An azo-based fluorescent probe for the detection of hypoxic tumor cells
- Corresponding author: Yang JIAO, jiaoyang@dlut.edu.cn
Citation:
Lei ZHANG, Cheng HE, Yang JIAO. An azo-based fluorescent probe for the detection of hypoxic tumor cells[J]. Chinese Journal of Inorganic Chemistry,
;2025, 41(6): 1162-1172.
doi:
10.11862/CJIC.20250081
QUEEN A, BHUTTO H N, YOUSUF M, SYED M A, HASSAN M I. Carbonic anhydrase Ⅸ: A tumor acidification switch in heterogeneity and chemokine regulation[J]. Semin. Cancer Biol., 2022,86:899-913. doi: 10.1016/j.semcancer.2022.01.001
SINGLETON D C, MACANN A, WILSON W R. Therapeutic targeting of the hypoxic tumour microenvironment[J]. Nat. Rev. Clin. Oncol., 2021,18:751-772. doi: 10.1038/s41571-021-00539-4
CHEN Z, HAN F, DU Y, SHI H, ZHOU W. Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions[J]. Signal Transduct. Target. Ther., 2023,870. doi: 10.1038/s41392-023-01332-8
LEE P, CHANDEL N S, SIMON M C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond[J]. Nat. Rev. Mol. Cell Biol., 2020,12:468-474.
ZHOU Q, XIANG J J, QIU N S, WANG Y C, PIAO Y, SHAO S Q, TANG J B, ZHOU Z X, SHEN Y Q. Tumor abnormality-oriented nanomedicine design[J]. Chem. Rev., 2023,123:10920-10989. doi: 10.1021/acs.chemrev.3c00062
CHEN D P, TANG Y Y, ZHU J W, ZHANG J J, SONG X J, WANG W J, SHAO J J, HUANG W, CHEN P, DONG X C. Photothermal-pHhypoxia responsive multifunctional nanoplatform for cancer photo chemo therapy with negligible skin phototoxicity[J]. Biomaterials, 2019,221119422. doi: 10.1016/j.biomaterials.2019.119422
NIA H T, MUNN L L, JAIN R K. Physical traits of cancer[J]. Science, 2020,370eaaz0868. doi: 10.1126/science.aaz0868
STYLIANOPOULOS T, MARTIN J D, CHAUHAN V P, JAIN R K. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors[J]. Proc. Natl. Acad. Sci. U. S. A., 2012,109:15101-15108. doi: 10.1073/pnas.1213353109
ACHARYA S, SAHOO S K. PLGA nanoparticles containing various anticancer agents and tumor delivery by EPR effect[J]. Adv. Drug Deliv. Rev., 2011,63:170-183. doi: 10.1016/j.addr.2010.10.008
CHEN Y Z, SONG W T, SHEN L M, QIU N S, HU M Y, LIU Y, LIU Q, HUANG L. Vasodilator hydralazine promotes nanoparticle penetration in advanced desmoplastic tumors[J]. ACS Nano, 2019,13:1751-1763.
FUKUMURA D, JAIN R K. Tumor microvasculature and microenvironment: Targets for antiangiogenesis and normalization[J]. Microvasc. Res., 2007,74:72-84. doi: 10.1016/j.mvr.2007.05.003
BINNEWIES M, ROBERTS E W, KERSTEN K, CHAN V, FEARON D F, MERAD M, COUSSENS L M, GABRILOVICH D I, ROSENBERG S O, HEDRICK C C, VONDERHEIDE R H, PITTET M J, JAIN R K, ZOU W P, HOWCROFT T K, WOODHOUSE E C, WEINBERG R A, KRUMMEL M F. Understanding the tumor immune microenvironment (TIME) for effective therapy[J]. Nat. Med., 2018,24:541-550. doi: 10.1038/s41591-018-0014-x
SEMENZA G L. Hypoxia-inducible factors: Coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype[J]. EMBO J., 2017,36:252-259. doi: 10.15252/embj.201695204
WU J C, WANG X, CHEN L, WANG J N, ZHANG J L, TANG J H, JI Y T, SONG J Y, WANG L, ZHAO Y X, ZHANG H, LI T H, SHENG J P, CHEN D, ZHANG Q, LIANG T B. Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma[J]. Bioact. Mater., 2023,20:259-270.
