Correction: Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer.

Correction for 'Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer' by Lili Yang et al., Biomater. Sci., 2021, 9, 443-455. DOI: 10.1039/D0BM00293C.

Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer.

The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). EGFR-TKI positron emission tomography (PET) probes based on the central quinazoline core show great potential for NSCLC diagnosis, and pre-clinical and clinical therapy monitoring. In our previous research, anilino quinazoline based PET probe, N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18F-MPG), have been developed, and it has been successfully demonstrated to be a powerful non-invasive imaging tool for differentiating EGFR mutation status and stratifying NSCLC patients for EGFR-TKI treatment in a clinical study (n = 75 patients). Moreover, it has been found that 18F-MPG shows excellent tumor targeting performance and good pharmacokinetic characteristics in NSCLC patients. These results motivate us to investigate the cancer treatment efficacy of non-radioactive F-MPG and its analogue N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-hydroxyethoxy)ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (OH-MPG) in vitro and in small animal models. Our studies revealed that both F-MPG and OH-MPG displayed high therapeutic effect to NSCLC cells (IC50 = 5.3 nM and 2.0 nM to HCC827 cells for F-MPG and OH-MPG, respectively). More importantly, compared with a standard EGFR-TKI, 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD153035), F-MPG and OH-MPG showed stronger tumor inhibition in preclinical models. Furthermore, the treatment efficacy of F-MPG or OH-MPG monitored by 18F-FDG-PET indicated that tumor uptake in treated groups was significantly decreased. Ex vivo experiments showed that the levels of serum biomarkers and pathological changes in the liver were significantly reduced in the F-MPG and OH-MPG group, compared to PD153035 treated group. In conclusion, EGFR targeted F-MPG and OH-MPG exhibit promising anti-tumor activity with limited liver damage, thus representing promising drug candidates for further investigation for combating the deadly NSCLC.

Development of a SPECT Tracer to Image c-Met Expression in a Xenograft Model of Non-Small Cell Lung Cancer.

Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of the c-Met signaling pathway contributes to tumorigenesis and cancer progression and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for NSCLC, and methods for noninvasive in vivo assessment of c-Met expression would improve NSCLC treatment and diagnosis. Methods: We developed a new c-Met-binding peptide (cMBP) radiotracer, 99mTc-hydrazine nicotinamide (HYNIC)-cMBP, for SPECT imaging. Cell uptake assays were performed on 2 NSCLC cell lines with different c-Met expressions: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2, and 4 h after injection of the probe. Blocking assays, biodistribution, and autoradiography were also conducted to determine probe specificity. Results:99mTc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than in H1299 cells. Biodistribution and autoradiography also showed significantly higher percentages of the injected dose for 99mTc-HYNIC-cMBP in H1993 tumors than in H1299 tumors at 0.5 h (4.74 ± 1.43%/g and 1.00 ± 0.37%/g, respectively; P < 0.05). H1993 tumors were clearly visualized at 0.5 h in SPECT images, whereas H1299 tumors were not observed at any time. The specificity of 99mTc-HYNIC-cMBP for c-Met was demonstrated by a competitive block with an excess of nonradiolabeled peptide. Conclusion: For c-Met-targeted SPECT imaging of NSCLC, we developed 99mTc-HYNIC-cMBP, a tracer that specifically binds to c-Met with favorable pharmacokinetics in vitro and in vivo.

Analysis of progress and challenges for various patterns of c-MET-targeted molecular imaging: a systematic review.

BACKGROUND: Mesenchymal-epithelial transition factor also named c-MET is a receptor tyrosine kinase for the hepatocyte growth factor that plays a pivotal role in tumorigenesis. c-MET-targeted therapies have been tested in preclinical models and patients, with significant benefits for cancer treatment. In recent years, many studies have shown that the expression level and activation status of c-MET are closely correlated to c-MET-targeted therapy response and clinical prognosis, thus highlighting the importance of evaluating the c-MET status during and prior to targeted therapy. Molecular imaging allows the monitoring of abnormal alterations of c-MET in real time and in vivo. RESULTS: In this review, we initially summarize the recent advances in c-MET-targeted molecular imaging, with a special focus on the development of imaging agents ranging in size from monoclonal antibody to small molecule. The aim of this review is to report the preclinical results and clinical application of all molecular imaging studies completed until now for in vivo detection of c-MET in cancer, in order to be beneficial to development of molecular probe and the combination of molecular imaging technologies for in vivo evaluation of c-MET. Various molecular probe targeted to c-MET possesses distinctive advantages and disadvantages. For example, antibody-based probes have high binding affinity but with long metabolic cycle as well as remarkable immunogenicity. CONCLUSIONS: Although studies for c-MET-targeted molecular imaging have made many important advances, most of imaging agents specifically target to extracellular area of c-MET receptor; however, it is difficult to reflect entirely activation of c-MET. Therefore, small molecule probes based on tyrosine kinase inhibitors, which could target to intracellular area of c-MET without any immunogenicity, should be paid more attention.