NQO1-Activatable Circular Antisense Oligonucleotides for Tumor-Cell-Specific Survivin Gene Silencing and Antitumor...

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• NAD(P)H:quinone oxidoreductase-1 (NQO1) is highly expressed in tumor cells.
• NQO1 can be utilized as a trigger for targeted drug release in tumors.
• Antisense oligonucleotides (ASOs) offer potential for gene silencing but require specific delivery strategies.

Purpose of the Study:

• To design and evaluate an NQO1-activatable circular antisense oligonucleotide (cASO) for tumor-specific gene silencing.
• To investigate the mechanism of NQO1-mediated activation and subsequent gene silencing.
• To assess the in vitro and in vivo efficacy of the cASO in a lung tumor model.

Main Methods:

• Design of a cASO incorporating an NQO1-responsive quinone propionate (Q3PA) and a self-immolative linker.
• Head-to-tail cyclization of the ASO to prevent premature mRNA binding.
• In vitro studies to assess tumor cell-specific activity.
• In vivo studies using an A549-Luc orthotopic lung tumor model to evaluate antitumor effects.

Main Results:

• The circular structure of the cASO prevented gene silencing until activated by NQO1.
• NQO1 triggered the conversion of the cASO to its linear, active form, leading to gene silencing.
• Significant tumor-cell-specific activity was observed in vitro.
• Substantial antitumor effects were demonstrated in vivo, linked to survivin expression suppression.

Conclusions:

• NQO1-activatable cASO is a viable strategy for tumor-specific gene silencing.
• The developed cASO system exhibits promising therapeutic potential for cancer treatment.
• This approach offers a novel prodrug strategy for enhanced ASO therapeutics.