¹⁸F-IRS PET/CT Molecular Imaging Study Of EGFR In Vivo Molecular Typing Of Lung Cancer

Background and PurposeEpidermal growth factor receptor is an oncogene that plays a prominent role in tumor growth and metastases.Although most NSCLC patients with tumors bearing EGFR mutations show high response and survival rates when treated with EGFR-TKIs,the vast majority of these patients eventually develop resistance to the treatment.EGFR-activating mutations are therefore useful biomarkers for identifying patients who will benefit from or became resistant to therapy with EGFR-TKIs.Thus,there is currently a great need for new approaches that could better characterize the mutation status and expression levels of EGFR in NSCLC.Thus,there is currently a great need for new approaches that could better characterize the mutation status and expression levels of EGFR in NSCLC.The purpose of this study was to prepare and evaluate a new radiotracer ¹⁸F-IRS for molecular imaging mutant EGF Receptors in vitro and vivo.MethodsSynthesis and quality control of ¹⁸F-IRS was performed as one-step synthesis.Uptake and efflux of 18F-IRS were performed with four NSCLC cell lines including HCC827,H1975,H358 and H520.In vivo tumor targeting and pharmacokinetics of the radiotracers were also evaluated in HCC827,H1975,H358 and H520tumor-bearing nude mice by PET/CT imaging.Ex vivo biodistribution assays were performed to quantify the accumulation of ¹⁸F-IRS in vivo.We labeled this small molecule with QD620 for flow cytometry and confocal imaging analyse.The inhibition ratio of F-IRS against four different lung cancer cell lines in 48h points was investigated by MTT method.The IC50 value and cell viability were calculated and sensitivety between different cell lines were compared.Results¹⁸F-IRS can be prepared with one-step radiolabelling followed by preparative HPLC-purification provided with radiochemical purity>98%(n>3).The uptakes of18F-IRS by HCC827 and HCC827 tumors were significantly higher than those of H358,H1975 and H520,and they were reduced by the addition of 100?M of gefitinib.Biodistribution experiments showed an accumulation of ¹⁸F-IRS in tumors of HCC827 xenografts was reached 4.94�0.38%ID/g,(mean�SD,n=3),significantly higher than H1975(1.68�0.29%ID/g),H328(1.63�0.08%ID/g),H358(1.71�0.17%ID/g)(mean�SD,n=3)after injected ¹⁸F-IRS in 2h.Flow cytometry and confocal imaging with QD620-IRS further demonstrated that binding specifically to HCC827 cells.¹⁸F-IRS accumulation was preferential in the tumor,which was NSCLC with responsive EGFR exon 19 deleted.¹⁸F-IRS showed high binding stability and specificity to 19 exon deleted EGFR mutation in vitro and vivo.Our laboratory designed and built the small molecular F-IRS targeted EGFR,which can inhibit lung cancer cell with different EGFR expression and mutation effectively.IRSF inhibit lung cancer cells with EGFR Exon 19 deletion mutation stronger than lung cancer with EGFR wide expression and negative expression.F-IRS were promising to be the next generation of molecular targeted drug and molecular imaging probes.Inhibition of F-IRS for HCC827 cell lines was statistically significant in 48h rather than other three cell lines.Conclusions¹⁸F-IRS shows high stability and specificity to EGFR 19 exon deleted mutation not only in vitro but also in vivo in NSCLC xenografts.Thus,PET/CT imaging with¹⁸F-IRS could potentially become a new approach for diagnosing NSCLC molecular-genetic patient subtypes as well as other EGFR-driven tumor types.