Abstract 69P
Background
Resistance to osimertinib is a major challenge in the treatment of lung cancer patients with EGFR-activating mutations. Exploring potential resistance-regulating targets for targeted drug combination delivery, while simultaneously enabling real-time visual monitoring of this process, is beneficial for overcoming drug resistance in lung cancer patients and improving their prognosis, offering significant clinical application value.
Methods
The film hydration method was used to prepare drug-loaded vesicles encapsulating osimertinib and RRM2 sgRNA, which were labeled with the radionuclide I-124 and the fluorescent dye Cy5.5. The physicochemical properties of the vesicles were characterized using transmission electron microscopy (TEM), thin-layer chromatography (TLC), and so on. The targeting ability and tracer value for lung cancer were evaluated using small animal in vivo optical imaging and Micro-PET/CT imaging. Cellular molecular experiments, bioinformatics analysis, and mouse models were employed to investigate the anticancer effects of the vesicles, as well as to elucidate its specific mechanisms.
Results
The constructed I-124 and Cy5.5 dual-labeled drug delivery vesicles (124I/Cy5.5-Osi/sgRRM2@FCLs) enabled precise diagnostic localization of mouse lung cancer through fluorescence imaging and micro-PET imaging techniques, and achieved dynamic quantitative monitoring of the drug’s targeted delivery and in vivo distribution, confirming that the vesicles specifically targets tumor regions and progressively accumulates in tissues over time. Furthermore, by targeting and reversing epithelial-mesenchymal transition (EMT) in tumor cells and inducing ferroptosis, the vesicles effectively overcame osimertinib resistance in lung cancer. The STING pathway-dependent tumor immunogenic cell death (ICD) was also activated to exert remarkedly anticancer effects.
Conclusions
The dual-modal tracing drug delivery vesicles enabled combined targeted drug delivery, effectively overcoming osimertinib resistance and exhibiting superior anticancer effects. And real-time dynamic monitoring of this process was achieved, facilitating the integration of diagnosis and therapy for lung cancer.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.