Fluorinated Cell-Penetrating Peptide for Co-Delivering siHIF-1α and Sorafenib to Enhance In Vitro Anti-Tumor Efficacy

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapy

Background:

• Sorafenib (SF) monotherapy is limited by tumor hypoxia, which worsens with treatment, restricting efficacy.
• Hypoxia-inducible factors (HIFs) play a critical role in tumor progression and angiogenesis, making them therapeutic targets.

Purpose of the Study:

• To develop a redox-responsive fluorinated peptide (DEN-TAT-PFC) for co-delivery of siRNA targeting HIF-1α (siHIF-1α) and sorafenib (SF).
• To evaluate the synergistic anti-tumor and anti-angiogenesis effects of the co-delivery system.

Main Methods:

• Synthesis of a fluorinated peptide (DEN-TAT-PFC) incorporating dendritic poly-lysine, TAT peptide, and perfluorocarbon.
• Co-loading of siHIF-1α and SF onto the DEN-TAT-PFC platform.
• Assessment of siRNA delivery efficiency (binding, release, uptake, endosomal escape, serum resistance).
• Evaluation of HIF-1α knockdown, VEGF expression, and anti-tumor/anti-angiogenesis effects in vitro and in vivo.

Main Results:

• The DEN-TAT-PFC system demonstrated enhanced siRNA delivery and GSH-responsive release.
• Co-delivery effectively reduced HIF-1α mRNA and protein levels, alleviating tumor hypoxia.
• Significant reduction in VEGF expression and substantial anti-tumor cell proliferation and anti-angiogenesis effects were observed.
• The peptide's oxygen-carrying capacity potentially aided in relieving the hypoxic microenvironment.

Conclusions:

• DEN-TAT-PFC serves as a versatile platform for co-delivering drugs and siRNA, particularly for fluorine-containing nano-systems.
• This co-delivery approach offers a promising strategy to overcome SF resistance caused by tumor hypoxia.
• The developed nano-system exhibits significant potential for enhanced cancer therapy by targeting both tumor cells and the tumor microenvironment.