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Trivalent Disulfide Unit-Masked System Efficiently Delivers Large Oligonucleotide.

Lei Wang1, Xiao Liu1, Yiliang Wu1

  • 1School of Pharmacy, Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China.

Molecules (Basel, Switzerland)
|September 14, 2024
PubMed
Summary

This study presents a novel disulfide unit-masked oligonucleotide system for enhanced drug delivery. This system demonstrates superior cellular uptake and liver distribution, offering a promising approach for oligonucleotide therapeutics.

Keywords:
cellular uptakedisulfide unitoligonucleotide delivery

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Area of Science:

  • Biotechnology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Oligonucleotide therapeutics show promise but face delivery challenges.
  • Disulfide bond chemistry offers potential for cell-membrane drug delivery systems.
  • Disulfide unit stability and effectiveness are influenced by substituent-induced dihedral angle changes.

Purpose of the Study:

  • To develop a novel disulfide unit-masked oligonucleotide hybrid for improved drug delivery.
  • To investigate the impact of a low dihedral angle disulfide unit on oligonucleotide delivery efficiency and stability.
  • To evaluate the system's performance in cellular uptake and in vivo distribution.

Main Methods:

  • Construction of a disulfide unit-masked oligonucleotide hybrid utilizing a low dihedral angle disulfide unit.
  • Cellular imaging to assess delivery efficiency and cytotoxicity compared to commercial liposomes.
  • In vivo distribution studies in mice to track biodistribution and duration of action.
  • Assessment of endocytosis-independent uptake mechanism via thiol reagent treatment.

Main Results:

  • The novel system exhibited superior cellular delivery efficiency compared to Lipo2000 without observable cytotoxicity.
  • Thiol reagents reduced cellular uptake by 57-74%, indicating an endocytosis-independent delivery mechanism.
  • In vivo studies showed rapid liver distribution and sustained action (>24 h) in mice.
  • The trivalent disulfide unit effectively masked and delivered large oligonucleotide drugs.

Conclusions:

  • The developed trivalent disulfide unit-masked system is effective for delivering large oligonucleotide drugs.
  • This platform shows potential for gene silencing in liver-related diseases due to efficient liver targeting and prolonged action.
  • The endocytosis-independent delivery mechanism offers a unique advantage for oligonucleotide therapeutics.