Early And Dynamic Monitoring Of Antiangiogenic Treatment Response In U87MG Xenograft By MicroPET/CT Imaging

Part One Biodistribution in healthy KM mice and micro PET/CT imaging in U87MG tumor-bearing nude mice of a new F-labeled cyclic RGD dimerObjective Integrin ανβ3 receptor plays an important role in promoting, sustaining and regulating the angiogenesis. It is overexpressed on neovascular endothelial cells and tumor cells. RGD peptide specifically binds to integrin ανβ3, which could evaluate growth status and invasiveness of tumor. This study aimed to investigate the biodistribution in healthy KM mice and micro PET/CT imaging in U87MG tumor-bearing mice of 18F-E[c(RGDfK)2].Methods 18F-E[c(RGDfK)2] was produced using an automated synthesis module via a simple one-step 18F-labeling strategy of the precursor 4-NO2-3-TFMBz-E[c(RGDfk)2], purified by semipreparative HPLC system. The radiochemical purity and stability in vivo were measured by analytical Radio-HPLC. The percentage activity of injection dose per gram of tissue (%ID/g) was calculated at 0.5,1,2,4h post injection of the probe. Micro PET/CT images of U87MG tumor-bearing nude mice with or without F-E[c(RGDfK)2] blocking were acquired at each time point.Results The labeling efficiency and radiochemical purity of 18F-E[c(RGDfK)2] were 10% and 98%, respectively.18F-E[c(RGDfK)2] was excreted via renal route, with a high blood clearance. The other organs had background-level activity accumulation. (At 1h, the %ID/g of kidney, liver, intestine, muscle and blood was 1.02±0.16、0.24± 0.06、0.35±0.03、0.13±0.03、0.11±0.03, respectively.) 18F-E[c(RGDfK)2] had initial high tumor uptake (5.2 ±0.56%ID/g) and good tumor-to-background contrast (5.36) at 1h post injection. Tumor uptake for blocking group was lower than those without blocking and T/M reduced to 1.57.Conclusion 18F-E[c(RGDfK)2] appears a promising PET molecular imaging probe targeting integrin ανβ3, with high tumor uptake. It could be suitable for prognosis evaluation of integrin-positive tumor, selection of vascular targeting therapy and therapy effect monitoring. without blocking and T/M reduced to 1.57.Conclusion 18F-E[c(RGDfK)2] appears a promising PET molecular imaging probe targeting integrin ανβ3, with high tumor uptake. It could be suitable for prognosis evaluation of integrin-positive tumor, selection of vascular targeting therapy and therapy effect monitoring.Part Two Early and dynamic monitoring of antiangiogenic treatment response in U87MG xenograft by longitudinal 18F-FDG MicroPET/CT imagingObjective Angiogenesis is a fundamental physiological process to support cancer growth and development. It occurs for almost all solid tumors such as Glioblastoma (GBM) and thus anti-angiogesis therapeutics are increasingly applied to treat various cancers. Antiangiogenic agents are predominant cytostatic therapeutics rather than cytotoxic, thus tumor-size based therapy evaluation (RECIST) is not effective to monitor therapecutic response. F-FDG molecular imaging can noninvasively detect glucose metabolism of tumor cells.It was aimed to dynamicallymonitor treatment response ofSunitinib, a multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities, in a xenograft model of Glioblastoma Multiforme (GBM), by 18F-FDGMicroPET/CT imaging in this study.Methods U87MG tumor-bearing nude mice were intragastrically injected with Sunitinib at a dose of 80 mg/kg for consecutive 7 days. Longitudinal I8F-FDG MicroPET/CT scans were acquired on day 0,1,3,7 and 13 after therapy initiation. Tumor sizes and mice weight were measured throughout the study. Tumor samples were collected for immunohistochemical (IHC) analysis with anti-Glut-1 and anti-CD31, respectively.Results The ratios of %ID/gmax of tumor to the contralateral muscle (T/M) of 18F-FDG in the Sunitinib group decreased slightly, only revealed significantly difference on day 13 compared to baseline (T/Mo= 4.37±0.22, T/M13=5.11±0.39, P<0.05). The T/M of 18F-FDG uptake in the control group fluctuated between 4.0 and 5.0 throughout the study. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study. T/M of 18F-FDG uptakes showed a bit positive correlation with the quantitative data of Glut-1, but revealed negative correlation with the quantitative data of MVD.Conclusion 18F-FDG PET revealed no significant difference upon Sunitinib treatment, suggesting limited value of monitoring antiangiogenisis treatment response. P<0.05). The T/M of 18F-FDG uptake in the control group fluctuated between 4.0 and 5.0 throughout the study. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study. T/M of 18F-FDG uptakes showed a bit positive correlation with the quantitative data of Glut-1, but revealed negative correlation with the quantitative data of MVD.Conclusion 18F-FDG PET revealed no significant difference upon Sunitinib treatment, suggesting limited value of monitoring antiangiogenisis treatment response.Part Three Early and dynamic monitoring of antiangiogenic treatment response in U87MG xenograft by longitudinal 18F-FLT MicroPET/CT imagingObjective Antiangiogenic agents are predominant cytostatic therapeutics rather than cytotoxic, thus tumor-size based therapy evaluation (RECIST) is not effective to monitor therapecutic response.18F-FLT molecular imaging can noninvasively detect proliferation of tumor cells, as destruction of vessels could cause decrease of tumor proliferation. It was aimed to dynamically monitor treatment response of Sunitinib, a multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities, in a xenograft model of Glioblastoma Multiforme (GBM), by 18F-FLT