AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Nano Research Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Research Article

AgInS2/ZnS quantum dots for noninvasive cervical cancer screening with intracellular pH sensing using fluorescence lifetime imaging microscopy

Wenhua Su1,§, Dan Yang2,§, Yulan Wang3,§, Yawei Kong1, Wanlu Zhang2, Jing Wang4, Yiyan Fei1, Ruiqian Guo2( ), Jiong Ma1,5,6( ), Lan Mi1,5( )
Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), School of Information Science and Technology, Fudan University, Shanghai 200433, China
Institute for Electric Light Sources, School of Information Science and Technology, Fudan University, Shanghai 200433, China
Department of Gynecology and Obstetrics, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
Institute of Photonic Chips, University of Shanghai for Science and Technology, Shanghai 200093, China Centre for Artificial-Intelligence Nanophotonics, School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
Institute of Biomedical Engineering and Technology, Academy for Engineer and Technology, Fudan University, 220 Handan Road, Shanghai 200433, China
Shanghai Engineering Research Center of Industrial Microorganisms, the Multiscale Research Institute of Complex Systems (MRICS), School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China

§ Wenhua Su, Dan Yang, and Yulan Wang contributed equally to this work.

Show Author Information

Graphical Abstract

An intracellular pH sensor AgInS2 (AIS)/ZnS quantum dots (QDs) with long fluorescence lifetimesare synthesized, and they exhibit a reduced fluorescence lifetime when in higher pH conditions.AIS/ZnS QDs combined with fluorescence lifetime imaging microscopy (FLIM) are used to evaluatethe ability for human cervical cancer (CC) screening for the first time. The proposed method has greatpromise for the noninvasive screening and diagnosis of CC, and the method may be applied to otherpH-related diseases in the future.

Abstract

Intracellular pH plays a critical role in biological functions, and abnormal pH values are related to various diseases. Here, we report on an intracellular pH sensor AgInS2 (AIS)/ZnS quantum dots (QDs) that show long fluorescence lifetimes of hundreds of nanoseconds and low toxicity. Fluorescence lifetime imaging microscopy (FLIM) combined with AIS/ZnS QDs is used for the imaging of live cells in different pH buffers and different cell lines. The FLIM images of AIS/ZnS QDs in live cells demonstrate different intracellular pH values in different regions, such as in lysosomes or cytoplasm. This method can also distinguish cancer cells from normal cells, and the fluorescence lifetime difference of the AIS/ZnS QDs between the two types of cells is 100 ± 7 ns. Most importantly, the exfoliated cervical cells from 20 patients are investigated using FLIM combined with AIS/ZnS QDs. The lifetime difference value between the normal and cervical cancer (CC) groups is 115 ± 9 ns, and the difference between the normal and the precancerous lesion group is 64 ± 9 ns. For the first time, the noninvasive method has been used for cervical cancer screening, and it has shown great improvement in sensitivity compared with a clinical conventional cytology examination.

Keywords

AIS/ZnS quantum dotsfluorescence lifetime imaging microscopyintracellular pH sensingcervical cancer screeningnoninvasive

Electronic Supplementary Material

Download File(s)
12274_2022_4104_MOESM1_ESM.pdf (840 KB)

References

1

Flinck, M.; Kramer, S. H.; Pedersen, S. F. Roles of pH in control of cell proliferation. Acta Physiol. (Oxf.) 2018, 223, e13068.
Crossref Google Scholar
2

Lan, A.; Lagadic-Gossmann, D.; Lemaire, C.; Brenner, C.; Jan, G. Acidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteria. Apoptosis 2007, 12, 573–591.
Crossref Google Scholar
3

Di Sario, A.; Bendia, E.; Omenetti, A.; De Minicis, S.; Marzioni, M.; Kleemann, H. W.; Candelaresi, C.; Saccomanno, S.; Alpini, G.; Benedetti, A. Selective inhibition of ion transport mechanisms regulating intracellular pH reduces proliferation and induces apoptosis in cholangiocarcinoma cells. Dig. Liver Dis. 2007, 39, 60–69.
Crossref Google Scholar
4

