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ChemCommChemical Communicationswww.rsc.org/chemcomm

ISSN 1359-7345

COMMUNICATIONMarilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyen et al. Reactivity diff erences of Sc

3N@C

2n (2n = 68 and 80). Synthesis of the

fi rst methanofullerene derivatives of Sc3N@D

5h-C

80

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H. Zhou, Z. Hu, N. Niu, S. A. Shahzad and C. Yu, Chem. Commun., 2017, DOI: 10.1039/C7CC00122C.

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a State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of

Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China

E-mail: hpzhou@ciac.ac.cn; congyu@ciac.ac.cn; Fax: (+86)-431-8526-2710 b University of the Chinese Academy of Sciences, Beijing 100049, P. R. China

c Department of Chemistry, COMSATS Institute of Information Technology,

Abbottabad 22060, Pakistan

Electronic Supplementary Information (ESI) available: Experimental details,

supporting figures. See DOI: 10.1039/x0xx00000x

‡These authors contributed equally to this work.

Received 00th January 20xx,

Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x

www.rsc.org/

Specific Detection of Cancer Cells through Aggregation-Induced

Emission of a Light-Up Bioprobe

Jian Chen,‡ab

Hong Jiang,‡ab

Huipeng Zhou,*ab

Zhenzhen Hu,ab

Niu Niu,ab

Sohail Anjum Shahzad,ac

and Cong Yu*ab

A cancer cell specific aptamer was labeled with an aggregation-

induced emission (AIE) probe for the first time. Using it as a light-

up bioprobe, a specific cancer cells detection method is

developed.

Cancer is a group of diseases involving abnormal cell growth.

Cancer cells grow and divide at a very rapid and unregulated

pace, and could invade or spread to other parts of the body.1

Highly sensitive and selective detection of cancer cells is of

great importance for both early diagnosis of cancer and

investigation of cancer metastasis.2 In recent years, a number of

cancer cell detection methods have been developed, which

include the fluorescent,3 chemiluminescent,4 electrochemical,5

surface-enhanced Raman scattering,6 surface plasmon

resonance,7 colorimetric8, and electrochemiluminescent9

methods. Compared with other methods, fluorescence-based

method has drawn growing attentions due to its high sensitivity,

rapid response, and simple manipulation.

Aggregation-induced emission (AIE) is a novel

photophysical phenomenon which has attracted considerable

interest in recent years.10 The molecules with AIE

characteristics are non-emissive in the monomeric form but

become highly emissive in the aggregated form as a result of

the restriction of intramolecular rotations, which could

significantly reduce the energy dissipation through nonradiative

means.11 Based on this observation, a number of AIE probes

have been developed for the applications in bioanalysis and

biosensing.12 The AIE probes are usually propeller-shape

molecules. Tetraphenylethene (TPE) is one of the most

important AIE probes, which has been widely used for the

construction of novel biosensing techniques.13

Aptamers are single-stranded DNA or RNA oligonucleotides

which can specifically and tightly bind to a variety of targets,

such as metal ions, small molecules, proteins, and even entire

viruses and cells.14 Compared with other recognition molecules

such as antibodies, aptamers are more stable, inexpensive and

can be synthesized and labeled chemically with ease.15 As a

result, a variety of aptamer-based biosensing methods have

been developed.14,16 In recent years, specific aptamers against

entire cancer cells have been reported.17 Using those aptamers

as novel and powerful affinity recognition ligands, several

aptamer-based cancer cell detection methods have been

developed.3b–3g

Scheme 1. Schematic illustration of the Ramos cells detection

strategy.

In this work, a cancer cell specific aptamer was labeled with

an AIE probe for the first time. Using it as a light-up bioprobe,

a specific cancer cell detection method is developed. Ramos

cells (human Burkitt’s lymphoma cells) were selected as the

model cancer cells. The overall sensing strategy is

schematically illustrated in Scheme 1. A Ramos cell specific

aptamer with both ends labeled with TPE probe (TPE-aptamer)

was designed and successfully synthesized. The TPE-aptamer

showed only very weak emission in an aqueous buffer solution.

