Abstract
920
Objectives: αvβ3 integrins are expressed on endothelial cells of newly formed blood vessels and play an important role in angiogenesis and cell migration of tumors. Radiolabeled ligands targeting αvβ3 integrin can be of great value for selection or response monitoring of cancer treatments. Various multimeric cyclic RGD analogues have been developed for in vivo imaging of αvβ3 integrins and are considered to have improved in vivo targeting characteristics, due to their enhanced affinity for αvβ3 integrin. Here, we present a direct comparison of the in vivo αvβ3 integrin targeting characteristics of 68Ga-labeled DOTA-E-[c(RGDfK)]2, TRAP-(RGD)3, fusarinine-C-(RGD)3, and THP-(RGD)3 in a human xenograft tumor model, in which αvβ3 integrins are solely expressed on the neovasculature of tumor endothelium and not on tumor cells.
Methods: DOTA-E-[c(RGDfK)]2, TRAP-(RGD)3, fusarinine-C-(RGD)3, and THP-(RGD)3 were labeled with gallium-68. Biodistribution studies of the four radiotracers (0.5 nmol per mouse, 10-15 MBq) were performed in mice with subcutaneously growing αvβ3 integrin expressing FaDu (human squamous cell carcinoma) xenografts at 1 hour post injection. The non-specific uptake of 68Ga-DOTA-E-[c(RGDfK)]2, 68Ga-TRAP-(RGD)3, 68Ga-fusarinine-C-(RGD)3, and 68Ga-THP-(RGD)3 was determined by coinjecting an excess unlabeled DOTA-E-[c(RGDfK)]2 (50 nmol) along with the radiolabeled radiotracers. PET/CT images of mice were acquired 1 hour post injection with an Inveon microPET/CT scanner.
Results: Tumor uptake in the FaDu tumor xenografts as measured ex vivo were 1.6 ± 0.5 %ID/g, 1.0 ± 0.2 %ID/g, 1.9 ± 0.3 %ID/g, and 2.2 ± 0.7 %ID/g for 68Ga-DOTA-E-[c(RGDfK)]2, 68Ga-TRAP-(RGD)3, 68Ga-fusarinine-C-(RGD)3, and 68Ga-THP-(RGD)3, respectively. 68Ga-fusarinine-C-(RGD)3 showed lower tumor-to-blood (3.1 ± 1.2) and lower tumor-to-muscle (3.6 ± 0.6) ratios compared to 68Ga-DOTA-E-[c(RGDfK)]2 (5.9 ± 2.9 and 4.6 ± 2.3 resp.), 68Ga-TRAP-(RGD)3 (5.0 ± 2.5 and 4.8 ± 1.2 resp.), and 68Ga-THP-(RGD)3 (6.8 ± 2.8 and 4.0 ± 1.2 resp.). Tumor-to-liver and tumor-to-kidney ratios were comparable for all four radiotracers.
Conclusion: In this head-to-head comparison in mice with FaDu xenografts, 68Ga-DOTA-E-[c(RGDfK)]2, 68Ga-TRAP-(RGD)3, 68Ga-fusarinine-C-(RGD)3, and 68Ga-THP-(RGD)3 allowed imaging ofαvβ3 integrin expression on tumor neovasculature. 68Ga-DOTA-E-[c(RGDfK)]2 and 68Ga-THP-(RGD)3 showed the highest tracer accumulation within tumor tissue, with 68Ga-THP-(RGD)3 showing the highest tumor-to-blood ratio. Research Support: