Selective Radioprotection by the Fusion Antioxidant Enzyme GS1XR Via an MMP-2/9-Cleavable Cell-Penetrating Switch.

Area of Science:

• Biochemistry and Molecular Biology
• Oncology
• Radiology and Imaging

Background:

• Radiotherapy is a cornerstone of cancer treatment, but it causes collateral damage to healthy tissues via oxidative stress.
• Developing radioprotective agents that spare normal tissues while maintaining therapeutic efficacy is a critical challenge.

Purpose of the Study:

• To evaluate the antioxidant and radioprotective potential of the engineered fusion enzyme GS1XR (GST-SOD1-X-R9).
• To determine GS1XR's efficacy in selectively protecting normal tissues from radiation-induced damage without compromising tumor control.

Main Methods:

• In vitro and in vivo assessments of GS1XR's cellular uptake, reactive oxygen species (ROS) scavenging, and antioxidant pathway modulation.
• Evaluation of GS1XR's effect on apoptosis, clonogenic survival, and hematopoietic injury following irradiation.
• Assessment of GS1XR's impact on tumor control in preclinical radiotherapy models.

Main Results:

• GS1XR efficiently entered normal cells in low matrix metalloproteinases (MMP)-2/9 environments, scavenging ROS and preserving the Nrf2 pathway.
• In high MMP-2/9 tumor microenvironments, GS1XR lost transmembrane capacity, reducing its ROS scavenging activity.
• GS1XR alleviated radiation-induced hematopoietic injury and did not impede radiotherapy-mediated tumor control in vivo.

Conclusions:

• GS1XR demonstrates microenvironment-responsive cell entry, enabling selective radioprotection of normal tissues.
• The enzyme effectively scavenges ROS and supports antioxidant pathways in normal cells.
• GS1XR achieves selective radioprotection while preserving the therapeutic benefits of radiotherapy for cancer treatment.