Dendritic amphiphilic siRNA: Selective albumin binding, in vivo efficacy, and low toxicity.

Autor:	Fakih HH; Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada.; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Tang Q; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Summers A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Shin M; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.; College of Pharmacy, Sookmyung Women's University, Yongsan-gu, Seoul, Korea., Buchwald JE; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Gagnon R; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Hariharan VN; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Cooper DA; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Watts JK; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA., Sleiman HF; Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Nov 17; Vol. 34, pp. 102080. Date of Electronic Publication: 2023 Nov 17 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.102080
Abstrakt:	Although an increasing number of small interfering RNA (siRNA) therapies are reaching the market, the challenge of efficient extra-hepatic delivery continues to limit their full therapeutic potential. Drug delivery vehicles and hydrophobic conjugates are being used to overcome the delivery bottleneck. Previously, we reported a novel dendritic conjugate that can be appended efficiently to oligonucleotides, allowing them to bind albumin with nanomolar affinity. Here, we explore the ability of this novel albumin-binding conjugate to improve the delivery of siRNA in vivo . We demonstrate that the conjugate binds albumin exclusively in circulation and extravasates to various organs, enabling effective gene silencing. Notably, we show that the conjugate achieves a balance between hydrophobicity and safety, as it significantly reduces the side effects associated with siRNA interactions with blood components, which are commonly observed in some hydrophobically conjugated siRNAs. In addition, it reduces siRNA monocyte uptake, which may lead to cytokine/inflammatory responses. This work showcases the potential of using this dendritic conjugate as a selective albumin binding handle for the effective and safe delivery of nucleic acid therapeutics. We envision that these properties may pave the way for new opportunities to overcome delivery hurdles of oligonucleotides in future applications. Competing Interests: H.H.F., A.K., and H.F.S. have filed a patent that covers the use of the dendritic conjugate in vivo for various applications. A.K. discloses ownership of stock in RXi Pharmaceuticals and Advirna; is a founder of Atalanta Therapeutics and Comanche Biopharma; and serves on the scientific advisory boards of Aldena Therapeutics, Prime Medicine, and Alltrna. V.N.H. is an employee of and holds stock options in Comanche Biopharma. (© 2023.)
Databáze:	MEDLINE
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