Development Of PET/MRI Dual Modality Probes For Early Diagnosis Of Lung Cancer

Lung cancer has become one of the cancers with highest incidence and mortality rates,the main reason is that it's difficult to detect lung cancer specifically and early.In recent years,enormous progress was made in the fusion of positron computer tomography?PET?and magnetic resonance imaging?MRI?.Compared to CT,MRI has excellent soft tissue contrast.While maintaining the original PET diagnostic sensitivity,the fusion of PET/MRI enables the improvement of diagnosis accuracy and resolution of the soft tissue.Therefore,the fusion of PET/MRI provides a powerful tool for the early diagnosis of lung cancer.Currently,¹⁸F is one of the nuclides widely used in clinical activities.Positive contrast agent gadolinium and negative contrast agent iron oxides are mainly used in MRI.Positive MRI contrast agent has advantages in the used of early diagnosis for lung cancer.Gadolinium has long-term toxicity,while iron oxide nanoparticles have good biocompatibility.The ultrasmall,superparamagnetic particles also have positive contrast effect.Meanwhile,?_v?₃ receptors are overexpressed in tumor angiogenesis,and EGFR are overexpressed in non-small cell lung cancer cells.Thus,particles targeting these receptors can improve the specificity of diagnosis in non-small cell lung cancer.This paper mainly includes four major parts:the preparation of ultra-small iron oxide nanoparticles;synthesis of PET/MRI dual-modality probe which simultaneously target to?_v?₃ receptors in tumor angiogenesis and EGFR;exploration of the specificity between targeting probes and receptors and preliminary in vivo study of the targeting probes.Superparamagnetic,water-soluble magnetic nanoparticles and nanoclusters were synthesized via the polyol method.The resulting 6.8 nm nanoparticles have low r₂/r₁of 3.93(r₁=12.2 mM^-1·s^-1,r₂=47.5 mM^-1·s^-1),which can be used as T₁ contrast agents.The 32.5 nm nanoclusters exhibited high r₂ value of 409.84 mM^-1·s^-1,which can be used as T₂ contrast agent.On this basis,used ultra-small size,superparamagnetic iron oxide nanoparticles?USPIO?as carrier,applied click chemistry method to conjugate targeting peptide RGD,GE11 and label ¹⁸F nuclide.This research built a stable,quick and efficient labeling method to label ¹⁸F nuclide to the particles surface.The radiochemical yield was 29.6%?after attenuation correction?,the radiochemical purity of ¹⁸F labeled nanoparticle>92%,radioactive stability>95%.Used A231 cells and H1299 cells to evaluate the specifity of the targeting probes,the results indicated that ¹⁹F-RGD@USPIO can target to A231 cells,¹⁹F-GE11@USPIO can target to H1299 cells,while dual-targeting probe ¹⁹F-RGD-GE11@USPIO had better targeting performance than the single-targeting probes.Magnetic resonance images showed ¹⁹F-RGD@USPIO can specifically target to tumor and improved the magnetic resonance signal.PET images showed ¹⁹F-USPIO particles mainly gathered in liver and kidney,indicated that the particles were metabolized by urine and faeces.There was very low signal in muscle,brain and bones site,which showed that ¹⁸F labeled particles were highly stable in vivo.