The Study On The Quantitive Analysis Of Tumor Integrinα_vβ₃Expression Level By U-SPECT-CT Imaging With Integrinα_vβ₃Targeting Radiotracer^99mTc-3P-RGD₂and Its Potent Application Value

Aim To investigate the quantitive analysis of tumor integrinαvβ3expressionlevel by U-SPECT-CT imaging with integrinαvβ3targeting radiotracer^99mTc-HYNIC-PEG4-E[PEG4-c（RGDfk）]2(^99mTc-3P-RGD₂) and its potent use forearly detection of tumor regional recurrence, distant metastasis, grading. It may offergreat information for patient selection for anti-angiogensis therapy and therapeuticeffect monitoring. Methods U-SPECT-CT fusion imaging was used for exactdelineation of tumor volume, including functional and necrotic tissues, andquantification of^99mTc radioactivity with the equipment of U-SPECT-II/CT. Weprepared the integrin αvβ3targeting radiotracer,^99mTc-3P-RGD₂, and finishedSPECT-CT imaging and biodistribution studies at different time points aftersubcutaneous implantion of tumor cells in nude mice. And relationship wasestablished between tumor uptake（percentage of injected dose%ID and percentage ofinjected dose per gram,%ID/g） with tumor integrin αvβ3expression level. On thebasis of the establishment of the subcutaneous tumor xenograft model and tumorregional recurrence model and lung, bone metastasis model, we investigatedU-SPECT-II/CT imaging for the quantification of tumor integrin αvβ3expression leveland early detection of tumor recurrence and metastasis with radiotracer^99mTc-3P-RGD₂. Different tumor models were established of different expressionlevel integrin αvβ3expression （U87MG glioma with high expression level anddifferentiated thyroid cancer low expression level of intergrinαvβ3）.^99mTc-3P-RGD₂U-SPECT-CT imaging was used to monitor the therapeutic effect of antiangiogenesis of tumors with different expression level of integrinα_vβ₃. Results: With anatomicaland function information, U-SPECT-CT fuion images was better for the delineationof tumor volume including functional and necrotic tissues. It was also found thatquantification of^99mTc radioactivity could be done based on U-SPECT-CT imagingwith little bias. Linear relationship was found between radiocounts on U-SPECT-CTand its real radioactivity with R²being0.9997. We prepared the kit for simple andconvenient radiolabeling of^99mTc-3P-RGD₂. Biodistribution studies of^99mTc-3P-RGD₂demonstrated that it was perfect with high tumor uptake and longretention time and rapid clearance for normal organs such as blood, liver and lung.Relationship between the tumor size （in cm3） and the tumor uptake （%/ID for totalradioactivity, and%ID/cm3for radioactivity density） determined by SPECT-CT andbiodistribution studies were established. They were similar to a great degree. Therelationship between the tumor volume and%ID of^99mTc-3P-RGD₂was modeled asquadratic polynomial fitting curve (R²>0.95for both SPECT-CT biodistributionstudies for tumors of0.01–2.0cm3. Linear relationship （R²=0.8954forSPECT-CT data and0.8929for biodistribution data） between the tumor size and%IDof^99mTc-3P-RGD₂when tumors were <1.0g or cm3. Tumor uptake （%ID/g） peakedwhen tumor size was0.15-0.25g or0.15-0.25cm3and decreased as tumor grewbecause of internal tumor necrosis. Linear relationship （R²=0.8117）was foundbetween tumor uptake （%ID/g） and integrinα_vβ₃expression level determined byimmunostaining studies. In recurrent and metastatic tumor models,^99mTc-3P-RGD₂U-SPECT-CT was definitely effective for early detection of tumor recurrence,micrometastasis in lung, bone and lymph nodes （with long diameter of1.0mm）.Therapeutic effect of anti-angiogensis was better in tumors of high tumor uptake of^99mTc-3P-RGD₂,in other words, high level integrin α_vβ₃expression, than tumor of lowlevel of uptake of^99mTc-3P-RGD₂. And tumor uptake decrease was obvious on day5 after anti-angiogenesis, much earlier than tumor volume changes.Conclusions: U-SPECT-CT fusion images can quantitively determine tumor volumeand tumor uptake of^99mTc-3P-RGD₂with equipment of U-SPECT-II/CT. It caneffectively reflect tumor integrin α_vβ₃expression level and early detect tumorrecurrence and micrometastasis. Based on this,^99mTc-3P-RGD₂U-SPECT-CTimaging was useful for tumor staging and grading and patient selection andtherapeutic effect prediction, dynamic monitoring of anti-angiogesis treatment。...