Upon the addition of Ramos cells, specific binding between the

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aptamer and the Ramos cells resulted in restrictions of the

intramolecular rotations of the TPE molecules. Turn-on

emission of the TPE-aptamer was observed, and a specific

fluorescence cancer cell detection method is therefore

established.

The synthetic route for the TPE-labeled Ramos cell specific

aptamer (TPE-aptamer) is shown in Scheme 2. A succinimidyl

ester-modified TPE derivative (compound 1) was prepared

(Figures S1–S6, Supporting Information).18 The aptamer with

amino functional groups labeled on both ends was coupled

directly with two molecules of compound 1. The resulting

crude product was purified by reverse-phase HPLC. Figure S7

shows the HPLC chromatograms of the crude product. The

peaks 1–4 are the unreacted aptamer (with absorption at 260 nm

only), single-TPE-labeled aptamer (with absorption at both 260

and 350 nm), dual-TPE-labeled aptamer (with absorption at

both 260 and 350 nm), and unreacted TPE (with absorption at

350 nm mainly), respectively. Peak 3 was collected, and pure

TPE-aptamer was obtained.

Scheme 2. Synthetic route for the TPE-aptamer.

Figure S8 shows the UV-vis absorption spectra of the

aptamer, compound 1 and the TPE-aptamer, respectively. It

was observed that the TPE-aptamer contained the

characteristic absorption of both the aptamer (maximum

absorption at 260 nm) and compound 1 (maximum absorption

at 350 nm). The results clearly indicate that the aptamer has

been successfully labeled with the TPE probe.

Figure S9 shows the emission spectra of compound 1 and the

TPE-aptamer in aqueous and organic solvents. In DMSO,

compound 1 (a hydrophobic molecule) mainly existed in the

monomeric form and showed no AIE emission. While in a

DMSO-water solvent mixture (v/v = 1/99), compound 1 had a

strong tendency to self-aggregate due to the strong hydrophobic

interactions among the probe molecules, thus strong compound

1 AIE emission was observed. In sharp contrast, the TPE-

aptamer showed only very weak emission in water but strong

emission in the DMSO-water solvent mixture (v/v = 99/1). The

results clearly suggest that the TPE-aptamer had better

solubility in an aqueous solution. Since the TPE molecules

were covalently labeled to the aptamer (an anionic polymer),

the negatively charged oligonucleotide phosphate backbone

diminished the tendency of TPE self-aggregation.

To investigate further the property of the TPE-aptamer,

control experiments were conducted. The TPE-aptamer was

digested into small fragments by nuclease S1. Figure S10

shows that, in an aqueous solution, after the digestion of the

TPE-aptamer with nuclease S1, a significant increase of TPE

AIE emission was observed. The results confirm that the

aptamer conjugated TPE molecules mainly existed in the

monomeric form, and the negatively charged oligonucleotide

effectively diminished the tendency of the TPE probe self-

aggregation. After the digestion with nuclease S1, the TPE

probe was released, and strong hydrophobic interactions among

the probe molecules caused strong AIE emission.

Figure 1. (a) Changes in emission spectrum of the TPE-

aptamer with the amount of Ramos cells added (0, 100, 200,

500, 1000, 2000, 3000, 4000, 5000, 10000, 15000 and 20000,

respectively). (b) Plot of the changes in emission intensity of

the TPE-aptamer at 470 nm against the amount of Ramos cells

added. Inset: expanded linear region of the curve.

The Ramos cell specific aptamer can specifically recognize

the immunoglobulin heavy mu chain on the surface of the

Ramos cells.3f Upon the addition of Ramos cells to the solution

of TPE-aptamer, specific binding between the aptamer and the

Ramos cells resulted in restrictions of the intramolecular

rotations of the TPE molecules. And strong AIE emission of the

TPE-aptamer was thus observed. Figures 1 and S11 show that,

in the presence of 2.5 µM of TPE-aptamer, the emission

intensity of the aptamer increased gradually with the addition of

increasing amounts of the Ramos cells (0 – 20,000). A linear

relationship was obtained at a Ramos cell range of 0 – 5,000.