ZHU H T Z, LI Q, SHI B B, GE F J, LIU Y Z, MAO Z W, ZHU H, WANG S, YU G C, HUANG F H, STANG P J. Dual-emissive platinum(Ⅱ) metallacage with a sensitive oxygen response for imaging of hypoxia and imaging guided chemotherapy[J]. Angew. Chem. - Int. Edit., 2020,59:20208-20214. doi: 10.1002/anie.202009442
ZHOU F, FU T, HUANG Q, KUAI H L, MO L T, LIU H L, WANG Q Q, PENG Y B, HAN D M, ZHAO Z L, FANG X H, TAN W H. Hypoxia-activated PEGylated conditional aptamer/antibody for cancer imaging with improved specificity[J]. J. Am. Chem. Soc., 2019,141:18421-18427. doi: 10.1021/jacs.9b05063
YAO S Y, YUE Y X, YING A K, HU X Y, LI H B, CAI K, GUO D S. An antitumor dual responsive host guest supramolecular polymer based on hypoxia-cleavable azocalix[J]. Angew. Chem.-Int. Edit., 2023,62e202213578. doi: 10.1002/anie.202213578
SHARMA A, ARAMBULA J F, KOO S, KUMAR R, SINGH H, SESSLER J L, KIM J S. Hypoxia targeted drug delivery[J]. Chem. Soc. Rev., 2019,48:771-813. doi: 10.1039/C8CS00304A
ZHANG S P, CHEN H, WANG L P, QIN X, JIANG B P, JI S C, SHEN X C, LIANG H. A general approach to design dual ratiometric fluorescent and photoacoustic probes for quantitatively visualizing tumor hypoxia levels in vivo[J]. Angew. Chem.-Int. Edit., 2022(61)e202107076.
ZHOU S Y, HU X L, XIA R, LIU S, PEI Q, CHEN G, XIE Z G, JING X B. A paclitaxel prodrug activatable by irradiation in a hypoxic microenvironment[J]. Angew. Chem. - Int. Edit., 2020,592319823205.
DU J J, SHI T C, LONG S R, CHEN P Z, SUN W, FAN J L, PENG X J. Enhanced photodynamic therapy for overcoming tumor hypoxia: From microenvironment regulation to photosensitizer innovation[J]. Coord. Chem. Rev., 2021,427213604. doi: 10.1016/j.ccr.2020.213604
CHEVALIER A, HARDOUIN J, RENARD P Y, ROMIEU A. Universal dark quencher based on"clicked"spectrally distinct azo dyes[J]. Org. Lett., 2013,15:6082-6085. doi: 10.1021/ol402972y
CHEVALIER A, MASSIF C, RENARD P Y, ROMIEU A. Bioconjugatable azo-based dark-quencher dyes: Synthesis and application to protease activatable far red fluorescent probes[J]. Chem. - Eur. J., 2013,19:1686-1699. doi: 10.1002/chem.201203427
CHEVALIER A, RENARD P Y, ROMIEU A. Azosulforhodamine dyes: A novel class of broad spectrum dark quenchers[J]. Org. Lett., 2014,16:3946-3949. doi: 10.1021/ol501753b
VERWILST P, HAN J Y, LEE J, MUN S, KANG H G, KIM J S. Reconsidering azobenzene as a component of small-molecule hypoxiamediated cancer drugs: A theranostic case study[J]. Biomaterials, 2017,115:104-114. doi: 10.1016/j.biomaterials.2016.11.023
GENG W C, JIA S R, ZHENG Z, LI Z H, DING D, GUO D S. A noncovalent fluorescence turn on strategy for hypoxia imaging[J]. Angew. Chem.-Int. Edit., 2019,58:2377-2381.