Pacheco-Liñán, P. J.; Bravo, I.; Nueda, M. L.; Albaladejo, J.; Garzón-Ruiz, A. Functionalized CdSe/ZnS quantum dots for intracellular pH measurements by fluorescence lifetime imaging microscopy. ACS Sens. 2020, 5, 2106–2117.
Crossref Google Scholar
5

Huang, M. J.; Liang, X. Y.; Zhang, Z. X.; Wang, J.; Fei, Y. Y.; Ma, J.; Qu, S. N.; Mi, L. Carbon dots for intracellular pH sensing with fluorescence lifetime imaging microscopy. Nanomaterials (Basel) 2020, 10, 604.
Crossref Google Scholar
6

Fang, B. Y.; Wang, D. J.; Huang, M. F.; Yu, G. H.; Li, H. Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer's disease or vascular dementia. Int. J. Neurosci. 2010, 120, 591–595.
Crossref Google Scholar
7

Mattson, M. P.; Pedersen, W. A.; Duan, W. Z.; Culmsee, C.; Camandola, S. Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases. Ann. N Y Acad. Sci. 1999, 893, 154–175.
Crossref Google Scholar
8

Chaumeil, M. M.; Valette, J.; Baligand, C.; Brouillet, E.; Hantraye, P.; Bloch, G.; Gaura, V.; Rialland, A.; Krystkowiak, P.; Verny, C. et al. pH as a biomarker of neurodegeneration in Huntington's disease: A translational rodent-human MRS study. J. Cereb. Blood Flow Metab. 2012, 32, 771–779.
Crossref Google Scholar
9

Swietach, P.; Vaughan-Jones, R. D.; Harris, A. L.; Hulikova, A. The chemistry, physiology and pathology of pH in cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2014, 369, 20130099.
Crossref Google Scholar
10

Han, J. Y.; Burgess, K. Fluorescent indicators for intracellular pH. Chem. Rev. 2010, 110, 2709–2728.
Crossref Google Scholar
11

Chen, M. M.; Chen, C. Y.; Shen, Z. W.; Zhang, X. L.; Chen, Y. Z.; Lin, F. F.; Ma, X. L.; Zhuang, C. Y.; Mao, Y. F.; Gan, H. C. et al. Extracellular pH is a biomarker enabling detection of breast cancer and liver cancer using CEST MRI. Oncotarget 2017, 8, 45759–45767.
Crossref Google Scholar
12

Lin, L. S.; Cong, Z. X.; Li, J.; Ke, K. M.; Guo, S. S.; Yang, H. H.; Chen, G. N. Graphitic-phase C3N4 nanosheets as efficient photosensitizers and pH-responsive drug nanocarriers for cancer imaging and therapy. J. Mater. Chem. B 2014, 2, 1031–1037.
Crossref Google Scholar
13

Pirsaheb, M.; Mohammadi, S.; Salimi, A.; Payandeh, M. Functionalized fluorescent carbon nanostructures for targeted imaging of cancer cells: A review. Microchim. Acta 2019, 186, 231.
Crossref Google Scholar
14

Battisti, A.; Digman, M. A.; Gratton, E.; Storti, B.; Beltram, F.; Bizzarri, R. Intracellular pH measurements made simple by fluorescent protein probes and the phasor approach to fluorescence lifetime imaging. Chem. Commun. (Camb.) 2012, 48, 5127–5129.
Crossref Google Scholar
15

Poëa-Guyon, S.; Pasquier, H.; Mérola, F.; Morel, N.; Erard, M. The enhanced cyan fluorescent protein: A sensitive pH sensor for fluorescence lifetime imaging. Anal. Bioanal. Chem. 2013, 405, 3983–3987.
Crossref Google Scholar
16

Wang, L.; Kang, X. J.; Pan, D. C. Gram-scale synthesis of hydrophilic PEI-coated AgInS2 quantum dots and its application in hydrogen peroxide/glucose detection and cell imaging. Inorg. Chem. 2017, 56, 6122–6130.
Crossref Google Scholar
17

Nideep, T. K.; Ramya, M.; Sony, U.; Kailasnath, M. MSA capped CdTe quantum dots for pH sensing application. Mater. Res. Expr. 2019, 6, 105002.
Crossref Google Scholar
18

Orte, A.; Alvarez-Pez, J. M.; Ruedas-Rama, M. J. Fluorescence lifetime imaging microscopy for the detection of intracellular pH with quantum dot nanosensors. ACS Nano 2013, 7, 6387–6395.
Crossref Google Scholar
19

Ripoll, C.; Roldan, M.; Contreras-Montoya, R.; Diaz-Mochon, J. J.; Martin, M.; Ruedas-Rama, M. J.; Orte, A. Mitochondrial pH nanosensors for metabolic profiling of breast cancer cell lines. Int. J. Mol. Sci. 2020, 21, 3731.
Crossref Google Scholar
20

Chen, C.; Zhang, P. F.; Zhang, L.; Gao, D. Y.; Gao, G. H.; Yang, Y.; Li, W. J.; Gong, P.; Cai, L. T. Long-decay near-infrared-emitting doped quantum dots for lifetime-based in vivo pH imaging. Chem. Commun. (Camb.) 2015, 51, 11162–11165.
Crossref Google Scholar
21

Zaffalon, M. L.; Pinchetti, V.; Camellini, A.; Vikulov, S.; Capitani, C.; Bai, B.; Xu, M.; Meinardi, F.; Zhang, J. T.; Manna, L. et al. Intrinsic and extrinsic exciton recombination pathways in AgInS2 colloidal nanocrystals. Energy Mater. Adv. 2021, 2021, 1959321.
Crossref Google Scholar
22

Kowalik, P.; Mucha, S. G.; Matczyszyn, K.; Bujak, P.; Mazur, L. M.; Ostrowski, A.; Kmita, A.; Gajewska, M.; Pron, A. Heterogeneity induced dual luminescence properties of AgInS2 and AgInS2-ZnS alloyed nanocrystals. Inorg. Chem. Front. 2021, 8, 3450–3462.
Crossref Google Scholar
23

Casey, J. R.; Grinstein, S.; Orlowski, J. Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 2010, 11, 50–61.
Crossref Google Scholar
24

Cardone, R. A.; Casavola, V.; Reshkin, S. J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat. Rev. Cancer 2005, 5, 786–795.
Crossref Google Scholar
25

Van Den Bergh, H. Early detection of lung cancer and the role of endoscopic fluorescence imaging. Med. Laser Applicat. 2003, 18, 20–26.
Crossref Google Scholar
26

Koliopoulos, G.; Nyaga, V. N.; Santesso, N.; Bryant, A.; Martin-Hirsch, P. P.; Mustafa, R. A.; Schünemann, H.; Paraskevaidis, E.; Arbyn, M. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst. Rev. 2017, 8, CD008587.
Crossref Google Scholar
27

Saslow, D.; Solomon, D.; Lawson, H. W.; Killackey, M.; Kulasingam, S. L.; Cain, J. M.; Garcia, F. A. R.; Moriarty, A. T.; Waxman, A. G.; Wilbur, D. C. et al. American Cancer society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J. Clin. 2012, 16, 175–204.
Crossref Google Scholar
28

Xie, J.; Pan, X. B.; Wang, M.; Ma, J. Y.; Fei, Y. Y.; Wang, P. N.; Mi, L. The role of surface modification for TiO2 nanoparticles in cancer cells. Colloids Surf. B Biointerf. 2016, 143, 148–155.
Crossref Google Scholar
29

