p53 mediated apoptosis by reduction sensitive shielding ternary complexes based on disulfide linked PEI ternary...

Area of Science:

• Biomaterials Science
• Gene Therapy
• Cancer Research

Background:

• Gene delivery systems are crucial for effective cancer therapy.
• Developing reduction-sensitive materials can improve intracellular drug release.
• Hyaluronic acid derivatives offer potential for targeted delivery.

Purpose of the Study:

• To develop and evaluate reduction-sensitive ternary complexes for efficient gene transfection.
• To investigate the role of these complexes in delivering the p53 tumor suppressor gene.
• To assess the anti-proliferative effects of p53 gene delivery on tumor cells.

Main Methods:

• Construction of DNA/polyethylenimine/hyaluronic acid-disulfide-carboxylic acid (DPS) ternary complexes.
• Fluorescence resonance energy transfer (FRET) for gene condensation analysis.
• Confocal laser scanning microscopy (CLSM) for intracellular fate tracking.
• Quantitative polymerase chain reaction (qPCR) and western blot for gene expression analysis.
• Flow cytometry for cell cycle and apoptosis evaluation.

Main Results:

• DPS complexes demonstrated enhanced DNA condensation and timely gene release under reductive conditions.
• DPS complexes exhibited efficient endosomal escape and intracellular gene delivery compared to stable complexes.
• Significant upregulation of p53 mRNA and protein levels was observed in tumor cells transfected with DPS-p53 complexes.
• Tumor cells showed a ~50% reduction in proliferation, increased sub-G1 phase population, and p53-dependent cell cycle perturbations.

Conclusions:

• Reduction-sensitive DPS ternary complexes are effective for targeted gene delivery.
• The enhanced p53 gene expression via DPS complexes induces significant p53-dependent anti-proliferative effects in tumor cells.
• These findings suggest DPS complexes as a promising strategy for cancer treatment.