Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules.

摘要: A promising strategy to enable patient stratification for targeted therapies is monitor the target expression in a tumor by radionuclide molecular imaging. Affibody molecules (7 kDa) are nonimmunoglobulin scaffold proteins with 25-fold smaller size than intact antibodies. They have shown an apparent potential as imaging probes both preclinical and clinical studies. Earlier, we found that hepatic uptake can be reduced incorporation of negatively charged purification tags at N-terminus molecules. We hypothesized liver might similarly positioning chelator N-terminus, where chelator-radionuclide complex will provide negative charges. To test this hypothesis, second generation synthetic anti-HER2 ZHER2:2891 molecule was synthesized labeled (111)In (68)Ga using DOTAGA DOTA chelators. The chelators were manually coupled forming amide bond. Labeling DOTAGA-ZHER2:2891 DOTA-ZHER2:2891 resulted stable radioconjugates. tumor-targeting biodistribution properties (111)In- (68)Ga-labeled conjugates compared SKOV-3 tumor-bearing nude mice 2 h postinjection. HER2-specific binding radioconjugates verified vitro vivo. Using gave significantly lower radioactivity blood radionuclides. (111)In-labeled showed more rapid clearance conjugates. most pronounced influence when they (68)Ga. higher tumor-to-blood (61 ± 6 vs 23 5, p < 0.05) tumor-to-liver (10.4 0.6 4.5 0.5, ratios chelator. This study demonstrated may used alter molecules, likely other scaffold-based probes, improvement contrast.