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Fluorescent Conjugates Based on Prostate-Specific Membrane Antigen Ligands as an Effective Visualization Tool for Prostate Cancer

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Abstract

Fluorescent dyes are widely used in histological studies and in intraoperative imaging, including surgical treatment of prostate cancer (PC), which is one of the most common types of cancerous tumors among men today. Targeted delivery of fluorescent conjugates greatly improves diagnostic efficiency and allows for timely correct diagnosis. In the case of PC, the protein marker is a prostate-specific membrane antigen (PSMA). To date, a large number of diagnostic conjugates targeting PSMA have been created based on modified urea. The review focuses on the conjugates selectively binding to PSMA and answers the following questions: What fluorescent dyes are already in use in the field of PC diagnosis? What factors influence the structure–activity ratio of the final molecule? What features should be considered when selecting a fluorescent tag to create new diagnostic conjugates? And what could be suggested to further development in this field at the present time?

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Abbreviations

2-MPPA:

2-(3-mercaptopropyl)pentatonic acid

2-PMPA:

2-(phosphonomethyl)- pentanedioic acid

DCL/ACUPA:

N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine

DOTA:

dodecantetraacetic acid

DUPA:

2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid

GPI:

2-[((3-amino-3-carboxypropyl)(hydroxy)phosphinyl)-methyl]pentane-1,5-dionic acid

MAG3 :

mercaptoacetiotriglycine

PSMA:

prostate-specific membrane antigen

References

  1. Jones, A. D., and Wilton, J. C. (2017) Can intra-operative fluorescence play a significant role in hepatobiliary surgery? Eur. J. Surg. Oncol., 43, 1622-1627, https://doi.org/10.1016/j.ejso.2017.02.015.

    Article  CAS  PubMed  Google Scholar 

  2. Fei, X., and Gu, Y. (2009) Progress in modifications and applications of fluorescent dye probe, Prog. Nat. Sci., 19, 1-7, https://doi.org/10.1016/j.pnsc.2008.06.004.

    Article  CAS  Google Scholar 

  3. Hemmer, E., Benayas, A., Légaré, F., and Vetrone, F. (2016) Exploiting the biological windows: current perspectives on fluorescent bioprobes emitting above 1000 nm, Nanoscale Horizons, 1, 168-184, https://doi.org/10.1039/c5nh00073d.

    Article  CAS  PubMed  Google Scholar 

  4. Sung, H., Ferlay, J., Siegel, R. L., and Laversanne, M. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 71, 209-249, https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  5. Jackson, P. F., Cole, D. C., Slusher, B. S., Stetz, S. L., Ross, L. E., Donzanti, B. F., and Trainor, D. A. (1996) Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated α-linked acidic dipeptidase, J. Med. Chem., 39, 619-622, https://doi.org/10.1021/jm950801q.

    Article  CAS  PubMed  Google Scholar 

  6. Kozela, E., Wrobel, M., Kos, T., Wojcikowski, J., Daniel, W. A., Wozniak, K. M., Slusher, B. S., and Popik, P. (2005) 2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice, Psychopharmacology (Berl), 183, 275-284, https://doi.org/10.1007/s00213-005-0182-5.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, A. X., Murelli, R. P., Barinka, C., Michel, J., Cocleaza, A., Jorgensen, W. L., Lubkowski, J., and Spiegel, D. A. (2010) A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules, J. Am. Chem. Soc., 132, 12711-12716, https://doi.org/10.1021/ja104591m.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barinka, C., Novakova, Z., Hin, N., Bíme, D., Ferraris, D. V., Duvall, B., Kabarriti, G., Tsukamoto, R., Budesinsky, M., Motlova, L., Rojas, C., Slusher, B. S., Rokob, T. A., Rulíšek, L., and Tsukamoto, T. (2019) Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors, Bioorg. Med. Chem., 27, 255-264, https://doi.org/10.1016/j.bmc.2018.11.022.

    Article  CAS  PubMed  Google Scholar 

  9. Barinka, C., Rojas, C., Slusher, B., and Pomper, M. (2012) Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer, Curr. Med. Chem., 19, 856-870, https://doi.org/10.2174/092986712799034888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cilibrizzi, A., Wang, J. T.-W., Memdouh, S., Iacovone, A., McElroy, K., Jaffar, N., Young, J. D., Hider, R. C., Blower, P., Al-Jamal, K., and Abbate, V. (2022) PSMA-targeted NIR probes for image-guided detection of prostate cancer, Colloids Surf. B Biointerfaces, 218, 112734, https://doi.org/10.1016/j.colsurfb.2022.112734.

