deprotection of the acetyl groups, to yield the target compound BPMI-18Lac. The compound BPMI-18Lac and its intermediates were fully characterized by NMR and HRMS analyses (Figures S1−S9). The PMI derivative PMI-9Lac (Figure 1) as a control molecule was synthesized by a similar method (Scheme S2), which was also fully characterized by NMR and HRMS analyses (Figures S10−S18). The optical properties of BPMI-18Lac and PMI-9Lac were studied by concentration-dependent UV−vis (Figure S19) and fluorescence spectra (Figure 2). As shown in Figure S19, BPMI-18Lac exhibited a broad absorption between 400 and 700 nm with a maximum band at 540 nm. With an increase in concentration, the absorption coefficient (ε) showed no obvious changes. The absorption coefficient (ε) intensity of the PMI-9Lac at 495 nm decreased with increasing the concentration, and the intensity of a shoulder peak between 550 and 600 nm increased because of the enhancement of the 382

DOI: 10.1021/acsmacrolett.9b00095 ACS Macro Lett. 2019, 8, 381−386

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ACS Macro Letters

self-interactions of PMI-9Lac. In addition, the fluorescence quantum yields of PMI-9Lac changed from 49.84% at high temperature (80 °C) to 8.40% at lower temperature (−40 °C), that is, approximately 6-fold fluorescence quenching. Compared with the lifetimes of PMI-9Lac, the longer lifetime of 5.45 ns for BPMI-18Lac was attributed to the lifetime of the PMI moiety in BPMI-18Lac, the short lifetime (0.90 ns) was attributed to the intermolecular π−π interactions, and the shorter lifetime (0.22 ns) was attributed to the intramolecular electron interactions between the perylene monoimide moieties linked by the C−C single bond. Upon decreasing the temperature, the lifetimes of BPMI-18Lac exhibited obvious changes in that the ratio of the long lifetime increased from 5.26% to 20.66%, but the lifetimes (τ1) changed only slightly between 5.59 and 5.08 ns. The short lifetimes (τ2) increased from 0.9 to 2.08 ns as the ratios changed from 41.91% to approximately 60% due to the enhancement of the intermolecular π−π interactions at the lower temperature. However, the ratios of the shorter lifetimes (τ3) decreased from 52.82% to 19.77% with the increase in the lifetime from 0.22 to 0.51 ns. Combined with the CIE enhancement behaviors, we can conclude that the CIE of BPMI-18Lac was mainly due to inhibition of the intramolecular electron interactions between the two perylene monoimide moieties linked by the C−C single bond. Upon decreasing the temperature, the intramolecular electron interactions between the perylene monoimide backbones were inhibited, so the ratio of the lifetime (τ3) decreased, and the ratio of the long lifetime (τ1) increased. Correspondingly, the intermolecular π−π interactions between the biperylene monoimide backbones were enhanced, resulting in an increase in the ratio of the short lifetime (τ2). The mechanism of the CIE phenomenon based on BPMI-18Lac was similar to the references’ results through inhibition of the fast quenching processes between intramolecular electron interactions.14 BPMI-18Lac showed a maximum absorption band at 540 nm and an emission band at 720 nm with a large Stokes shift of 180 nm, which was related to the strong intramolecular electron interactions. Furthermore, the CIE phenomenon was confirmed by the fluorescence quantum yields, which changed from 1.08% at high temperature (80 °C) to 7.00% at low temperature (−40 °C), that is, an approximately 7-fold fluorescence enhancement. Benefiting from the lactose-based glycodendrimer conjugates, BPMI-18Lac not only possessed good water solubility, but also showed potentially selective binding interactions with proteins. Carbohydrate−protein interactions possess wide biological functions, including cell adhesion, virus inflammation, cancer metastasis, and immune response.39 Glycodendrimers as multivalent glycoclusters have been widely used as antiviral agents,40,41 immunomodulatory agents,42 and in mimicking biological membranes.43 The carbohydrate−protein interactions based on BPMI18Lac were investigated by fluorescence spectra at −20 °C (Figure S25). BPMI-18Lac showed a maximum emission band at 730 nm. Upon addition of peanut agglutinin (PNA) lectins, the fluorescence intensity of BPMI-18Lac exhibited a progressive increase, but with no obvious shift of the emission band. Furthermore, the binding constant (K) of BPMI-18Lac with PNA was calculated to be 6.2 × 107 M−1 (3.4 × 106 M−1 for monomeric lactose, valency corrected) by fitting the maximum emission (Figure S25b) through a non-linearsquares curve-fitting method.44 Moreover, the carbohydrate−

Figure 3. Temperature-dependent fluorescence spectra and the fluorescence intensity changes of BPMI-18Lac (a and b, λex = 540 nm, 2 × 10−5 M) and PMI-9Lac (c and d, λex = 495 nm, 1 × 10−5 M) in a water solution containing 39.7 g of CaCl2 in 100 g of H2O.

stacking interactions under high concentrations or low temperature.36−38 AIE molecules exhibited concentrationand cooling-induced emission because of the inhibition of intramolecular rotations and vibrations.21−28 The CIE phenomenon based on non-AIE molecules was limited.29−31 According to the concentration-, temperature-, and solventdependent UV−vis and fluorescence spectra, we can conclude that BPMI-18Lac is a novel CIE molecular backbone. The mechanism of the CIE phenomenon of BPMI-18Lac was investigated by time-resolved fluorescence spectra. At 80 °C, BPMI-8Lac showed triple exponential function decays (Figure S24a and Table 1) with lifetimes of 5.45 ns (5.26%), Table 1. Fluorescence Lifetimes and Quantum Yields of BPMI-18Lac at Different Temperatures (λex = 540 nm) °C

