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Open AccessArticle

Trimeric Small Interfering RNAs and Their Cholesterol-Containing Conjugates Exhibit Improved Accumulation in Tumors, but Dramatically Reduced Silencing Activity

Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk 630090, Russia
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Academic Editor: Andrea Trabocchi
Molecules 2020, 25(8), 1877; https://doi.org/10.3390/molecules25081877
Received: 13 March 2020 / Revised: 16 April 2020 / Accepted: 16 April 2020 / Published: 18 April 2020
(This article belongs to the Special Issue Bioconjugation Strategies in Drug Delivery and Molecular Imaging)
Cholesterol derivatives of nuclease-resistant, anti-MDR1 small-interfering RNAs were designed to contain a 2’-OMe-modified 21-bp siRNA and a 63-bp TsiRNA in order to investigate their accumulation and silencing activity in vitro and in vivo. The results showed that increasing the length of the RNA duplex in such a conjugate increases its biological activity when delivered using a transfection agent. However, the efficiency of accumulation in human drug-resistant KB-8-5 cells during delivery in vitro in a carrier-free mode was reduced as well as efficiency of target gene silencing. TsiRNAs demonstrated a similar biodistribution in KB-8-5 xenograft tumor-bearing SCID mice with more efficient accumulation in organs and tumors than cholesterol-conjugated canonical siRNAs; however, this accumulation did not provide a silencing effect. The lack of correlation between the accumulation in the organ and the silencing activity of cholesterol conjugates of siRNAs of different lengths can be attributed to the fact that trimeric Ch-TsiRNA lags mainly in the intercellular space and does not penetrate sufficiently into the cytoplasm of the cell. Increased accumulation in the organs and in the tumor, by itself, shows that using siRNA with increased molecular weight is an effective approach to control biodistribution and delivery to the target organ. View Full-Text
Keywords: siRNA; TsiRNA; 2’-O-methyl modifications; cholesterol conjugates; Dicer-substrate siRNA; MDR1; biodistribution siRNA; TsiRNA; 2’-O-methyl modifications; cholesterol conjugates; Dicer-substrate siRNA; MDR1; biodistribution
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Chernikov, I.V.; Gladkikh, D.V.; Karelina, U.A.; Meschaninova, M.I.; Ven’yaminova, A.G.; Vlassov, V.V.; Chernolovskaya, E.L. Trimeric Small Interfering RNAs and Their Cholesterol-Containing Conjugates Exhibit Improved Accumulation in Tumors, but Dramatically Reduced Silencing Activity. Molecules 2020, 25, 1877.

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