    Article  CAS  PubMed  Google Scholar 

  11. Petrov, S. A., Machulkin, A. E., Uspenskaya, A. A., Zyk, N. Y., Nimenko, E. A., Garanina, A. S., Petrov, R. A., Polshakov, V. I., Grishin, Y. K., Roznyatovsky, V. A., Zyk, N. V., Majouga, A. G., and Beloglazkina, E. K. (2020) Polypeptide-based molecular platform and its docetaxel/sulfo-Cy5-containing conjugate for targeted delivery to prostate specific membrane antigen, Molecules, 25, 5784, https://doi.org/10.3390/molecules25245784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, T., Jabbes, M., Nedrow-Byers, J. R., Wu, L. Y., Bryan, J. N., and Berkman, C. E. (2011) Detection of prostate-specific membrane antigen on HUVECs in response to breast tumor-conditioned medium, Int. J. Oncol., 38, 1349-1355, https://doi.org/10.3892/ijo.2011.946.

    Article  CAS  PubMed  Google Scholar 

  13. Humblet, V., Lapidus, R., Williams, L. R., Tsukamoto, T., Rojas, C., Majer, P., Hin, B., Ohnishi, S., De Grand, A. M., Zaheer, A., Renze, J. T., Nakayama, A., Slusher, B. S., and Frangioni, J. V. (2005) High-affinity near-infrared fluorescent small-molecule contrast agents for in vivo imaging of prostate-specific membrane antigen, Mol. Imaging, 4, 448-462, https://doi.org/10.2310/7290.2005.05163.

    Article  PubMed  Google Scholar 

  14. Jing, Y., Cai, M., Zhou, L., Jiang, J., Gao, J., and Wang, H. (2020) Application of an inhibitor-based probe to reveal the distribution of membrane PSMA in dSTORM imaging, Chem. Commun., 56, 13241-13244, https://doi.org/10.1039/D0CC04889E.

    Article  CAS  Google Scholar 

  15. Matsuoka, D., Watanabe, H., Shimizu, Y., Kimura, H., Ono, M., and Saji, H. (2021) Synthesis and evaluation of a novel near-infrared fluorescent probe based on succinimidyl-Cys-C(O)-Glu that targets prostate-specific membrane antigen for optical imaging, Bioorg. Med. Chem. Lett., 27, 4876-4880, https://doi.org/10.1016/j.bmcl.2017.09.037.

    Article  CAS  Google Scholar 

  16. Ye, S., Zhang, H., Fei, J., Wolstenholme, C. H., and Zhang, X. (2021) A general strategy to control viscosity sensitivity of molecular rotor-based fluorophores, Angew. Chem. Int Ed., 60, 1339-1346, https://doi.org/10.1002/anie.202011108.

    Article  CAS  Google Scholar 

  17. Karimi, A., Börner, R., Mata, G., and Luedtke, N. W. (2020) A highly fluorescent nucleobase molecular rotor, J. Am. Chem. Soc., 142, 14422-14426, https://doi.org/10.1021/jacs.0c05180.

    Article  CAS  PubMed  Google Scholar 

  18. Kopka, K., Benešová, M., Bařinka, C., Haberkorn, U., and Babich, J. (2017) Glu-ureido-based inhibitors of prostate-specific membrane antigen: Lessons learned during the development of a novel class of low-molecular-weight theranostic radiotracers, J. Nucl. Med., 58, 17S-26S, https://doi.org/10.2967/jnumed.116.186775.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, J., Rakhimbekova, A., Duan, X., Yin, Q., Foss, C. A., Fan, Y., Xu, Y., Li, X., Cai, X., Kutil, Z., Wang, P., Yang, Z., Zhang, N., Pomper, M. G., Wang, Y., Bařinka, C., and Yang, X. (2021) A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging, Nat Commun., 12, 5460, https://doi.org/10.1038/s41467-021-25746-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lincoln, R., Bossi, M. L., Remmel, M., D’Este, E., Butkevich, A. N., and Hell, S. W. (2022) A general design of caging-group-free photoactivatable fluorophores for live-cell nanoscopy, Nat. Chem., 14, 1013-1020, https://doi.org/10.1038/s41557-022-00995-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, Y., Dhara, S., Banerjee, S. R., Byun, Y., Pullambhatla, M., Mease, R. C., and Pomper, M. G. (2009) A low molecular weight PSMA-based fluorescent imaging agent for cancer, Biochem. Biophys. Res. Commun., 390, 624-629, https://doi.org/10.1016/j.bbrc.2009.10.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang, X., Huang, S. S., Heston, W. D. W., Guo, H., Wang, B. C., and Basilion, J. P. (2014) Development of targeted near-infrared imaging agents for prostate cancer, Mol. Cancer Ther., 13, 2595-2606, https://doi.org/10.1158/1535-7163.MCT-14-0422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang, S. S., Wang, X., Zhang, Y., Doke, A., Difilippo, F. P., and Heston, W. D. (2014) Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker, Prostate, 74, 702-713, https://doi.org/10.1002/pros.22789.

