Study On Interleukin-11 Receptor Targeted Imaging In Malignant Tumors

Background:Bone metastasis is more common in malignant tumors.The bone metastasis has a longer development period and the hidden characteristics.Clinically,there are no means of high specificity and sensitivity in the diagnosis of bone metastases.Therefore,it is deserved to explore new diagnostic methods for malignant tumors and bone metastases.With the further research on the mechanism of tumor,the role of cytokines and chemokines in tumor development has been discovered and proved.In recent years,many studies showed that interleukin-11?Interleukin-11,IL-11?and its receptor?IL-11,receptor,IL-11R?involved in the development of tumor.The IL-11R can be used as a potential target for malignant tumors and bone metastases.Objective:In this study,we discussed the expression of IL-11R alpha on malignant tumor cells and established the configuration of a small molecule peptide and modified peptides binding to IL-11R alpha.Through in vitro and in vivo experimental research,to explore the feasibility of IL-11R alpha as a diagnosis and treatment target in malignant tumors with positive expression of IL-11R,especially in breast cancer and prostate cancer of high bone metastasis.Methods:1.With the means of Western blots and direct immunofluorescence staining,to detect the expression level of IL-11R protein in malignant tumor cells,especially in breast cancer cells and prostate cancer cells.The basis of the whole study is to establish the feasibility of IL-11R alpha as the research target.2.We synthesized an IL-11 analogue,which was a small-molecule cyclic peptide KC CGRRAGGSC with specific binding ability to IL-11R.On this basis,NIR dye Cy7 labeled optical probe Cy7-KC CGRRAGGSC,positron gallium-68 labeled probe ⁶⁸Ga-NOTA-KC,and single photon iodine-131 labeled probe ¹³¹I-Tyr-KC CGRRAGGSC were established.The studies of quality controls and binding properties were performed of peptides and modified structure in vitro.3.The breast cancer and prostate cancer xenograft models in nude mice were established.Through the multimodal approaches of optical and radionuclide imaging in vivo,to study the targeted imaging feasibility of using IL-11R mediated molecular probe.4.Based on the specific binding to breast cancer and prostate cancer of high bone metastasis,to study the feasibility of IL-11R alpha mediated treatment.We used CCK-8 method to study the inhibition of tumor cell proliferation,transwell assay and cell scratch experiment to study the migration of tumor cells,and Western blot method to show the expression of IL-11R protein and p-STAT3/STAT3 protein change,with the different doses of ¹³¹I-Tyr-KC CGRRAGGSC intervention.Results:1.Compared to normal cells,there were positive expression of IL-11R alpha in different tumor cells,especially in BT549,MDA-MB-231 and MCF-7 breast cancer cells,and PC-3M,PC-3 and DU-145 prostate cancer cells.2.We succeeded to synthesize NIR dye labeled optical probe Cy7-KC CGRRAGGSC and radiolabeled probe ⁶⁸Ga-NOTA-KC and ¹³¹I-Tyr-KC CGRRAGGSC.The binding abilities of labeled probes were confirmed by cell immunofluorescence staining,which provided the basis for further experimental research.3.The results of near infrared molecular imaging and radionuclide imaging confirmed by KC CGRRAGGSC as the carrier,the labeled probes had fast clearance through urinary excretion and specifically targeting to tumors of IL-11R alpha high expression,that had relatively high T/NT ratios.4.The radionuclide labeled probe 132I-Tyr-KCCGRRAGGSC,targeting to IL-11R alpha,had effective inhibition in migration and proliferation of prostate cancer cells,and decreased IL-11R expression and p-STAT3/STAT3 expression.Conclusion:1.IL-11R can be used as the target of IL-11R positive malignant tumor.2.IL-11R mediated multimodal molecular probes could be used in targeted imaging of malignant tumor and bone metastasis of IL-11R high expression.3.Using KC CGRRAGGSC as the carrier,there were positive inhibition effects of radiolabeled probes on IL-11R positive tumor cells.4.IL-11R mediated multimodal molecular probes may provide a new way for the diagnosis and treatment of malignant tumors and bone metastases with IL-11R positive expression.