Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Conventional cancer therapies lack specificity, causing off-target effects.
• Tumor hypoxia activates Hypoxia Inducible Factor (HIF), promoting cancer cell survival and resistance.
• Pancreatic cancer exhibits high CD44 expression and hypoxia, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate targeted nanoparticle (NP)-based small interfering RNA (siRNA) efficacy in downregulating HIF-1α in pancreatic cancer.
• To evaluate the impact of chitosan molecular weight on NP performance for targeted gene silencing.

Main Methods:

• Hyaluronic acid (HA)-functionalized chitosan (CS) nanoparticles loaded with siRNA targeting HIF-1α were developed.
• Two formulations using low molecular weight (LMW) and high molecular weight (HMW) CS were prepared.
• In vitro and in vivo studies assessed NP internalization, gene silencing efficacy, and HIF-1α knockdown.

Main Results:

• Chitosan molecular weight affected HA-CD44 interaction and siRNA release kinetics.
• LMW CS NPs demonstrated faster cellular uptake, while HMW CS NPs showed superior gene knockdown in vitro.
• Both LMW and HMW CS NPs significantly reduced HIF-1α and downstream gene expression in vivo.

Conclusions:

• HMW and LMW CS-based NPs exhibit distinct delivery and gene silencing properties.
• Both nanoparticle formulations show promise for targeted pancreatic cancer therapy.
• These NPs are effective in overcoming challenges posed by the hypoxic tumor microenvironment.