LI X D, WEI Y S, WU Y C, YIN L C. Hypoxia-induced pro-protein therapy assisted by a self catalyzed[J]. Angew. Chem. - Int. Edit., 2020,59:22544-22553. doi: 10.1002/anie.202004008
SHE D J, HUANG H H, LI J M, PENG S J, WANG H, YU X R. Hypoxia-degradable zwitterionic phosphorylcholine drug nanogel for enhanced drug delivery to glioblastoma[J]. Chem. Eng. J., 2021,408127359. doi: 10.1016/j.cej.2020.127359
DONG B L, SONG W H, KONG X Q, ZHANG N, LIN W Y. Visualizing cellular sodium hydrosulfite (Na2S2O4) using azo-based fluorescent probes with a high signal-to-noise ratio[J]. J. Mater. Chem. B, 2019,7:730-733. doi: 10.1039/C8TB02487A
CHEVALIER A, PIAO W, HANAOKA K, NAGANO T, RENARD P Y, ROMIEU A. Azobenzene caged sulforhodamine dyes: A novel class of'turn-on'reactive probes for hypoxic tumor cell imaging[J]. Methods Appl. Fluoresc., 2015,3044004.
PIAO W, TSUDA S, TANAKA Y, MAEDA S, LIU F Y, TAKAHASHI S, KUSHIDA Y, KOMATSU T, UENO T, TERAI T, NAKAZAWA T, UCHIYAMA M, MOROKUMA K, NAGANO T, HANAOKA K. Development of azo based fluorescent probes to detect different levels of hypoxia[J]. Angew. Chem.-Int. Edit., 2013,52:13028-13032. doi: 10.1002/anie.201305784
CHEVALIER A, MERCIER C, SAUREL L, ORENGA S, RENARD P Y, ROMIEU A. The first latent green fluorophores for the detection of azoreductase activity in bacterial cultures[J]. Chem. Commun., 2013,49:8815-8817. doi: 10.1039/c3cc44798g
CEINOS S G, RIVERO A R, GELLA F R, FUENTE S S, PASTOR S G, CALVO N, ORREGO A H, GUISAN J M, CORRAL I, RODRIGUEZ F S, RIBAGORDA M. Turn-on fluorescent biosensors for imaging hypoxia-like conditions in living cells[J]. J. Am. Chem. Soc., 2022,144:8185-8193. doi: 10.1021/jacs.2c01197
KUMARI R, SUNIL D, NINGTHOUjAM R S, KUMAR N A. Azodyes as markers for tumor hypoxia imaging and therapy: An up-todate review[J]. Chem.-Biol. Interact., 2019,307:91-104. doi: 10.1016/j.cbi.2019.04.034
WANG C Y, ZHANG S P, HUANG J H, CUI L, HU J, TAN S Y. Novel designed azo substituted semi cyanine fluorescent probe for cytochrome P450 reductase detection and hypoxia imaging in cancer cells[J]. RSC Adv., 2019,9:21572-21577. doi: 10.1039/C9RA02741F
MAHESHWARAN M, KUMAR K K S. DFT and electrochemical determination of Hg2+ and Pb2+ in water using polyaniline-quinoxaline composite modified GCE electrode[J]. J. Mol. Liq., 2024,398124317. doi: 10.1016/j.molliq.2024.124317
ZHU W P, DAI M, XU Y F, QIAN X H. Novel nitroheterocyclic hypoxic markers for solid tumor: Synthesis and biological evaluation[J]. Bioorg. Med. Chem., 2008,16:3255-3260. doi: 10.1016/j.bmc.2007.12.011
CUI C F, GAO X, JIA X C, JIAO Y, DUAN C Y. A rhodamine Bbased turn on fluorescent probe for selective recognition of mercury(Ⅱ) ions[J]. Inorg. Chim. Acta, 2021,520120285. doi: 10.1016/j.ica.2021.120285
HASANINEjAD A, ZARE A, MOHAMMADIZADEH M R, SHEKOUHY M. Lithium bromide as an efficient, green, and inexpensive catalyst for the synthesis of quinoxaline derivatives at room temperature[J]. Green Chem. Lett. Rev., 2010,3:143-148. doi: 10.1080/17518251003619192