τ1

%

τ2

%

τ3

%

χ2

80 70 60 50 40 30 20 10 0 −10 −20 −30 −40

5.45 5.50 5.50 5.36 5.48 5.39 5.59 5.48 5.31 5.14 5.08 5.11 5.19

5.26 5.07 4.91 4.95 5.31 5.94 6.55 8.20 10.14 11.87 14.99 16.81 20.66

0.90 1.01 1.09 1.20 1.30 1.41 1.54 1.67 1.75 1.77 1.89 1.97 2.08

41.91 43.68 48.50 51.46 54.76 58.34 60.30 60.70 63.07 62.91 61.70 60.85 59.57

0.22 0.27 0.28 0.31 0.33 0.34 0.37 0.40 0.40 0.41 0.46 0.46 0.51

52.82 51.25 46.59 43.59 39.93 35.72 33.14 31.09 26.78 25.22 23.31 22.35 19.77

1.228 1.259 1.189 1.299 1.202 1.289 1.283 1.298 1.146 1.254 1.152 1.191 1.238

0.90 ns (41.91%), and 0.22 ns (52.82%), respectively. As the control molecule, PMI-9Lac showed a single lifetime of 4.90 ns at 80 °C (Figure S24b and Table S1). With the decrease of temperature, the lifetime of PMI-9Lac changed from 4.90 to 5.04 ns (Table S1). Moreover, a shorter lifetime of PMI-9Lac appeared between 0.29 and 1.86 ns, the ratio of which increased from 2.17% to 4.96% between the temperature of 20 and −40 °C. The shorter and longer lifetimes of PMI-9Lac were attributed to the intermolecular π−π interactions and 383

DOI: 10.1021/acsmacrolett.9b00095 ACS Macro Lett. 2019, 8, 381−386

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ACS Macro Letters

In summary, a glycodendrimer-modified biperylene monoimide derivative (BPMI-18Lac) was synthesized. BPMI-18Lac as novel CIE molecule exhibited cooling-induced emission enhancement, especially when the temperature was lower than the freezing temperature. When the temperature decreased from 80 to −40 °C, the fluorescence intensity of BPMI-18Lac increased approximately 7-fold. The CIE mechanism of BPMI18Lac was due to the inhibition of the intramolecular electron interactions between the perylene monoimide moieties linked by a C−C single bond. Furthermore, BPMI-18Lac showed fluorescence enhancement sensing of PNA lectin at −20 °C, which indicated that BPMI-18Lac has a potential application for low-temperature sensing. In addition, BPMI-18Lac as a multivalent glycodendrimer showed selective fluorescence imaging for HepG2 cells through the ASGP receptor on the cell surface. Importantly, this work developed a novel watersoluble CIE molecule for potential application at below freezing temperature.

protein interactions of BPMI-18Lac with different proteins were investigated by turbidity assay (Figure S26). Upon addition of BPMI-18Lac to the PNA solution, the turbidity exhibited an immediate increase (Figure S26). However, the turbidity of BPMI-18Lac with concanavalin A (Con A) and bovine serum albumin (BSA) proteins showed no obvious changes (Figure S26). These results indicated that BPMI18Lac exhibited selective binding with PNA lectin.45 It is well-known that the surfaces of cancer cells possess some selective recognition proteins and receptors, especially for carbohydrate-based glycoprotein.46 Among them, the asialoglycoprotein receptor (ASGP-R) has been widely investigated due to its selective recognition of galactose residues and overexpression in hepatic parenchymal cells (HepG2 cells).47,48 BPMI-18Lac possessed a multivalent glycodendrimer and exhibited a large Stokes shift (more than 180 nm) and is good for fluorescence imaging. The cell viabilities of HepG2 cells, HeLa cells, and MCF-7 cells treated with BPMI-18Lac were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) experiment. The cancer cells were incubated at 37 °C for 48 h after the addition of BPMI-18Lac, and the cell viability of BPMI18Lac was determined to be more than 85% (Figure S27) at concentrations of 0.2, 1.0, 5.0, and 25 μM, indicating that BPMI-18Lac was not toxic under the conditions of the fluorescence imaging experiment. Carbohydrate-based selective fluorescence imaging of BPMI-18Lac against HepG2 cells, HeLa cells and MCF-7 cells was investigated under incubation for 2 h by confocal imaging. As shown in Figure 4a−c, the

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.9b00095. Experimental section, NMR and HRMS spectra, synthesis, and additional figures (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ke-Rang Wang: 0000-0002-5607-6552 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank National Nature Science Foundation of China (21372059, 21572044, and 21778013) and the Natural Science Foundation of Hebei Province (B2016201254) for financial support.

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REFERENCES

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Figure 4. Confocal microscopic images of HepG2 cells (a−c), HeLa cells (d−f), and MCF-7 cells (g−i) after incubation with BPMI18Lac (10 μM) in PBS buffer at 37 °C for 2 h in the form of excited at 540 nm.

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DOI: 10.1021/acsmacrolett.9b00095 ACS Macro Lett. 2019, 8, 381−386

Letter

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DOI: 10.1021/acsmacrolett.9b00095 ACS Macro Lett. 2019, 8, 381−386