Covalent conjugates based on nanodiamonds with doxorubicin and a cytostatic drug from the group of 1,3,5-triazines: Synthesis, biocompatibility and biological activity

Vladimir V Sharoyko; Grigory M Berdichevsky; Lubov V Vasina; Olga S Shemchuk; Dmitriy N Maystrenko; Oleg E Molchanov; Abdelsattar O E Abdelhalim; Alexey V Nashchekin; Dmitry A Nerukh; Grigorii V Tochilnikov; Igor V Murin; Konstantin N Semenov

doi:10.1016/j.bbagen.2023.130384

Covalent conjugates based on nanodiamonds with doxorubicin and a cytostatic drug from the group of 1,3,5-triazines: Synthesis, biocompatibility and biological activity

Biochim Biophys Acta Gen Subj. 2023 Sep;1867(9):130384. doi: 10.1016/j.bbagen.2023.130384. Epub 2023 May 19.

Affiliations

¹ Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia; Institute of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, Saint Petersburg, 198504, Russia; A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, 70 Leningradskaya Ulitsa, Saint Petersburg, 197758, Russia. Electronic address: sharoyko@gmail.com.
² Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia.
³ Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia; Institute of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, Saint Petersburg, 198504, Russia.
⁴ A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, 70 Leningradskaya Ulitsa, Saint Petersburg, 197758, Russia.
⁵ Institute of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, Saint Petersburg, 198504, Russia; Environmental Research Department, National Center for Social and Criminological Research (NCSCR), 4 Agouza, Giza, 11561, Egypt.
⁶ Ioffe Physical-Technical Institute of the Russian Academy of Sciences, 26 Polytekhnicheskaya 194021, Saint Petersburg, Russia.
⁷ Department of Mathematics, Aston University, Birmingham B4 7ET, UK.
⁸ Petrov Research Institute of Oncology, 68 Leningradskaia Street, Pesochny, Saint Petersburg 197758, Russia.
⁹ Institute of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, Saint Petersburg, 198504, Russia.
¹⁰ Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6-8, Saint Petersburg 197022, Russia; Institute of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, Saint Petersburg, 198504, Russia; A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, 70 Leningradskaya Ulitsa, Saint Petersburg, 197758, Russia. Electronic address: knsemenov@gmail.com.

PMID: 37209777
DOI: 10.1016/j.bbagen.2023.130384

Abstract

We report the synthesis of covalent conjugates of nanodiamonds with doxorubicin and a cytostatic drug from the class of 1,3,5-triazines. The obtained conjugates were identified using a number of physicochemical methods (IR-spectroscopy, NMR-spectroscopy, XRD, XPS, TEM). As a result of our study, it was found that ND-СONH-Dox and ND-COO-Diox showed good hemocompatibility, since they did not affect plasma coagulation hemostasis, platelet functional activity, and erythrocyte membrane. The ND-COO-Diox conjugates are also capable of binding to human serum albumin due to the presence of ND in their composition. In the study of the cytotoxic properties of ND-СONH-Dox and ND-COO-Diox in the T98G glioblastoma cell line, indicating that ND-СONH-Dox and ND-COO-Diox demonstrate greater cytotoxicity at lower concentrations of Dox and Diox in the composition of the conjugates compared to individual drugs; the cytotoxic effect of ND-COO-Diox was statistically significantly higher than that of ND-СONH-Dox at all concentrations studied. Greater cytotoxicity at lower concentrations of Dox and Diox in the composition of conjugates compared to individual cytostatics makes it promising to further study the specific antitumor activity and acute toxicity of these conjugates in models of glioblastoma in vivo. Our results demonstrated that ND-СONH-Dox and ND-COO-Diox enter HeLa cells predominantly via a nonspecific actin-dependent mechanism, while for ND-СONH-Dox a clathrin-dependent endocytosis pathway. All data obtained provide that the synthesized nanomaterials show a potential application as the agents for intertumoral administration.

Keywords: 1,3,5-triazine; Antiradical activity; Biocompatibility; Cytotoxicity; Doxorubicin; Endocytosis; Hemocompatibility; Nanodiamond.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytostatic Agents*
Doxorubicin / chemistry
Glioblastoma*
HeLa Cells
Humans
Nanodiamonds* / chemistry

Substances

Cytostatic Agents
Nanodiamonds
Doxorubicin