PET imaging of 68Ga-NODAGA-RGD, as compared with 18F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma

Abstract

BackgroundTracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma.MethodsNude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD.ResultsBoth tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density.Conclusions68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0405-5) contains supplementary material, which is available to authorized users.

Micro-PET imaging of angiogenesis based on 18F-RGD for assessment liver metastasis in colorectal cancer

“…Our viewpoint was consistent with previous reviews, that 18 F-RGD is a promising tracer for tumor angiogenesis imaging and monitoring anti-angiogenesis therapy in solid tumor [25,26]. In Sibel lsal's study, they also veri ed that the expression of integrin αvβ3, which are targeted by RGD-based peptides tracer, was associated with cell proliferation in glioblastoma [27].…”

Head and neck tumors angiogenesis imaging with 68Ga-NODAGA-RGD in comparison to 18F-FDG PET/CT: a pilot study

“…All HNSCC primary tumors, lymph nodes, and metastases detected on 18 F-FDG PET/CT images were also seen with the angiogenesis radiotracer. Only few studies have been conducted in humans; while Haubner et al [20] demonstrated that 68 Ga-NODAGA-RGD uptake was not sufficient to be used in patients with hepatocellular carcinoma, other authors reported sufficient uptake for diagnostic purpose in human xenografts of esophageal carcinoma, melanoma, and glioblastoma [18,21]. As both 68 Ga-NODAGA-RGD and 18 F-Galacto-RGD demonstrated similar preclinical results [22], our results are in line with the previous work by Beer et al [8], who concluded that thanks to its significant uptake, 18 F-Galacto-RGD might be used for the assessment of angiogenesis and for planning and response evaluation of α v β 3 targeted therapies in HNSCC.…”

“…68 Ga-NODAGA-RGD uptake beyond 18 F-FDG avid areas could thus reflect the presence of the formation of neovessels. Isal et al [21] demonstrated that tumor areas with high 68 Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and integrin expressions irrespective of cell density in engrafted glioblastomas. This seems to be different in HNSCC, as we did not find any significant association between tracers' uptake and HNSCC grade.…”

Head and neck tumors angiogenesis imaging with 68Ga-NODAGA-RGD in comparison to 18F-FDG PET/CT: A pilot study.

“…To this purpose we conducted a one-to-one comparison of tracers to assess the clinical potential of PET/CT images were also seen with the angiogenesis radiotracer. Only few studies have been conducted in humans; while Haubner et al [20] demonstrated that 68 Ga-NODAGA-RGD uptake was not sufficient to be used in patients with hepatocellular carcinoma, other authors reported sufficient uptake for diagnostic purpose in human xenografts of esophageal carcinoma, melanoma and glioblastoma [18,21]. As both 68 Ga-NODAGA-RGD and 18 F-Galacto-RGD demonstrated similar preclinical results [22], our results are in line with the previous work by Beer et al [8], who concluded that thanks to its significant uptake, 18 F-Galacto-RGD might be used for the assessment of angiogenesis and for planning and response evaluation of α v β 3 targeted therapies in HNSCC.…”

“…68 Ga-NODAGA-RGD uptake beyond 18 F-FDG avid areas could thus reflect the presence of the formation of neovessels. Isal et al [21] demonstrated that tumor areas with high 68 Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and integrins expressions irrespective of cell density in engrafted glioblastomas. This seems to be different in HNSCC, as we did not find any significant association between tracers' uptake and HNSCC grade.…”