Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg. © 2021 American Chemical Society. All rights reserved.

Authors
Machulkin A.E.1 , Shafikov R.R.1, 10 , Uspenskaya A.A.1 , Petrov S.A.1 , Ber A.P.1 , Skvortsov D.A.1, 11 , Nimenko E.A.1 , Zyk N.U.1 , Smirnova G.B.6 , Pokrovsky V.S. 6, 7 , Abakumov M.A.3 , Saltykova I.V.1 , Akhmirov R.T.8 , Garanina A.S.3 , Polshakov V.I.9 , Saveliev O.Y.9 , Ivanenkov Y.A.1, 3, 2, 4, 5 , Aladinskaya A.V.2 , Finko A.V.1 , Yamansarov E.U.1 , Krasnovskaya O.O.1, 3 , Erofeev A.S.1, 3 , Gorelkin P.V.1, 3 , Dontsova O.A.1, 10 , Beloglazkina E.K.1 , Zyk N.V.1 , Khazanova E.S.12 , Majouga A.G.1, 3, 8
Publisher
American Chemical Society
Number of issue
8
Language
English
Pages
4532-4552
Status
Published
Volume
64
Year
2021
Organizations
  • 1 Chemistry Department, Lomonosov Moscow State University, Leninskie Gory GSP-1, Moscow, 119991, Russian Federation
  • 2 Moscow Institute of Physics and Technology, State University, 9 Institutskiy Lane, Dolgoprudny City Moscow Region, 141700, Russian Federation
  • 3 National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow, 119049, Russian Federation
  • 4 Federal State Unitary Enterprise Dukhov Automatics Research Institute, Moscow, 127055, Russian Federation
  • 5 Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Oktyabrya Prospekt 71, Ufa, 450054, Russian Federation
  • 6 N.N. Blokhin Cancer Research Center, 24 Kashirskoye sh., Moscow, 115478, Russian Federation
  • 7 RUDN University, Miklukho-Maklaya str. 6, Moscow, 117198, Russian Federation
  • 8 Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow, 125047, Russian Federation
  • 9 Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, 119991, Russian Federation
  • 10 Shemyakin and Ovchinnikov Institute of Bioorganic, Chemistry Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow, 117997, Russian Federation
  • 11 Faculty of Biology and Biotechnologies, Higher School of Economics, Myasnitskaya 13, Moscow, 101000, Russian Federation
  • 12 Izvarino Pharma LLC, v. Vnukovskoe, Vnukovskoe sh., 5th km., Moscow, 108817, Russian Federation
Keywords
antineoplastic agent; fluorescent dye; FOLH1 protein, human; glutamate carboxypeptidase II; ligand; membrane antigen; animal; cell survival; chemistry; drug effect; drug screening; fluorescence imaging; human; male; metabolism; mouse; nude mouse; prostate tumor; structure activity relation; synthesis; tissue distribution; tumor cell line; xenograft; Animals; Antigens, Surface; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Fluorescent Dyes; Glutamate Carboxypeptidase II; Humans; Ligands; Male; Mice; Mice, Nude; Optical Imaging; Prostatic Neoplasms; Structure-Activity Relationship; Tissue Distribution; Transplantation, Heterologous
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