    Article  CAS  PubMed  Google Scholar 

  24. Tang, W., and Becker, M. L. (2014) “Click” reactions: a versatile toolbox for the synthesis of peptide-conjugates, Chem. Soc. Rev., 43, 7013-7039, https://doi.org/10.1039/c4cs00139g.

    Article  CAS  PubMed  Google Scholar 

  25. Ciuk, A. K., and Lindhorst, T. K. (2015) Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency, Beilstein J. Org. Chem., 11, 668-674, https://doi.org/10.3762/bjoc.11.75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Machulkin, A. E., Uspenskaya, A. A., Ber, A. P., Petrov, S. A., Saltykova, I. V., Ivanenkov, Y. A., Skvortsov, D. A., Erofeev, A. S., Gorelkin, P. V., Beloglazkina, E. K., Belov, E. Iu., Khazanova, E. S., and Majouga, A. G. (2019) Peptide agent comprising a urea derivative based PSMA-binding ligand, a method for preparing the same, and use for producing a conjugate with a drug and diagnostic agent, RF Patent 2697519.

  27. Machulkin, A. E., Shafikov, R. R., Uspenskaya, A. A., Petrov, S. A., Ber, A. P., Skvortsov, D. A., Nimenko, E. A., Zyk, N. U., Smirnova, G. B., Pokrovsky, V. S., Abakumov, M. A., Saltykova, I. V., Akhmirov, R. T., Garanina, A. S., Polshakov, V. I., Saveliev, O. Y., Ivanenkov, Y. A., Aladinskaya, A. V., Finko, A. V., Yamansarov, E. U., Krasnovskaya, O. O., Erofeev, A. S., Gorelkin, P. V., Dontsova, O. A., Beloglazkina, E. K., Zyk, N. V., Khazanova, E. S., and Majouga, A. G. (2021) Synthesis and biological evaluation of PSMA ligands with aromatic residues and fluorescent conjugates based on them, J. Med. Chem., 64, 4532-4552, https://doi.org/10.1021/acs.jmedchem.0c01935.

    Article  CAS  PubMed  Google Scholar 

  28. Weissleder, R. (2001) A clearer vision for in vivo imaging: progress continues in the development of smaller, more penetrable probes for biological imaging, Nat. Biotechnol., 19, 316-317, https://doi.org/10.1038/86684.

    Article  CAS  PubMed  Google Scholar 

  29. Kularatne, S. A., Thomas, M., Myers, C. H., Pravin, G., Kanduluru, A. K., Crian, C. J., and Cichocki, B. N. (2019) Evaluation of novel prostate-specific membrane antigen-targeted near-infrared imaging agent for fluorescence-guided surgery of prostate cancer, Clin. Cancer Res., 25, 177-187, https://doi.org/10.1158/1078-0432.CCR-18-0803.

    Article  CAS  PubMed  Google Scholar 

  30. Kelderhouse, L. E., Chelvam, V., Wayua, C., Mahalingam, S., Poh, S., Kularatne, S. A., and Low, P. S. (2013) Development of tumor-targeted near infrared probes for fluorescence guided surgery, Bioconjug. Chem., 24, 1075-1080, https://doi.org/10.1021/bc400131a.

    Article  CAS  PubMed  Google Scholar 

  31. Raveenthiran, S., Esler, R., Yaxley, J., and Kyle, S. (2019) The use of 68Ga-PET/CT PSMA in the staging of primary and suspected recurrent renal cell carcinoma, Eur. J. Nucl. Med. Mol. Imaging, 46, 2280-2288, https://doi.org/10.1007/s00259-019-04432-2.

    Article  PubMed  Google Scholar 

  32. Salas Fragomeni, R. A., Amir, T., Sheikhbahaei, S., Harvey, S. C., Javadi, M. S., Solnes, M. B., Kiess, A. P., Allaf, M. E., Pomper, M. G., Gorin, M. A., and Rowe, S. P. (2018) Imaging of nonprostate cancers using PSMA-targeted radiotracers: rationale, current state of the field, and a call to arms, J. Nucl. Med., 59, 871-877, https://doi.org/10.2967/jnumed.117.203570.

    Article  CAS  PubMed  Google Scholar 

  33. Kellogg, R. E., and Bennett, R. G. (1964) Radiationless intermolecular energy transfer. III. Determination of phosphorescence efficiencies, https://doi.org/10.1063/1.1725672.

    Article  CAS  Google Scholar 

  34. Derks, Y. H. W., Rijpkema, M., Amatdjais-Groenen, H. I. V., Loeff, C. C., Roode, K. E., Kip, A., Laverman, P., Lüthe, S., Heskamp, S., and Löwik, D. W. P. M. (2022) Strain-promoted azide–alkyne cycloaddition-based PSMA-targeting ligands for multimodal intraoperative tumor detection of prostate cancer, Bioconjug. Chem., 33, 194-205, https://doi.org/10.1021/acs.bioconjchem.1c00537.

