Cell-penetrating peptide and cationic liposomes mediated siRNA delivery to arrest growth of chronic myeloid leukemia cells in vitro

Vera Vysochinskaya; Yana Zabrodskaya; Olesya Dovbysh; Anton Emelyanov; Vladimir Klimenko; Nikolay Knyazev; Ivan Terterov; Marya Egorova; Alexey Bogdanov; Michael Maslov; Andrey Vasin; Michael Dubina

doi:10.1016/j.biochi.2024.01.006

Cell-penetrating peptide and cationic liposomes mediated siRNA delivery to arrest growth of chronic myeloid leukemia cells in vitro

Biochimie. 2024 Jan 10:221:1-12. doi: 10.1016/j.biochi.2024.01.006. Online ahead of print.

Authors

Affiliations

¹ Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, St. Petersburg, 197376, Russian Federation; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, St. Petersburg, 194064, Russian Federation. Electronic address: vera.vysochinskaya@influenza.spb.ru.
² Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, St. Petersburg, 197376, Russian Federation; Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, St. Petersburg, 194064, Russian Federation.
³ Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, St. Petersburg, 194064, Russian Federation.
⁴ First Pavlov State Medical University of St. Petersburg, L'va Tolstogo str. 6-8, St. Petersburg, 197022, Russian Federation.
⁵ Saint Petersburg Clinical Research and Practical Center of Specialized Types of Medical Care (Oncological) named after N.P., Napalkov, St. Petersburg, 197758, Russian Federation.
⁶ ITMO University, School of Physics and Engineering, Kronverkskiy pr. 49, St. Petersburg, 197101, Russian Federation.
⁷ Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, St. Petersburg, 197376, Russian Federation.
⁸ Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 86 Vernadsky Ave, Moscow, 119571, Russian Federation.
⁹ Russian Academy of Sciences, 14 Leninskiy pr., Moscow, 119991, Russian Federation.

PMID: 38215931
DOI: 10.1016/j.biochi.2024.01.006

Abstract

Gene silencing through RNA interference (RNAi) is a promising therapeutic approach for a wide range of disorders, including cancer. Non-viral gene therapy, using specific siRNAs against BCR-ABL1, can be a supportive or alternative measure to traditional chronic myeloid leukemia (CML) tyrosine kinase inhibitor (TKIs) therapies, given the prevalence of clinical TKI resistance. The main challenge for such approaches remains the development of the effective delivery system for siRNA tailored to the specific disease model. The purpose of this study was to examine and compare the efficiency of endosomolytic cell penetrating peptide (CPP) EB1 and PEG₂₀₀₀-decorated cationic liposomes composed of polycationic lipid 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2Х3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) for anti-bcr-abl siRNA delivery into the K562 human CML cell line. We show that both EB1 and 2Х3-DOPE-DSPE-PEG₂₀₀₀ (0.62 % mol.) liposomes effectively deliver siRNA into K562 cells by endocytic mechanisms, and the use of liposomes leads to more effective inhibition of expression of the targeted gene (BCR-ABL1) and cancer cell proliferation. Taken together, these findings suggest that PEG-decorated cationic liposomes mediated siRNA delivery allows an effective antisense suppression of certain oncogenes, and represents a promising new class of therapies for CML.

Keywords: BCR-ABL1; Cationic liposomes; Cell penetrating peptides; siRNA.