PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility. © 2021 Elsevier Masson SAS

Authors
Machulkin A.E. 1 , Uspenskaya A.A.1 , Zyk N.Y.1 , Nimenko E.A.1 , Ber A.P.1 , Petrov S.A.1 , Shafikov R.R.1, 9 , Skvortsov D.A.1, 10 , Smirnova G.B.6 , Borisova Y.A.6 , Pokrovsky V.S. 6, 7 , Kolmogorov V.S.3 , Vaneev A.N.3 , Ivanenkov Y.A.1, 3, 2, 4, 5 , Khudyakov A.D.1 , Kovalev S.V.1 , Erofeev A.S.3 , Gorelkin P.V.3 , Beloglazkina E.K.1 , Zyk N.V.1 , Khazanova E.S.11 , Majouga A.G.1, 3, 8
Publisher
Elsevier Masson SAS
Language
English
Status
Published
Number
113936
Volume
227
Year
2022
Organizations
  • 1 Lomonosov Moscow State University, Chemistry Dept., Leninskie Gory, Building 1/3, 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 The 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 Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow, 117997, Russian Federation
  • 10 Faculty of Biology and Biotechnologies, Higher School of Economics, Myasnitskaya 13, Moscow, 101000, Russian Federation
  • 11 LLC Izvarino-Pharma, V. Vnukovskoe, Vnukovskoe Sh., 5th Km., Building 1, Moscow, 108817, Russian Federation
Keywords
Antitumor agents; Conjugates; Docetaxel; Drug delivery; Prostate cancer; Prostate-specific membrane antigen
Date of creation
06.07.2022
Date of change
06.07.2022
Short link
https://repository.rudn.ru/en/records/article/record/83937/
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