Objective  To develop an ultra-sensitive nanoparticle contrast agent for magnetic resonance angiography (MRA), to establish a highly sensitive imaging method for complicated vascular structures, and to provide imaging evidence for precision diagnosis, treatment, prognosis, and individualized treatment of ischemic stroke.

Methods  A dual-modality MRA contrast agent was prepared through ligand exchange of ultra-small NaGdF₄ nanocrystals synthesized via a high temperature method, with biocompatible polyethylene glycol (PEG-dp) ligands. The basic structure, morphology, size distribution, and relaxation rate of the NaGdF₄ nano contrast agent were characterized using transmission electron microscopy (TEM), a particle size potential analyzer, and a 7.0 T small-animal MRI scanner. A total of 6 healthy male SPF-grade BALB/c mice were selected and randomly divided into two groups, a NaGdF₄ group and a Gd-DTPA group. The mice in the two groups were injected with NaGdF₄ nanoparticle contrast agent or clinical Gd-DTPA contrast agent (0.1 mmol Gd³⁺/kg) via the tail vein. MRA images were obtained using a 7.0 T small animal magnetic resonance imaging system before and after the injection. A total of 6 healthy male SPF-grade Sprague Dawley (SD) rats were selected to establish a right middle cerebral artery occlusion (rMCAO) model to simulate ischemic stroke. The rats were injected with NaGdF₄ nano-contrast agent (0.1 mmol Gd³⁺/kg) via the tail vein. Before and after the injection, brain MRI images of the rats were obtained using a 7.0 T small animal magnetic resonance imaging system. The in vitro and in vivo biological safety of the nano contrast agent was verified through cytotoxicity and hemolysis experiments and HE staining.

Results  Uniform spherical oil-phase NaGdF₄ nanocrystals with an average particle size of approximately (4.43 ± 0.46) nm were successfully prepared. After ligand exchange, biocompatible water-phase nanocrystals were obtained with a hydrodynamic size of 16.1 nm and a surface potential of －1.9 mV. The relaxation performance of this nanocrystal contrast agent was significantly superior to that of the clinical contrast agent Gd-DTPA. The longitudinal molar relaxivity rate (r₁) of the NaGdF₄ nano contrast agent was 8.84 mM⁻¹s⁻¹, while the transverse molar relaxivity rate (r₂) was 27.36 mM⁻¹s⁻¹, which were 1.96 times (4.52 mM⁻¹s⁻¹) and 3.37 times (8.13 mM⁻¹s⁻¹) those of Gd-DTPA, respectively. It also demonstrated excellent biocompatibility. NaGdF₄-enhanced MRA achieved high-resolution vascular imaging and effectively enabled the differentiation of the ischemic area, infarct core, and ischemic penumbra in an animal model of ischemic stroke.

Conclusion  The multi-parameter MRA based on NaGdF₄ nanoparticles provides critical imaging evidence for the clinical diagnosis and prognosis of ischemic stroke.