Reconsidering azobenzene as a component of small-molecule hypoxia-mediated cancer drugs: A theranostic case study

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Pharmacology

Background:

• Mitochondrial targeting drug delivery systems (DDS) are crucial for cancer therapy.
• Azobenzene derivatives offer potential for hypoxia-activated prodrugs and imaging.
• Developing theranostic agents with tumor selectivity and reduced side effects remains a challenge.

Purpose of the Study:

• To develop and evaluate a novel azobenzene-based theranostic DDS for cancer therapy.
• To investigate the hypoxia-activated prodrug release and fluorescence imaging capabilities.
• To assess the therapeutic efficacy and mechanistic pathways of the DDS in vivo.

Main Methods:

• Synthesis of a mitochondrial-targeting DDS incorporating an azobenzene scaffold.
• In vitro and in vivo evaluation of azoreduction, fluorescence, and prodrug activation under hypoxic conditions.
• In vivo therapeutic experiments and ex vivo tissue analysis, including gene, protein, and proteomic studies.

Main Results:

• The DDS demonstrated tissue selectivity for aggressive tumors.
• Efficient in vitro and in vivo azoreduction led to tumor-site fluorescence and prodrug activation.
• Significant tumor growth reduction, tissue normalization, reduced angiogenesis, and suppressed proliferation were observed.
• Mechanistic studies revealed circumvention of drug resistance and induction of mitochondria-mediated apoptosis.

Conclusions:

• The azobenzene-based theranostic DDS is effective in targeting aggressive tumors and activating prodrugs under hypoxia.
• The system exhibits significant therapeutic benefits, including tumor growth inhibition and tissue normalization.
• Azobenzene derivatives show promise for hypoxia-activated cancer theranostics, warranting further investigation.