Preclinical Research And Clinical Application Of ⁶⁸Ga-NODAGA-R01-MG And ⁶⁸Ga-DOTA-TATE PET/CT Imaging Of Tumor And Tumor-induced Osteomalacia

Project ?Preclinical research and clinical application of integrin ?v?6 receptor targeted 68Ga-NODAGA-R01-MG PET/CT imagingObjective:Integrin ?v?6 is a cell surface receptor less expressed in healthy tissue but overexpressed in a variety of cancers and fibrosis.Overexpression of integrin ?v?6 is often associated with malignant potential and poor prognosis.In this study,we described the synthesis and preclinical evaluation of a 68Ga-labeled integrin ?v?6-targeting peptide 68Ga-NODAGA-R01-MG,and its biodistribution in healthy volunteers and clinical application of 68Ga-NODAGA-R01-MG in various tumors using PET/CT imaging.Methods:68Ga-NODAGA-R01-MG was synthesized by manual method of adding 68Ga from germanium-gallium generator into NODAGA-R01.The in vitro stability test,enterotoxin test,toxicology test and mouse biodistribution study were performed.Cell binding and blocking tests were performed using pancreatic BxPC-3(integrin ?v?6-positive)and HEK293T(integrin avp6-negative)cell lines.MicroPET imaging of 68Ga-NODAGA-R01-MG were performed using pancreatic BxPC-3 and HEK293T tumor mouse models.In clinical study,six healthy volunteers and 21 patients with various tumors were recruited for 68Ga-NODAGA-R01-MG PET/CT imaging.Tumor patients also went through 18F-FDG PET/CT imaging for comparison.SUMmax and SUVmean of tumors were calculated.(SUVs tumor/SUVs blood)were also calculated in 68Ga-NODAGA-R01-MG PET/CT imaging.Seven patients with tumors also went through duel-time PET/CT imaging using 68Ga-NODAGA-R01-MG at 40 min and 90 min post tracer injection.Mann-Whitney U was used for statistical analysis and p<0.05 was considered significant difference.Results:68Ga-NODAGA-R01-MG was prepared in high radiochemical purity(>99%).And were aseptic,pyrogen-free and non-toxic.In the mouse biodistribution study,68Ga-NODAGA-R01-MG was cleared rapidly from the blood and had high biodistribution in the kidney,bladder and GI tract.In cell binding and blocking study,68Ga-NODAGA-R01-MG showed high integrin ?v?6-binding specificity.MicroPET imaging on mice tumor models showed high uptake in BxPC-3 tumors but not in HEK293T tumors.In all healthy volunteers,injection of 68Ga-NODAGA-R01-MG was well tolerated with no adverse or clinically detectable pharmacologic effects being noticed or reported.Tracers mainly accumulated at kidney and bladder.SUVmax and SUVmean of malignant tumors were 5.4±3.4,3.1±1.9,respectively.SUVratio between malignant tumors and background were 3.7±2.2(SUVmax),3.9±2.7(SUVmean),respectively.SUVmax and SUVmean of benign lesions were 4.7±1.8,2.5±0.6,respectively.SUVratio between benign lesions and background were 2.8±0.8(SUVmax),3.0±0.4(SUVmean),respectively.There was no significant difference between the uptake 68Ga-NODAGA-R01-MG of malignant tumors both and benign lesions(p>0.05).In all 21 patients with tumors,the tumor detection rate using 68Ga-NODAGA-R01-MG was 76.2 0-%(16/21),and 70.6%(12/17)for malignant tumors.In the duel-time imaging using 68Ga-NODAGA-R01-MG,early and late time point tracer uptake showed no significant difference(SUVmax:4.1±1.5 vs.3.6±1.2,p>0.05;SUVmean:2.3±0.7 vs.2.0±0.7,p>0.05).Tumor detection was both positive using the two tracers in 14 cases,and 4 cases were only 18F-FDG positive but 68Ga-NODAGA-R01-MG negative.Tumor 68Ga-NODAGA-R01-MG and 18F-FDG SUVmax were 5.0 ±3.3 and 8.3±3.4 respectively(p<0.05).Conclusion:68Ga-NODAGA-R01-MG could be successfully synthesized with high radiochemical purity and good stability,and can specifically target to integrin ?v?6 tumor models.In the preliminary clinical study,68Ga-NODAGA-R01-MG is safe and has a low background uptake in human,and can detect some tumors using PET/CT imaging.68Ga-NODAGA-R01-MG PET/CT does not perform better than 18F-FDG PET/CT,but it may provide integrin UVPV receptor expression and may guide the choice of the treatment.68Ga-NODAGA-R01-MG is a promising tracer that has great clinical translation potential.Project ?Comparison of the 68Ga-DOTATATE PET/CT and Bone Scintigrap--hy in the Evaluation of Tumor-induced OsteomalaciaPurpose:Tumor-induced osteomalacia(TIO)is a chronic,devastating disease.In this retrospective investigation,we aim to assess the application of 8Ga-DOTA-TATE PET/CT for detecting the culprit tumor of TIO,and compared its value with 99mTc-MDP bone scintigraphy.Methods:A total 91 patients with confirmed TIO from 2009 to 2017 were collected and retrospectively reviewed.All images of 99mTc-MDP bone scintigraphy and 68Ga-DOTA-TATE PET/CT were studied by two nuclear physicians using visual analysis to define the location of potential TIO lesions.Tumor diameter was also measured from anatomic images.Images from 68Ga-DOTA-TATE PET/CT and 99mTc-MDP bone scintigraphy were compared and evaluated together with pathological examinations and clinical follow-ups.Results:The mean age of 91 patients(48 male,43 female)with TIO was 42 years(rang,13-70years).The mean length of the disease from the onset of the symptom to the final diagnoses was 5.8 years(1-22 years).The range of serum phosphate level was 0.20-0.75 mmol/L.The tumors size measured from anatomic images ranged from 0.5 cm to 8 cm(2.3 cm ±1.6 cm).68Ga-DOTA-TATE showed positive findings in 65(100%)of the total 65 osteomalacia patients,in which 36 cases were in the bone,27 cases in the soft tissue and 2 cases in both soft tissue and bone.In all 91 patients with 99mTc-MDP bone scintigraphy,23.1%of the patients(21 of 91)have positive finding of potential tumor sites,in which 13 cases were in the bone,6 cases in the soft tissue and 2 cases in both soft tissue and bones.In the 65 patients with both 68Ga-DOTA-TATE PET/CT and 99mTc-MDP bone scintigraphy,68Ga-DOTA-TATE PET/CT can detect 65 lesions while 99mTc-MDP can detect 16 lesions.In those lesions with positive 68Ga-DOTA-TATE but negative 99mTc-MDP uptake,55.1%(27/49)located at bon and 44.9%(22/49)at soft tissues.Conclusions:68Ga-DOTA-TATE PET/CT scan is an accurate imaging modality in the detection of tumors causing TIO,Although findings of whole-body scintigraphy are nonspecific in patients with TIO,careful evaluation of bone scintigraphy results can be helpful in guiding further evaluation in some patients.