Huang, X. Y.; Huang, Y.; Yan, F. P.; Xue, X. G.; Zhang, K. X.; Cai, P.; Zhang, X. W.; Zhang, X. Y. Constructing defect-related subband in silver indium sulfide QDs via pH-dependent oriented aggregation for boosting photocatalytic hydrogen evolution. J Colloid Interf. Sci. 2021, 593, 222–230.
Crossref Google Scholar
30

Ning, Y. Y.; Cheng, S. M.; Wang, J. X.; Liu, Y. W.; Feng, W.; Li, F. Y.; Zhang, J. L. Fluorescence lifetime imaging of upper gastrointestinal pH in vivo with a lanthanide based near-infrared τ probe. Chem. Sci. 2019, 10, 4227–4235.
Crossref Google Scholar
31

Jia, X. F.; Li, J.; Wang, E. K. One-pot green synthesis of optically pH-sensitive carbon dots with upconversion luminescence. Nanoscale 2012, 4, 5572–5575.
Crossref Google Scholar
32

Liu, X. X.; Yang, C. L.; Zheng, B. Z.; Dai, J. Y.; Yan, L.; Zhuang, Z. J.; Du, J.; Guo, Y.; Xiao, D. Green anhydrous synthesis of hydrophilic carbon dots on large-scale and their application for broad fluorescent pH sensing. Sens. Actuat. B Chem. 2018, 255, 572–579.
Crossref Google Scholar
33

Zhao, W.; Song, C.; Pehrsson, P. E. Water-soluble and optically pH-sensitive single-walled carbon nanotubes from surface modification. J. Am. Chem. Soc. 2002, 124, 12418–12419.
Crossref Google Scholar
34

Yang, M.; Li, B. Y.; Zhong, K. L.; Lu, Y. Photoluminescence properties of N-doped carbon dots prepared in different solvents and applications in pH sensing. J. Mater. Sci. 2017, 53, 2424–2433.
Crossref Google Scholar
35

Oh, N.; Park, J. H. Surface chemistry of gold nanoparticles mediates their exocytosis in macrophages. ACS Nano 2014, 8, 6232–6241.
Crossref Google Scholar
36

Dunn, K. W.; Kamocka, M. M.; McDonald, J. H. A practical guide to evaluating colocalization in biological microscopy. Am. J. Physiol. Cell Physiol. 2011, 300, C723–742.
Crossref Google Scholar
37

Miri, A. K.; Heris, H. K.; Tripathy, U.; Wiseman, P. W.; Mongeau, L. Microstructural characterization of vocal folds toward a strain-energy model of collagen remodeling. Acta Biomater. 2013, 9, 7957–7967.
Crossref Google Scholar
38

Iversen, T. G.; Skotland, T.; Sandvig, K. Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies. Nano Today 2011, 6, 176–185.
Crossref Google Scholar
39

Nagy, A.; Zane, A.; Cole, S. L.; Severance, M.; Dutta, P. K.; Waldman, W. J. Contrast of the biological activity of negatively and positively charged microwave synthesized CdSe/ZnS quantum dots. Chem. Res. Toxicol. 2011, 24, 2176–2188.
Crossref Google Scholar
40

Martens, T. F.; Remaut, K.; Demeester, J.; De Smedt, S. C.; Braeckmans, K. Intracellular delivery of nanomaterials: How to catch endosomal escape in the act. Nano Today 2014, 9, 344–364.
Crossref Google Scholar
41

Zhang, Y.; Mi, L.; Wang, P. N.; Lu, S. J.; Chen, J. Y.; Guo, J.; Yang, W. L.; Wang, C. C. Photoluminescence decay dynamics of thiol-capped CdTe quantum dots in living cells under microexcitation. Small 2008, 4, 777–780.
Crossref Google Scholar
42

Chao, S. C.; Wu, G. J.; Huang, S. F.; Dai, N. T.; Huang, H. K.; Chou, M. F.; Tsai, Y. T.; Lee, S. P.; Loh, S. H. Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells. World J. Stem. Cells 2018, 10, 196–211.
Crossref Google Scholar
43

