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Development of Cell-type specific anti-HIV gp120 aptamers for siRNA delivery
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Albumin-Binding Aptamer Chimeras for Improved siRNA Bioavailability.

Jonah C Rosch1, Ella N Hoogenboezem2, Alexander G Sorets2

  • 1Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN USA.

Cellular and Molecular Bioengineering
|April 11, 2022
PubMed
Summary

Albumin-binding aptamer-siRNA chimeras enhance siRNA bioavailability by improving circulation half-life. This novel approach offers a promising strategy for nucleic acid drug delivery, overcoming limitations of short interfering RNA therapeutics.

Keywords:
AlbuminAptamerDrug deliverysiRNA

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Area of Science:

  • Biotechnology
  • Drug Delivery
  • Nucleic Acid Therapeutics

Background:

  • Short interfering RNAs (siRNAs) are potent gene-targeting drugs but face challenges with poor in vivo pharmacokinetics, including rapid clearance and degradation.
  • Albumin, a high-concentration serum protein with a long half-life, is an effective carrier for improving drug bioavailability.
  • Developing strategies to enhance siRNA stability and circulation time is crucial for their therapeutic application.

Purpose of the Study:

  • To develop albumin-binding aptamer-siRNA chimeras to improve the bioavailability of siRNA therapeutics.
  • To create a novel drug delivery system by fusing aptamers to siRNAs.
  • To evaluate the molecular and pharmacokinetic properties of these novel chimeras.

Main Methods:

  • Modified RNA-binding aptamers were generated using Systematic Evolution of Ligands through Exponential Enrichment (SELEX).
  • Aptamers were directly fused to siRNA via in vitro transcription to create aptamer-siRNA chimeras.
  • In vitro and in vivo assays were performed to assess stability, gene knockdown, and pharmacokinetic properties.

Main Results:

  • Albumin-binding aptamer-siRNA chimeras demonstrated stability in serum while retaining potent gene knockdown capabilities.
  • The best-performing chimera (Clone 1) exhibited a 1.6-fold increase in circulation half-life compared to a control.
  • In vivo studies confirmed improved bioavailability of the aptamer-siRNA chimeras.

Conclusions:

  • Albumin-binding aptamer-siRNA chimeras effectively improve siRNA bioavailability without compromising biological activity.
  • This chimera approach represents a promising strategy for enhancing siRNA drug delivery.
  • Further development of aptamer-siRNA conjugates could overcome key limitations in siRNA therapeutics.