    Article  CAS  PubMed  Google Scholar 

  35. Baranski, A. C., Schäfer, M., Bauder-Wüst, U., Roscher, M., Schmidt, J., Stenau, E., Simpfendörfer, T., Teber, D., Maier-Hein, L., Hadaschik, B., Haberkorn, U., Eder, M., and Kopka, K. (2018) PSMA-11-derived dual-labeled PSMA inhibitors for preoperative PET imaging and precise fluorescence-guided surgery of prostate cancer, J. Nucl. Med., 59, 639-645, https://doi.org/10.2967/jnumed.117.201293.

    Article  CAS  PubMed  Google Scholar 

  36. Kommidi, H., Guo, H., Nurili, F., Vedvyas, Y., Jin, M. M., McClure, T. D., Ehdaie, B., Sayman, H. B., Akin, O., Aras, O., and Ting, R. (2018) 18F-Positron emitting/trimethine cyanine-fluorescent contrast for image-guided prostate cancer management, J. Med. Chem., 61, 4256-4262, https://doi.org/10.1021/acs.jmedchem.8b00240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Aras, O., Demirdag, C., Kommidi, H., Guo, H., Pavlova, I., Aygun, A., Karayel, E., Pehlivanoglu, H., Yeyin, N., Kyprianou, N., Chen, N., Harmsen, S., Sonmezoglu, K., Lundon, D. J., Oklu, R., Ting, R., Tewari, A., Akin, O., and Sayman, H. B. (2021) Small molecule, multimodal, [18F]-PET and fluorescence imaging agent targeting prostate-specific membrane antigen: first-in-human study, Clin. Genitourin. Cancer, 19, 405-416, https://doi.org/10.1016/j.clgc.2021.03.011.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Aras, O., Demirdag, C., Kommidi, H., Pavlova, I., Boyko, V., Lundon, D. J., Ting, R., Tewari, A., Akin, O., and Sayman, H. B. (2021) Simultaneous injection of 18F-BF3- Cy3-ACUPA and non-radioactive Cy7-ACUPA probes: a promising pre-biopsy PET and ex vivo fluorescence imaging approach to evaluate prostate cancer, Eur. J. Nucl. Med. Mol. Imaging, 48, 3732-3733, https://doi.org/10.1007/s00259-021-05344-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Derks, Y. H. W., van Lith, S. A. M., Amatdjais-Groenen, H. I. V., Wouters, L. W. M., Kip, A., Franssen, G. M., Laverman, P., Löwik, D. W. P. M., Heskamp, S., and Rijpkema, M. (2022) Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer, Eur. J. Nucl. Med. Mol. Imaging, 49, 2425-2435, https://doi.org/10.1007/s00259-022-05685-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Uspenskaya, A. A., Nimenko, E. A., Machulkin, A. E., Beloglazkina, E. K., and Majouga, A. G. (2021) The importance of linkers in the structure of PSMA ligands, Curr. Med. Chem., 28, 1-31, https://doi.org/10.2174/0929867328666210804092200.

    Article  CAS  Google Scholar 

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Funding

The research was financially supported by the Russian Science Foundation, grant no. 23-23-00297 (Synthetic design of carbocyanine dye conjugates with PSMA-selective ligands in order to create a diagnostic tool for prostate tumor tissue imaging), https://rscf.ru/project/23-23-00297/ [in Russian].

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Authors and Affiliations

  1. Faculty of Chemistry, Lomonosov Moscow State University, 119991, Moscow, Russia

    Anastasiia A. Uspenskaia, Pavel A. Krasnikov, Elena K. Beloglazkina & Aleksei E. Machulkin

  2. RUDN University, 117198, Moscow, Russia

    Aleksei E. Machulkin

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  1. Anastasiia A. Uspenskaia
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  2. Pavel A. Krasnikov
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  3. Elena K. Beloglazkina
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  4. Aleksei E. Machulkin
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A.A.U. – concept, writing the text; P.A.K. – work design; E.K.B. –writing and reviewing the text, A.E.M. – concept, writing and editing the text.

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Correspondence to Anastasiia A. Uspenskaia.

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The authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies involving human participants or animals performed by any of the authors.

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Uspenskaia, A.A., Krasnikov, P.A., Beloglazkina, E.K. et al. Fluorescent Conjugates Based on Prostate-Specific Membrane Antigen Ligands as an Effective Visualization Tool for Prostate Cancer. Biochemistry Moscow 88, 953–967 (2023). https://doi.org/10.1134/S0006297923070088

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