Preclinical Evaluation of a Protein-Based Nanoscale Contrast Agent for MR Angiography at an Ultralow Dose

Jianmin Li,1,2,&ast; Wenyi Zhang,1,2,&ast; Shuang Liu,1,2,&ast; Fan Yang,2 Yupeng Zhou,2 Lin Cao,1,2 Yiming Li,1,2 Yunfei Guo,1,2 Xiang Qi,1,2 Guoping Xu,1 Jing Peng,1 Yang Zhao1,2 1Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Zhao; Jing Peng, Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China, Email yang.zhao@tmu.edu.cn; jing.peng@tmu.edu.cnPurpose: BSA-biomineralized Gd nanoparticles (Gd@BSA NPs) have been recognized as promising nanoscale MR contrast agents. The aim of this study was to carry out a preclinical evaluation of these NPs in a middle-sized animal model (rabbits).Methods: New Zealand white rabbits were treated intravenously with Gd@BSA NPs (0.02 mmol Gd/kg) via a clinically-used high-pressure injector, with commercial Gd-diethylene triamine pentaacetate (Gd-DTPA)-injected group as control. Then MR angiography was performed according to the standard clinical protocol with a 3.0-T MR scanner. The SNR and CNR of the main arteries and branches were monitored. Pharmacokinetics and bioclearance were continuously evaluated in blood, urine, and feces. Gd deposition in vital organs was measured by ICP‒MS. Weight monitoring, HE staining, and blood biochemical analysis were also performed to comprehensively estimate systemic toxicity.Results: The ultrasmall Gd@BSA NPs (< 6 nm) exhibited high stability and T1 relaxivity. Compared to Gd-DTPA, Gd@BSA NPs demonstrated superior vascular system imaging performance at ultralow doses, especially of the cardiac artery and other main branches, and exhibited a significantly higher SNR and CNR. Notably, the Gd@BSA NPs showed a shorter half-life in blood, less retention in organs, and improved biocompatibility.Conclusion: The preclinical evaluations here demonstrated that Gd@BSA NPs are promising and advantageous MR CA candidates that can be used at a low dose with excellent MR imaging performance, thus suggesting its further clinical trials and applications.Keywords: preclinical evaluation, ultralow dose, high-pressure injector, MR angiography