SPIO-DOX-microbubble complex with ultrasound for MRI image-guided drug delivery in a rat glioma model

Abstract

The major obstacles that limit the success of delivery chemotherapeutic substances in brain tumors is their ability to reach the lesion at necessary doses while minimizing deposition at healthy locations to reduce nonspecific toxicity. Lately, administration of therapeutic substances after blood-brain barrier disruption (BBBD) by microbubbles (MBs) with focused ultrasound (FUS) has been demonstrated to partially and temporally promote the delivery of therapeutic or imaging substances into the brain. However, it is still hard to estimate the quantitative accumulation and spatial distribution of delivered agents within the treatment region. This study proposed a Doxorubicin (DOX)-superparamagnetic iron oxide (SPIO)-conjugated MBs (DS-MB) for brain tumor drug delivery. The magnetic modifying of DOX benefits not only direct tracking of the drug transportation under magnetic resonance imaging (MRI), but also implementation of magnetic targeting (MT) to improve local accumulation of the delivered drug. Twenty C6 glioma cell implanted rats were utilized in this study. The payload of DOX and SPIO was 380 ± 71.6 µg and 200 ± 19.6 µg by spectrometer and inductively coupled plasma-atomic emission spectroscopy (ICP-AES), respectively. On day 11 following the tumor implantation, FUS (frequency = 1 MHz, energy = 0.3 MPa, sonication = 6 min, duty cycle = 5%) was applied following DS-MB IV injection. Subsequently, a 0.48 T permanent magnet was attached to the rati|s scalp for MT. The location of tumor and DS complexes were assessed by MR T2-weighted (T2W) images and SWI images. The deposition of DS complexes within brain was quantified by ICP-AES and high performance liquid chromatography (HPLC). The deposition of DS complex within treatment region can be largely improved by the procedure of MT (6.9 fold of SPIO, 24.9 fold of DOX). The variance in MRI R2 value was highly correlated with DS complexes accumulation as estimated by ICP-AES (R2 = 0.69) and HPLC (R2 = 0.77), confirming the feasibility of tracing of DOX distribution via MRI. We considered that with FUS, DS-MB can be utilized to produce BBBD and permit delivery of chemotherapeutic agent, suggesting that DS-MB can potentially serve as advanced theranostics multifunction agents.