Near Infrared-emitting Persistent Luminescent Nanoprobes For Liver Cancer Imaging And Intraoperative Navigation

BackgroundAccurate localization of the lesion before hepatectomy and complete surgical excision will be beneficial to the long-term survival of patients.Optical molecular imaging technology has the advantages of real-time,high sensitivity and high resolution,and it has potential application value in hepatectomy.In recent years,the application of NIR-emitting persistent luminescent nanoparticles(NPLNPs)has attracted more and more attention in bioimaging.The temporal separation of excitation and luminescence properties of NPLNPs makes them ideal as in vivo luminescence imaging contrast reagents,providing new possibilities for long-term in vivo high-sensitivity imaging of tumor.Therefore,increasing attention has focused on the development and application of NPLNPs.At present,there are few reports on the application of NIR persistent luminescent nanoprobes in liver cancer imaging and intraoperative navigation.ObjectiveThe objective of this study is to prepare a NPLNPs ZnGa2O4Cr0.004(ZGC),which can meet the requirements of CT imaging and continuous luminescence imaging,in order to achieve accurate location of preoperative tumors and to guide accurate surgical excision.MethodsZGC is synthesized by hydrothermal synthesis.The morphology and size of ZGC were observed by a transmission electron microscopy and a scanning electron microscopy.The distribution of hydration particle size of probes was measured with Dynamic Light Scattering by the Malvern Zeta sizer;Optical characterization of ZGC was detected by fluorescence spectrophotometer.Subsequently,the cytotoxicity of the probe was determined by the MTS method,the tissue toxicity of the probe was observed by histopathology.In vitro experiments were performed to detect the performance of NIR persistent luminescence imaging and CT imaging.In biological applications,the IVIS imaging system was used to observe the biological distribution and metabolism of the probe in the healthy mice.Then,the IVIS imaging system was used to carry out the continuous luminescence imaging of the nude mice with subcutaneous liver cancer.Subcutaneous tumor-bearing mice were utilized to explore the feasibility of ZGC as a contrast agent for in vivo persistent luminescence imaging applications.The CT imaging of the orthotopic liver cancer in nude mice was performed by the CT imaging device self-made in the laboratory,and the tumor location was performed before the operation.Finally,the feasibility of persistent luminescence imaging for liver-resection guidance is verified.Results1.The characterization results of ZGC show that the particle size is concentrated at about 10 nm,which is a single crystal spinel structure with good dispersibility.The emission peak of ZGC is 696 nm,and the afterglow after 5 minutes of excitation under a UV lamp of 254 nm wavelength is sustainable for about 5 hours.When the afterglow is weak,the probe can be activated again with the LED lamp for 1 min,and the afterglow can continue for about 60 mins.2.Toxicity tests of ZGC show that ZGC is neither cytotoxic nor toxic to tissues.3.The results of persistent luminescence imaging and CT imaging in vitro show that the persistent luminescence intensity and CT value of the probe are linearly correlated with the concentration of the probe.4.The results of the ZGC in vivo biodistribution in healthy mice show that the probe mainly enriched in liver.5.The results of multimodal CT imaging and continuous persistent luminescence imaging in tumor-bearing mice show that the positive contrast of CT signal and afterglow signal in liver tissue was significantly enhanced,but there was no obvious enhancement signal in tumor.6.Experimental results of persistent luminescence-guided liver cancer surgery shown that the persistent luminescence imaging of ZGC can accurately locate the tumor during operation accurately and guide the hepatectomy.ConclusionWe developed an NRI persistent luminescent nanoprobes(ZGC),with good stability and biocompatibility.It can be used for CT imaging and continuous luminescence imaging,providing accurate tumor location before surgery.Meanwhile,the characteristics of continuous luminescence imaging can also guide the resection of liver cancer,help to locate the lesion accurately and guide more thorough tumor resection.Above all,this multi-modality nanoprobe has great potential for accurate liver cancer imaging and resection guidance.