Construction of Pepstatin A-Conjugated ultrasmall SPIONs for targeted positive MR imaging of epilepsy-overexpressed P-glycoprotein

Abstract

Surgical resection of the epileptogenic region is typically regarded to be practical and efficient for complete elimination of intractable seizures, which cannot be simply controlled by anti-epileptic drugs alone. To achieve a precision removal of the epileptogenic region and even a surgical cure, molecular imaging of epilepsy markers is highly essential for non-invasive accurate detection of the epileptogenic region. In this work, a peptide-targeted nanoprobe, based on ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs), PA-USPIONs, was elaborately constructed to enable highly selective delivery and sensitive T1-weighted positive magnetic resonance (MR) imaging of the epileptogenic region. Especially, Pepstatin A (PA), a small peptide which can specifically target to P-glycoprotein (P-gp) overexpressed at the epileptogenic region in a kainic acid (KA)-induced mice model of seizures, was conjugated onto the surface of PEGylated USPIONs. It has been demonstrated that the as-constructed PA-USPIONs nanoprobes have favorable T1 contrast enhancement and high r1 relaxivity compared with the clinically used T1-MR contrast agent (Gd-DTPA) by systematic in vitro and vivo assessments. Importantly, the toxicity evaluation, especially to brains, was assessed by the histological as well as hematological examinations, demonstrating that the fabricated PA-USPIONs nanoprobes are featured with excellent biocompatibility, guaranteeing the further potential clinical application. This first report on the development of USPIONs as T1-weighted MR contrast agents for active targeting of the epileptogenic region holds the high potential for precise resection of the according lesion in order to achieve therapeutic, often curative purposes.