Eur J Pharm Biopharm . Pronounced therapeutic potential of oligonucleotides fixed on inorganic nanoparticles against highly pathogenic H5N1 influenza A virus in vivo

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Eur J Pharm Biopharm


. 2021 Mar 19;S0939-6411(21)00072-2.
doi: 10.1016/j.ejpb.2021.03.006. Online ahead of print.
Pronounced therapeutic potential of oligonucleotides fixed on inorganic nanoparticles against highly pathogenic H5N1 influenza A virus in vivo


Asya Levina ¹ , Marina Repkova ¹ , Nadezhda Shikina ² , Zinfer Ismagilov ² , Maxim Kupryushkin ¹ , Anna Pavlova ¹ , Natalia Mazurkova ³ , Dmitrii Pyshnyi ¹ , Valentina Zarytova ⁴



Affiliations

• PMID: 33753212
• DOI: 10.1016/j.ejpb.2021.03.006

Abstract

This study describes the effective attack of oligonucleotides on the viral genome of highly pathogenic H5N1 influenza A virus (IAV) in vivo using for the first time the new delivery system consisting of biocompatible low-toxic titanium dioxide nanoparticles and immobilized polylysine-containing oligonucleotides with the native (ODN) and partially modified (ODN_m) internucleotide bonds. Intraperitoneal injection of the TiO₂?PL-ODN nanocomposite provided 65-70% survival of mice, while intraperitoneal or oral administration of TiO₂?PL-ODN_m was somewhat more efficient (?80% survival). The virus titer in the lung was reduced by two-three orders of magnitude. The nanocomposites are nontoxic to mice under the used conditions. TiO₂ nanoparticles, unbound ODN, and the nanocomposite bearing the random oligonucleotide showed an insignificant protective effect, which indicates the ability of targeted oligonucleotides delivered in mice in the nanocomposites to site-specifically interact with complementary RNAs. The protection of oligonucleotides in nanocomposites by TiO₂ nanoparticles and partial modification of the internucleotide bonds provides a continued presence of oligonucleotides in the body for the effective and specific action on the viral RNA. The proposed oligonucleotide delivery system can claim not only to effectively inhibit IAV genes but also to turn off other genes responsible for diseases caused by nucleic acids.

Keywords: Influenza A virus; TiO(2)-based nanocomposites; mice; oligonucleotides; virus titer.