TY - JOUR

T1 - In vivo hypotensive effect of aminosilanol-based nanocomposites bearing antisense oligonucleotides

AU - Levina, Asya

AU - Repkova, Marina

AU - Kupryushkin, Maxim

AU - Seryapina, Alisa

AU - Shevelev, Oleg

AU - Pyshnyi, Dmitrii

AU - Zarytova, Valentina

AU - Markel, Arcady

N1 - Funding Information: The research was supported by the State-funded budget projects, Russia ( 121031300042-1 and FWNR-2022-0019 ) and Russian Foundation for Basic Research, Russia (grant no. 20-04-00119 ). Publisher Copyright: © 2022 Elsevier B.V.

PY - 2022/9

Y1 - 2022/9

N2 - The search for new effective drugs for the treatment of arterial hypertension continues to be an urgent task. We studied the effect of aminosilanol nanocomposites (Si∼ODN) that contained antisense oligonucleotides on the blood pressure in the hypertensive ISIAH rat strain, an experimental model of stress-sensitive arterial hypertension. The intraperitoneal, intravenous, and inhalation administration of Si∼ODN targeted to mRNAs of the AT1A, ADRB1, and ACE1 genes decreased systolic blood pressure by 12–40 mm Hg. The use of scrambled oligonucleotides led to no antisense effect. The proposed in vivo delivery system was shown to be suitable for oligonucleotides with both natural and modified internucleotide bonds. The Si∼ODN nanocomposites demonstrated the absence of toxicity under the studied conditions. The intravenous administration of a fluorescently labeled nanocomposite led to its accumulation in the animal's liver and kidneys, and when inhaled, a certain amount was detected in the brain. The content of the label reaches a maximum one day after the treatment and is almost eliminated from the body in two weeks. The best way to correct hypertension in ISIAH rats using the studied nanocomposites may be periodic inhalation of the nanocomposite that carries an oligonucleotide targeted to ACE1-mRNA.

AB - The search for new effective drugs for the treatment of arterial hypertension continues to be an urgent task. We studied the effect of aminosilanol nanocomposites (Si∼ODN) that contained antisense oligonucleotides on the blood pressure in the hypertensive ISIAH rat strain, an experimental model of stress-sensitive arterial hypertension. The intraperitoneal, intravenous, and inhalation administration of Si∼ODN targeted to mRNAs of the AT1A, ADRB1, and ACE1 genes decreased systolic blood pressure by 12–40 mm Hg. The use of scrambled oligonucleotides led to no antisense effect. The proposed in vivo delivery system was shown to be suitable for oligonucleotides with both natural and modified internucleotide bonds. The Si∼ODN nanocomposites demonstrated the absence of toxicity under the studied conditions. The intravenous administration of a fluorescently labeled nanocomposite led to its accumulation in the animal's liver and kidneys, and when inhaled, a certain amount was detected in the brain. The content of the label reaches a maximum one day after the treatment and is almost eliminated from the body in two weeks. The best way to correct hypertension in ISIAH rats using the studied nanocomposites may be periodic inhalation of the nanocomposite that carries an oligonucleotide targeted to ACE1-mRNA.

KW - Antisense oligonucleotides

KW - Arterial hypertension

KW - ISIAH rats

KW - Si-based nanocomposites

UR - http://www.scopus.com/inward/record.url?scp=85135924013&partnerID=8YFLogxK

U2 - 10.1016/j.jddst.2022.103612

DO - 10.1016/j.jddst.2022.103612

M3 - Article

AN - SCOPUS:85135924013

VL - 75

JO - Journal of Drug Delivery Science and Technology

JF - Journal of Drug Delivery Science and Technology

SN - 1773-2247

M1 - 103612

ER -