MicroPET/CT imaging in this study.Methods U87MG tumor-bearing nude mice were intragastrically injected with Sunitinib at a dose of 80 mg/kg for consecutive 7 days. Longitudinal 18F-FLT MicroPET/CT scans were acquired on day 0,1,3,7 and 13 after therapy initiation. Tumor sizes and mice weight were measured throughout the study. Tumor samples were collected for immunohistochemical (IHC) analysis of proliferation and microvessel density (MVD) with anti-Ki67 and anti-CD31, respectively.Results The ratios of %ID/gmax of tumor to the contralateral muscle (T/M) of 18F-FLT in the Sunitinib group decreased from baseline to day 3 (T/Mo= 2.98± 0.33, T/M3= 2.23± 0.36, P= 0.000), rapidly reached the bottom on day 7 when therapy stopped (T/M7= 1.96±0.35, P= 0.000), then recovered onday 13 (T/M13= 3.09±0.29, P> 0.05). The T/M of 18F-FLT uptake in the control group remained around 3.0 throughout the study. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study.18F-FLT uptakes of tumor in the treatment group were correlated with the Ki67 index and MVD.Conclusion Early therapy response to Sunitinib could be predicted via 18F-FLT PET, which will contribute to mornitoring antiangiogenisis treatment. 0.33, T/M3= 2.23± 0.36, P= 0.000), rapidly reached the bottom on day 7 when therapy stopped (T/M7= 1.96±0.35, P= 0.000), then recovered onday 13 (T/M13= 3.09±0.29, P> 0.05). The T/M of 18F-FLT uptake in the control group remained around 3.0 throughout the study. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study.18F-FLT uptakes of tumor in the treatment group were correlated with the Ki67 index and MVD.Conclusion Early therapy response to Sunitinib could be predicted via 18F-FLT PET, which will contribute to mornitoring antiangiogenisis treatment.Part Four Early and dynamic monitoring of antiangiogenic treatment response in U87MG xenograft by longitudinal 18F-FMISO MicroPET/CT imagingObjective 18F-FMISO molecular imaging can noninvasively detect hypoxia of tumor cells, as destruction of vessels couJd cause aggravation of tumor hypoxia. It was aimed to dynamically monitor treatment response of Sunitinib, a multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities, in a xenograft model of Glioblastoma Multiforme (GBM), by 18F-FMISO MicroPET/CT imaging in this study.Methods U87MG tumor-bearing nude mice were intragastrically injected with Sunitinib at a dose of 80 mg/kg for consecutive 7 days. Longitudinal 18F-FMISO MicroPET/CT scans were acquired on day 0,1,3,7 and 13 after therapy initiation. Tumor sizes and mice weight were measured throughout the study. Tumor samples were collected for immunohistochemical (IHC) analysis of hypoxia and microvessel density (MVD) with anti-HIF-1α and anti-CD31, respectively.Results The ratios of %ID/gmax of tumor to the contralateral muscle (T/M) of 18F-FMISO in the Sunitinib group decreased from baseline to day 3 (T/Mo= 2.04± 0.18, T/M3= 1.57±0.12, P< 0.01), rised again on day 7 when therapy stopped (T/M7 = 1.87±0.19, P> 0.05). The T/M of 18F-FMISO uptake in the control group kept rising. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study. T/M of 18F-FMISO uptakes were correlated with the quantitative data of MVD, but uncorrelated with the quantitative data of HIF-1α.Conclusion 18F-FMISO uptake of tumor could change following Sunitinib treatment, but 18F-FMISO uptake not always reflect hypoxia caused by antiangiogenisis treatment. = 1.87±0.19, P> 0.05). The T/M of 18F-FMISO uptake in the control group kept rising. There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study. T/M of 18F-FMISO uptakes were correlated with the quantitative data of MVD, but uncorrelated with the quantitative data of HIF-1α.Conclusion 18F-FMISO uptake of tumor could change following Sunitinib treatment, but 18F-FMISO uptake not always reflect hypoxia caused by antiangiogenisis treatment.Part Five Early and dynamic monitoring of antiangiogenic treatment response in U87MG xenograft by longitudinal 18F-ML10 MicroPET/CT imagingObjective 18F-ML10 molecular imaging can noninvasively detect apoptosis of tumor cells, as destruction of vessels could cause increase of tumor apoptosis. It was aimed to dynamically monitor treatment response of Sunitinib, a multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities, in a xenograft model of Glioblastoma Multiforme (GBM), by 18F-ML10 MicroPET/CT imaging in this study.Methods U87MG tumor-bearing nude mice were intragastrically injected with Sunitinib at a dose of 80 mg/kg for consecutive 7 days. Longitudinal 18F-ML10 MicroPET/CT scans were acquired on day 0,1,3,7 and 13 after therapy initiation. Tumor sizes and mice weight were measured throughout the study. Tumor samples were collected for immunohistochemical (IHC) analysis of Tunel and microvessel density (MVD) with anti-CD31.Results The ratios of %ID/gmax of tumor to the contralateral muscle (T/M) of 18F-ML10 in the Sunitinib group increased throughout the study, T/M on day 1,3,7 and 13 shown significant difference compared to day 0 (P< 0.01). The T/M of 18F-FLT uptake in the control group on day 1 and 3 were lower than T/M in treatment group (P< 0.01). There was no difference for the tumor size between the two groups until Day 11 (P= 0.015) and also no significant differences were observed in mice weight during the whole study.18F-ML10 uptakes of tumor were correlated with the quantitative data of AI, and shown a bit negative correlation with the quantitative data of MVD.Conclusion Early therapy response to Sunitinib could be predicted via 18F-ML10 PET, which will contribute to mornitoring antiangiogenisis treatment.