Precision Chemoradiotherapy via EGFR Targeting with Radiotherapy-Activated Drug Conjugates.

Area of Science:

• Oncology
• Radiotherapy
• Drug Delivery

Background:

• Concurrent chemoradiotherapy (CCRT) combines chemotherapy and radiotherapy to improve efficacy.
• Limitations of CCRT include systemic toxicity and suboptimal drug delivery.
• Targeted drug delivery systems are needed to enhance therapeutic outcomes for deep-seated tumors.

Purpose of the Study:

• To develop and evaluate radiotherapy-triggered antibody-drug conjugates (RT-ADCs) for targeted cancer therapy.
• To leverage X-ray irradiation for localized drug release at the tumor site.
• To assess the efficacy of RT-ADCs in preclinical models targeting EGFR-expressing tumors.

Main Methods:

• Design of RT-ADCs incorporating an X-ray-responsive azobenzene linker and an antibody targeting EGFR.
• In vitro and in vivo evaluation of RT-ADC accumulation at tumor sites.
• Assessment of X-ray-induced azobenzene linker cleavage and subsequent cytotoxic agent release.
• Evaluation of tumor growth inhibition (TGI) and median survival time (MST) in mouse models.

Main Results:

• RT-ADCs demonstrated precise targeting of EGFR-expressing tumor cells.
• X-ray irradiation triggered localized release of cytotoxic agents via azobenzene linker cleavage.
• In vivo studies showed near-complete tumor eradication, with TGI exceeding 90%.
• Median survival time was significantly extended in the RT-ADC treatment group.

Conclusions:

• RT-ADCs represent a promising strategy for targeted cancer therapy, particularly for deep-seated tumors.
• The radiotherapy-triggered drug release mechanism enhances therapeutic efficacy and minimizes systemic toxicity.
• RT-ADC technology holds substantial potential for clinical application in oncology.