Superparamagnetic iron oxide nanoparticle-loaded nanodroplets for dual-modal ultrasound/magnetic resonance imaging-guided drug delivery

Abstract

Recently, ultrasound-sensitive nanodroplets (NDs) have been developed as controlled-release drug delivery systems. However, the high pressure and frequency of ultrasound (US) waves were needed to induce acoustic droplet vaporization (ADV) for triggering drug release. In this study, folic acid (FA) targeted NDs with an alginate (Alg) shell containing methotrexate (MTX) as a chemotherapy drug and superparamagnetic iron oxide nanoparticles (SPIONs) as an ADV promotor and a magnetic resonance (MR) imaging contrast agent were successfully synthesized. The physicochemical properties of NDs including the size, morphology, ultrasound echogenicity, magnetic properties, MR relaxivity, and drug release patterns were evaluated. In vitro ultrasound imaging showed that NDs can generate highly echogenic microbubbles (MBs). Additionally, SPIONs/MTX ND with a relaxivity value of 87.59 mM⁻¹ s⁻¹ can act as a T₂-weighted MRI contrast agent. Folate receptor-positive 4T1 cells and folate receptor-negative L929 cells were utilized. The cell experiments and blood cytotoxicity evaluations proved that SPIONs/MTX-FA NDs are highly biocompatible with no hemolytic activity. The cellular uptake of FA-functionalized NDs increased by 3.2-fold compared to that of non-functionalized NDs, and it was further enhanced, more than three times, after US exposure. The MTT assay demonstrated that the cell viability for ultrasound-exposed samples treated with SPIONs/MTX NDs was significantly decreased in comparison to blank NDs which is related to more drug release from NDs. It was concluded that SPIONs/MTX-FA NDs have significant potential as theranostic agents for dual-modal US/MRI-guided and acoustically-activated drug delivery.