The linear regression equation is E = 0.067A + 84.55

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(correlation coefficient R2 = 0.999), in which E is the emission

intensity of the TPE-aptamer at 470 nm and A is the amount

of Ramos cells. Our assay is quite sensitive compared with the

previously reported fluorometric methods.3b,3e,3g Without the

use of any signal amplification, 100 Ramos cells could be

easily detected.

Selectivity of the assay was studied. Five cancer cell lines

(HeLa, CCRF-CEM, MCF-7, A549 and HepG2) and one

normal cell line (L929) were selected. Figure 2 shows that,

under the same experimental conditions, 20,000 Ramos cells

could induce obvious AIE emission increase of the TPE-

aptamer. In contrast, the other cells of the same amount could

not induce noticeable emission increase. The results clearly

indicate that the assay is highly selective for Ramos cells.

Figure 2. Selectivity of the assay. Columns a–g: Ramos, HeLa,

CCRF-CEM, MCF-7, A549, HepG2 and L929, respectively.

Assay conditions: 2.5 µM TPE-aptamer; 20 mM phosphate

buffer, pH 7.4; the amount of cell added, 20,000 each.

The assay was also tested in complex sample mixtures. TPE-

aptamer (2.5 µM) and Ramos cells of different amounts were

added to human serum (80%), and the sample mixtures were

tested. Figure S12 shows that the more Ramos cells were

spiked, the larger emission intensity increase of the TPE-

aptamer was obtained. The results clearly indicate that the

assay could also be used in complex sample mixtures.

Figure 3. Selective fluorescence imaging of cancer cells.

Bright-field images of the Ramos (a), CCRF-CEM (b) and

HeLa (c) cells; and fluorescence images of the Ramos (b),

CCRF-CEM (d) and HeLa (f) cells.

The assay could also be used for the specific fluorescence

imaging of cancer cells. Ramos, CCRF-CEM and HeLa cells

were tested. Figure 3 shows that, in the presence of 2.5 µM

TPE-aptamer and 10,000 of Ramos cells, the AIE emission of

the TPE-aptamer could be easily observed. Under the same

experimental conditions, CCRF-CEM and HeLa cells could not

give noticeable AIE fluorescence. The results clearly suggest

that the assay could also be used for the specific fluorescence

imaging of cancer cells. In addition, cytotoxicity study of the

TPE-aptamer was conducted (Figure S13). The results clearly

indicate that our probe is nontoxic to the cells. In summary, a cancer cell specific aptamer is labeled with an

AIE probe for the first time, and a selective detection method

for cancer cells based on aggregation induced emission is

developed. A TPE labeled Ramos cell specific aptamer (TPE-

aptamer) was synthesized. The TPE-aptamer shows very

weak emission in an aqueous buffer solution. Upon the addition

of Ramos cells, specific binding between the aptamer and

Ramos cells resulted in restrictions of intramolecular rotations

of the TPE probe molecules. Strong AIE emission of the TPE-

aptamer was observed, and a selective Ramos cell detection

method is established.

Our assay has several important features. First, it offers a

convenient “mix-and-detect” approach, which is simple and

fast. Second, it is based on the fluorescence “turn-on” mode,

which could considerably reduce the likelihood of false-

positive signals associated with the “turn-off” assay. Third,

without the use of any signal amplification, highly sensitive

cancer cell detection could be easily accomplished. Fourth, our

assay could be used in complex sample mixtures, and also be

used for the specific fluorescence imaging of cancer cells. Fifth,

the AIE probe has certain unique characteristics, the

fluorescence turn on does not rely on energy transfer or

nanomaterials. We envision that the principle of our assay

could be employed for the development of novel AIE and

nucleic acid aptamer based sensing techniques for the detection

of various targets.

This work was supported by the National Natural Science

Foundation of China (21561162004, 21275139), the Science

and Technology Development Project (International

Collaboration Program) of Jilin Province (20160414040GH),

and the Natural Science Foundation of Jilin Province

(20150101183JC).

Notes and references

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