[68Ga]NODAGA-RGD – Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

Abstract

PurposeThis study was designed to determine safety, tolerability, and radiation burden of a [68Ga]NODAGA-RGD-PET for imaging integrin αvβ3 expression in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Moreover, metabolic stability and biokinetic data were compiled.MethodsAfter injection of 154–184 MBq [68Ga]NODAGA-RGD three consecutive PET/CT scans were acquired starting 8.3 ± 2.1, 36.9 ± 2.8, and 75.1 ± 3.4 min after tracer injection. For metabolite analysis, blood and urine samples were analyzed by HPLC. For dosimetry studies, residence time VOIs were placed in the corresponding organs. The OLINDA/EXM program was used to estimate the absorbed radiation dose.ResultsThe radiopharmaceutical was well tolerated and no drug-related adverse effects were observed. No metabolites could be detected in blood (30 and 60 min p.i.) and urine (60 min p.i.). [68Ga]NODAGA-RGD showed rapid and predominantly renal elimination. Background radioactivity in blood, intestine, lung, and muscle tissue was low (%ID/l 60 min p.i. was 0.56 ± 0.43, 0.54 ± 0.39, 0.22 ± 0.05, and 0.16 ± 0.8, respectively). The calculated effective dose was 21.5 ± 5.4 μSv/MBq, and the highest absorbed radiation dose was found for the urinary bladder wall (0.26 ± 0.09 mSv/MBq). No increased uptake of the tracer was found in HCC compared with the background liver tissue.Conclusions[68Ga]NODAGA-RGD uptake in the HCCs lesions was not sufficient to use this tracer for imaging these tumors. [68Ga]NODAGA-RGD was well tolerated and metabolically stable. Due to rapid renal excretion, background radioactivity was low in most of the body, resulting in low radiation burden and indicating the potential of [68Ga]NODAGA-RGD PET for non-invasive determination of integrin αvβ3 expression.

The uptake exploration of 68Ga-labeled NGR in well-differentiated hepatocellular carcinoma xenografts: Indication for the new clinical translational of a tracer based on NGR

“…Even though HCCs are worldwide malignant tumors with high incidence of morbidity, there has been little progress in their detection by radio-labeled probes. Roland et al utilized [ 68 Ga]NODAGA-RGD to image patients with HCCs, but the probe uptake by the HCC tumors and the tumor/liver ratio were both insufficient for HCC detection (44). This may be attributed to the low receptor expression and the higher background radioactivity in the cirrhotic liver leading to poor detection.…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…A variety of RGD-peptides-binding to integrin receptors-are based on the cyclic pentapeptide c(RGDfV), which shows high stability in vivo (for a review, see, e.g., [4]). For example, no metabolites of [ 68 Ga]Ga-NODAGA-RGD (where NODAGA is 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) were found in the blood and urine of patients over the whole observation period up to 1 h post-injection [5]. However, problematic might be that, due to cyclisation, the flexibility of the peptide is reduced which, in the case of the RGD-peptides, improved the target selectivity but can also negatively influence the affinity of the peptide.…”

Preparation of 68Ga‐Mg‐Ca‐phytate colloid and its evaluation as a liver imaging agent

“…Quantitative hepatobiliary function was evaluated with experimental soluble agents such as 68 Ga‐IDA‐tetrabromo‐o‐cresolphthalein in rats, or 68 Ga‐1,2‐dihydroxyanthraquinone (alizarin) in rats, dogs and humans . The 68 Ge/ 68 Ga‐generator has more recently stimulated the invention of many new experimental positron emission tomography (PET) agents, including 68 Ga‐DTPA‐galactosyl‐HSA for imaging a functional hepatocellular mass in rats, 68 Ga‐NOTA‐neolactosyl‐HSA for imaging the asialoglycoprotein receptor in mice, and 68 Ga‐NODAGA‐RGD for evaluation of patients with hepatocellular carcinoma and liver cirrhosis . The early particulate agents included 68 Ga‐chromic phosphate colloid, 68 Ga‐iron hydroxide colloid, or the gamma‐emitting 113m In‐Ca‐phytate and 113m In‐hydroxide colloid .…”

“…6 The 68 Ge/ 68 Ga-generator has more recently stimulated the invention of many new experimental positron emission tomography (PET) agents, including 68 Ga-DTPA-galactosyl-HSA for imaging a functional hepatocellular mass in rats, 7 68 Ga-NOTA-neolactosyl-HSA for imaging the asialoglycoprotein receptor in mice, 8 and 68 Ga-NODAGA-RGD for evaluation of patients with hepatocellular carcinoma and liver cirrhosis. 9 The early particulate agents included 68 Ga-chromic phosphate colloid, 10 68 Ga-iron hydroxide colloid, 11 or the gamma-emitting 113m In-Ca-phytate and 113m In-hydroxide colloid. 12 The PET molecules required complex radiolabelling steps to prepare, and 113m In has since become unavailable, which may explain their lack of advancement into the clinical domain.…”

“…Solutions were transferred/added using an insulin syringe (0.5 or 1 mL; Becton Dickinson & Co, Singapore). The acidity of liquids was determined using universal indicator pH strips (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Reaction vials were heated in a dry bath (DBH20D; Ratek Instruments, VIC, Australia) to heat the contents at 100°C, then allowed to stand at room temperature (RT, 23°C) or stored cold in a refrigerator (5±3°C).…”