Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T₁-Weighted Magnetic Resonance Imaging and Chemotherapy

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The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (<5 nm) are promising T₁-weighted contrast agents for magnetic resonance imaging (MRI) due to their good biocompatibility compared with Gd-chelates. However, the best particle size of ES-MIONs for T₁ imaging is still unknown because the synthesis of ES-MIONs with precise size control to clarify the relationship between the r₁ (or r₂/r₁) and the particle size remains a challenge. In this study, we synthesized ES-MIONs with seven different sizes below 5 nm and found that 3.6 nm is the best particle size for ES-MIONs to be utilized as T₁-weighted MR contrast agent. To enhance tumor targetability of theranostic nanoparticles and reduce the nonspecific uptake of nanoparticles by normal healthy cells, we constructed a drug delivery system based on the 3.6 nm ES-MIONs for T₁-weighted tumor imaging and chemotherapy. The laser scanning confocal microscopy (LSCM) and flow cytometry analysis results demonstrate that our strategy of precise targeting via exposure or hiding of the targeting ligand RGD₂ on demand is feasible. The MR imaging and chemotherapy results on the cancer cells and tumor-bearing mice reinforce that our DOX@ES-MION3@RGD₂@mPEG3 nanoparticles are promising for high-resolution T₁-weighted MR imaging and precise chemotherapy of tumors.