Ultrasmall iron oxide nanoparticles with MRgFUS for enhanced magnetic resonance imaging of orthotopic glioblastoma

Ultrasmall iron oxide nanoparticles (USIO NPs) are expected to become the next generation T1 contrast agents; however, their diagnostic and therapeutic potential for primary brain tumors (such as glioblastoma multiforme, GBM) is yet to be explored. At present, the main challenge is the effective hindering of biological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Herein, we aimed to investigate whether the USIO NPs, in combination with MR-guided focused ultrasound (MRgFUS), could intensify MR imaging of GBM. In this study, we presented zwitterionic USIO NPs for enhanced MR imaging of both xenografted and orthotopic GBM mouse models. We first synthesized citric-stabilized USIO NPs with a size of 3.19 +/- 0.76 nm, modified with ethylenediamine, and decorated with 1,3-propanesultone (1,3-PS) to form USIO NPs-1,3-PS. The obtained USIO NPs-1,3-PS exhibited good cytocompatibility and cellular uptake efficiency. MRgFUS, in combination with microbubbles, provided a non-invasive and safe technique for BBB opening, which, in turn, promoted the delivery of USIO NPs-1,3-PS in orthotopic GBM. This developed USIO NP nanoplatform may improve the precision imaging of solid tumors and therapeutic efficacy in the central nervous system. We report a zwitterionic USIO-based platform for tumor T1WI not only in a subcutaneous tumor, but also in an orthotopic GBM with MRgFUS-mediated BBB opening. The formed USIO NPs-1,3-PS may improve the precision imaging and therapeutic efficacy of GBM.