ELMES R B P. Bioreductive fluorescent imaging agents: Applications to tumor hypoxia[J]. Chem. Commun., 2016,52:8935-8956. doi: 10.1039/C6CC01037G
ZHANG H, FAN J L, WANG J Y, ZHANG S Z, DOU B R, PENG X J. An off-on COX-2-specific fluorescent probe: Targeting the golgi apparatus of cancer cells[J]. J. Am. Chem. Soc., 2013,135:11663-11669. doi: 10.1021/ja4056905
LUO S H, LIU Y C, WANG F Y, FEI Q, SHI B, AN J C, ZHAO C C, TUNG C H. A fluorescent turn-on probe for visualizing lysosomes in hypoxic tumor cells[J]. Analyst, 2016,141:2879-2882. doi: 10.1039/C6AN00369A
CHEVALIER A, RENARD P Y, ROMIEU A. Azo-based fluorogenic probes for biosensing and bioimaging: Recent advances and upcoming challenges[J]. Chem.-Asian J., 2017,12:2008-2028. doi: 10.1002/asia.201700682
YILDIZ E, KARADENIZ B, YILDIZ A M, RENCUZOGULLARI E. Bivalent and trivalent transition metal complexes of azo compounds derived from anthraquinone and their mutagenic-teratogenic effects[J]. Chinese J. Inorg. Chem., 2013,29(3):595-604.
ZHANG J J, YAN M, LU W, XU L, WANG X Q. Bivalent and trivalent transition metal complexes of azo compounds derived from anthraquinone and their mutagenic-teratogenic effects[J]. Chinese J. Inorg. Chem., 2021,37(6):1071-1079.
ZHANG C L, ZHANG J J, SHEN Y, LU J C, HUANG F, XU L. A highly sensitive ratiometric fluorescence probe for Zn2+ detection in living cells[J]. Chinese J. Inorg. Chem., 2022,38(8):1623-1632.
WANG C, YANG M, DENG X Y, HE M L. A fluorescence-enhanced probe based on benzimidazole for bisulfite and its practical application[J]. Chinese J. Inorg. Chem., 2020,36(4):762-768.
LIU Y R, ZHANG D T, QU Y W, TANG F, WANG H, DING A X, LI L. Advances in small-molecule fluorescent pH probes for monitoring mitophagy[J]. Chem. Biomed. Imaging, 2024,2:81-97. doi: 10.1021/cbmi.3c00070
GONZALEZ G A, OSUjI E U, FIUR N C, CLARK M G, MA S, LUKOV L L, ZHANG C. Alteration of lipid metabolism in hypoxic cancer cells[J]. Chem. Biomed. Imaging, 2025,3:25-34. doi: 10.1021/cbmi.4c00050
CHEN Y Y, JIANG H, HAO T T, ZHANG N, LI M Y, WANG X Y, WANG X X, WEI W, ZHAO J. Fluorogenic reactions in chemical biology: Seeing chemistry in cells[J]. Chem. Biomed. Imaging, 2023,1:590-619. doi: 10.1021/cbmi.3c00029
SHI J C, TIAN Y M, WU W N, WANG Y, LI X X. A quinoxalinecontaining Schiff base probe for the selective and sensitive detection of Zn2+ and imaging application in living cells[J]. Chinese J. Inorg. Chem., 2023,39(7):1295-1302.
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λex=400 nm.
λex=400 nm, λem=550 nm.
1: Na+, 2: K+, 3: Ca2+, 4: Cu2+, 5: Mg2+, 6: Zn2+, 7: L-Glu, 8: L-Tyr, 9: L-Arg, 10: L-Asp, 11: L-Pro, 12: L-Hcy, 13: L-Cys, 14: GSH, 15: H2O2, 16: ATP, 17: BSA, 18: Gluox, 19: Cyt C, 20: SDT; Data were presented as the mean value±SD (n=3).
Scale bar=40 μm; Data were presented as the mean value±SD (n=3, *p < 0.05, **p < 0.01, ***p < 0.001).
Scale bar=40 μm; Data were presented as the mean value±SD (n=3, *p < 0.05, **p < 0.01, ***p < 0.001).