Development of Iron Oxide Based Nanoparticles as Dual-Modality Imaging Probes




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Dual-modality (MR/nuclear) imaging can combine exquisite anatomical resolution with superior molecular sensitivity, and significantly facilitate the accuracy of cancer diagnosis. However, the application of this technique is hampered by the paucity of sensitive dual-modality imaging probes that target tumors specifically. Here we synthesized dual-modality imaging probes by doping positron- or gamma-emitting nuclides to the core of dextran-coated superparamagnetic iron oxide nanoparticles (NUSPIONs). The synthesized nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), atomic force microscope (AFM), and high performance liquid chromatography (HPLC). The evaluations of these nanoparticles were performed both in vitro and in vivo. Four radioisotopes (111In, 177Lu, 64Cu, and 77As) were successfully incorporated into the core of nanoparticles. The purification of nanoparticles via centricon filter accelerated the separation process effectively without apparent aggregation. These nanoparticles exhibited good in vitro stability in both phosphate buffered saline (> 99% intact) and rat serum (> 92% intact) out to 72 h, and the high r2-to-r1 ratio indicating their potential as MRI T2 contrast agents. Two distinctly sized 177Lu-doped nanoparticles (NUSPION-1 and NUSPION-2 with hydrodynamic radii of 11.8 񠱮3 nm and 30.6 񠰮5 nm respectively) were used for biodistribution studies in normal mice. NUSPION-1 showed significantly (p < 0.0001) higher uptake and longer retention in blood and less uptake in liver and spleen than NUSPION-2, which is advantageous for both passive and active targeting. Due to its optimal tissue distribution pattern, NUSPION-1 was chosen for further in vivo evaluation in PC-3 tumor-bearing mice. High tumor uptake and contrast ratios of tumor-to-muscle and tumor-to-blood were observed. A proof-of-principle dual-modality imaging study was carried out by a virtually single-dose injection in PC-3 tumor-bearing mice. The tumors were visualized by both MRI and autoradiography. Post-MRI Prussian blue iron staining and post-autoradiographic imaging biodistribution confirmed the accumulation of nanoparticles in tumors. Taken together, we have demonstrated a practical method to develop iron oxide based MRI/nuclear imaging probes.