Superparamagnetic iron-oxide drug-loading microbubbles for concurrent magnetic resonance imaging monitoring and focused-ultrasound enhanced brain-tumor drug delivery

Focused ultrasound (FUS) with microbubbles (MBs) has been confirmed to achieve the blood-brain barrier disruption (BBBD). Magnetic resonance imaging (MRI) can monitor the contrast agent leakage such as superparamagnetic iron oxide (SPIO) after BBBD, which relies on indirect drug-contrast agent relationship and fails to perform direct drug quantification/distribution monitoring. This study proposed a novel doxorubicin-loaded and SPIO-conjugated MB (DOX-SPIO-MB) that can open BBB and concurrently perform drug delivery. Moreover, we also illustrate the feasibility of using external magnetic targeting (MT) to enhance the drug delivery in rat GBM model. Rats implanted with C6 glioma cells were used. At 11 days postimplantation, FUS (frequency = 0.5 MHz, energy = 4 W, duty cycle = 5%, sonication = 6 min) was performed following DOX-SPIO-MB injection. A 0.5 T magnet was attached to the rat's scalp for acting MT. The BBBD were confirmed by Evans blue stained imaging. Results showed that DOX-SPIO-MB indeed have the superparamagnetic property and good acoustic stability. Combing with FUS sonication, DOX-SPIO-MBs can concurrently perform DOX delivery and BBBD. This study confirmed that the DOX-SPIO-MB with FUS exposure can concurrently serve as an excellent theranostic tools to increase blood-brain tumor permeability and enhance brain tumor drug delivery.