Persi, E.; Duran-Frigola, M.; Damaghi, M.; Roush, W. R.; Aloy, P.; Cleveland, J. L.; Gillies, R. J.; Ruppin, E. Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nat. Commun. 2018, 9, 2997.
Crossref Google Scholar
44

Pal, A.; Ahmad, K.; Dutta, D.; Chattopadhyay, A. Boron doped carbon dots with unusually high photoluminescence quantum yield for ratiometric intracellular pH sensing. ChemPhysChem 2019, 20, 1018–1027.
Crossref Google Scholar
45

Galenkamp, K. M. O.; Sosicka, P.; Jung, M.; Recouvreux, M. V.; Zhang, Y. J.; Moldenhauer, M. R.; Brandi, G.; Freeze, H. H.; Commisso, C. Golgi acidification by NHE7 regulates cytosolic pH homeostasis in pancreatic cancer cells. Cancer Discov. 2020, 10, 822–835.
Crossref Google Scholar
46

Llopis, J.; McCaffery, J. M.; Miyawaki, A.; Farquhar, M. G.; Tsien, R. Y. Measurement of cytosolic, mitochondrial, and Golgi pH in single living cells with green fluorescent proteins. Proc. Natl. Acad. Sci. USA 1998, 95, 6803–6808.
Crossref Google Scholar
47

Leone, R. D.; Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 2020, 20, 516–531.
Crossref Google Scholar
48

Webb, B. A.; Chimenti, M.; Jacobson, M. P.; Barber, D. L. Dysregulated pH: A perfect storm for cancer progression. Nat. Rev. Cancer 2011, 11, 671–677.
Crossref Google Scholar
49

White, K. A.; Grillo-Hill, B. K.; Barber, D. L. Cancer cell behaviors mediated by dysregulated pH dynamics at a glance. J. Cell Sci. 2017, 130, 663–669.
Crossref Google Scholar
50

Wang, W. S.; Liu, Y.; Niu, J.; Lin, W. Y. Discriminating normal and inflammatory models by viscosity changes with a mitochondria-targetable fluorescent probe. Analyst 2019, 144, 6247–6253.
Crossref Google Scholar
51

Ordóñez-Hernández, J.; Jiménez-Sánchez, A.; García-Ortega, H.; Sánchez-Puig, N.; Flores-Álamo, M.; Santillan, R.; Farfán, N. A series of dual-responsive Coumarin-Bodipy probes for local microviscosity monitoring. Dyes Pigments 2018, 157, 305–313.
Crossref Google Scholar
52

Chen, W.; Han, J. Y.; She, J. X.; Wang, F. L.; Zhu, L.; Yu, R. Q.; Jiang, J. H. Simultaneous imaging of lysosomal and mitochondrial viscosity during mitophagy using molecular rotors with dual-color emission. Chem. Commun. (Camb) 2020, 56, 7797–7800.
Crossref Google Scholar
53

Orij, R.; Urbanus, M. L.; Vizeacoumar, F. J.; Giaever, G.; Boone, C.; Nislow, C.; Brul, S.; Smits, G. J. Genome-wide analysis of intracellular pH reveals quantitative control of cell division rate by pHc in Saccharomyces cerevisiae. Genome Biol. 2012, 13, R80.
Crossref Google Scholar
Nano Research
Volume 15 Issue 6,
June 2022
Pages 5193-5204
DOI: 10.1007/s12274-022-4104-1
Cite this article:
Su W, Yang D, Wang Y, et al. AgInS2/ZnS quantum dots for noninvasive cervical cancer screening with intracellular pH sensing using fluorescence lifetime imaging microscopy. Nano Research, 2022, 15(6): 5193-5204. https://doi.org/10.1007/s12274-022-4104-1
Topics:
Nano biology

1062

Views

11

Crossref

9

Web of Science

9

Scopus

1

CSCD

Altmetrics
Received: 21 October 2021
Revised: 24 December 2021
Accepted: 27 December 2021
Published: 07 March 2022
© Tsinghua University Press 2022
Return