Development of a Novel Dual-Order Protein-Based Nanodelivery Carrier That Rapidly Targets Low-Grade Gliomas with Microscopic Metastasis in Vivo

[Image: see text] Clinically diagnosing low-grade gliomas and microscopic metastatic tumors in the spinal cord using magnetic resonance imaging (MRI) is challenging, as the blood–brain barrier (BBB) almost completely excludes the MRI contrast agent gadopentetate dimeglumine, GdDTPA (Magnevist), from the brain. The development of a more efficient, safe, and broad-spectrum glioma diagnosis and treatment would therefore have a great clinical value. Based on the high expression levels of both transferrin receptor 1 (TfR1) and low-density lipoprotein receptor-related protein 1 (LRP1) in BBB-related cells and glioma cells, we designed a novel protein nanoparticle, ferritin-HREV107-Angiopep-2 (Fn-Rev-Ang). We found that Fn-Rev-Ang rapidly crossed the BBB in mice and had drug-loading properties. Moreover, the brain MRI signal intensity ratio associated with Fn-Rev-Ang-GdDTPA was higher than that associated with Fn-GdDTPA alone. Importantly, gliomas with diameters below 1 mm and microscopic metastatic tumors in the spinal cord were successfully detected in mice by MRI with Fn-Rev-Ang-GdDTPA, which is not possible using the current clinical MRI technology. In addition, Fn-Rev-Ang-loaded doxorubicin had a strong inhibitory effect on mouse brain gliomas and their metastasis, which significantly prolonged the animal survival time. Thus, our newly constructed Fn-Rev-Ang nanodelivery carrier may help expand the use of MRI to the early diagnosis and treatment of microscopic tumors, thereby offering a possible basis for improving the survival rate of patients with gliomas and microscopic spinal metastatic tumors.