Tumor Microenvironment Responsive TPZ-Loaded Core-Shell Polymeric Nanoparticles for Selective Cancer Bioreductive...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Tumor hypoxia is a significant challenge for anti-cancer drug efficacy.
• Developing targeted drug delivery systems is crucial for overcoming hypoxia-induced resistance.

Purpose of the Study:

• To design and evaluate hypoxia-responsive nanoparticles (APAP NPs) for targeted delivery of tirapazamine (TPZ) to hypoxic breast cancer.
• To investigate the efficacy of APAP NPs in enhancing drug penetration and activity within hypoxic tumor microenvironments.

Main Methods:

• Synthesis of gold nanoparticles (AuNPs) coated with polyethylene imine (PEI) and a hypoxia-cleavable mPEG-AZO linker.
• Evaluation of nanoparticle behavior under normoxic and hypoxic conditions using 2D cell cultures and 3D spheroids (MDA-MB-231, MCF-7).
• Assessment of cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential, apoptosis, cell uptake, and spheroid destruction.

Main Results:

• APAP NPs demonstrated significant cytotoxicity against MDA-MB-231 cells, lowering TPZ IC50.
• Enhanced ROS generation and reduced mitochondrial membrane potential were observed under hypoxia.
• Widespread apoptosis, reduced cell adhesion, increased cell uptake (~100-fold under hypoxia), and destruction of MCF-7 spheroids were achieved.

Conclusions:

• APAP@TPZ nanoparticles serve as biocompatible, multi-stage activating platforms for enhanced HAP delivery to hypoxic tumors.
• The system promotes selective eradication of hypoxic breast cancer microtumors through PEG detachment and TPZ bioreduction.